Whole Exome Sequencing of a Patient with a Milder Phenotype of Xeroderma Pigmentosum Group C.

A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent's SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population.

Background Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. Objectives The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. Methods To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. Results Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. Limitations The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. Conclusion Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.

Serum 25-Hydroxy Vitamin D Levels and Association of Vitamin D Receptor Gene Polymorphisms in Vitiligo.

BACKGROUND: The role of vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms has been established in many autoimmune diseases, including vitiligo, but the result is still controversial. OBJECTIVES: The aim of this study was to investigate the serum vitamin D levels in vitiligo patients and to compare the association of VDR gene polymorphisms in vitiligo patients and healthy controls. METHODS: We collected the data of age, sex, serum 25-hydroxy vitamin D (25[OH]D) level, thyroid autoantibodies, disease duration, types of vitiligo, family history and the affected body surface area of vitiligo from 172 patients. And we analyzed the VDR gene polymorphisms in 130 vitiligo and 453 age-sex-matched control subjects. RESULTS: The mean serum level of 25(OH)D in 172 vitiligo patients was 18.75 ± 0.60 ng/mL, which had no significant difference with a mean serum value of 25(OH)D in the Korean population. However, there were significant differences according to the duration of the disease and family history. Also, there were no significant differences in the genotypic and allelic distributions of 37 examined SNPs of VDR gene between vitiligo patients and healthy controls. CONCLUSION: Serum level of 25(OH)D in vitiligo patients was not significantly different from the mean serum value of the Korean population. Also, there were no significant differences in the genotypic distributions of VDR gene between vitiligo patients and healthy controls.

Association of GZMB polymorphisms and susceptibility to non-segmental vitiligo in a Korean population.

Non-segmental vitiligo (NSV) is the most common type of vitiligo, which is characterized by chronic and progressive loss of melanocytes. Genetic factors have been shown to play a key role in NSV in association and family studies. Granzyme B is a serine protease found in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells that play an important role in inducing apoptotic changes of target cells. Several recent studies have provided evidence that polymorphism in the GZMB gene might be associated with autoimmune disease. A total of 249 NSV patients and 455 healthy controls were recruited to determine whether single nucleotide polymorphisms (SNPs) [rs2236337 (3' untranslated region, UTR), rs2236338 (Tyr247His), rs11539752 (Pro94Ala), rs10909625 (Lys80Lys), rs8192917 (Arg55Gln), and rs7144366 (5' near gene)] in GZMB gene contribute to the risk of developing NSV. Genotyping was performed using a single 192.24 Dynamic Array IFC. Data were analyzed using EP1 SNP Genotyping Analysis software to obtain genotype calls. Among the six SNPs tested, five SNPs (rs2236337, rs2236338, rs11539752, rs10909625, and rs8192917) showed significant association with NSV susceptibility. Among them, rs2236338, rs11539752, rs10909625, and rs8192917 remained a statistically significant association following multiple correction test. The five SNPs were located within a block of linkage disequilibrium. Haplotypes T-A-G-T-T and C-G-C-C-C consisting of rs2236337, rs2236338, rs11539752, rs10909625, and rs8192917 demonstrated significant association with NSV. Our results suggest that GZMB polymorphisms are associated with the development of NSV.

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo.

BACKGROUND: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. OBJECTIVE: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. METHODS: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. RESULTS: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. LIMITATIONS: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races. CONCLUSION: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.

Development of evidence-based consensus on critical issues in the management of patients with vitiligo: A modified Delphi study.

BACKGROUND/PURPOSE: Vitiligo remains a major challenge in dermatology. However, much of the treatment remains unclear, because little evidence is available. We sought to answer some critical questions pertaining to management of vitiligo patients. METHODS: A modified Delphi process among 31 vitiligo experts was conducted. A total of 12 clinical vitiligo treatment questions without clear answers were collected via a vote. To address each question, two members performed systematic literature reviews and prepared draft statements along with the levels of evidence and strength of recommendation. After reviewing the draft, all expressed their extent of agreement from 1 (strong disagreement) to 9 (strong agreement) for each item. The drafts were revised to reflect suggested comments. Discussion continued until all members agreed with the ultimate decision. RESULTS: The consensus process was completed after five rounds. We identified the best answers to 12 key questions, including issues on long-term phototherapy, systemic and topical corticosteroids, topical calcineurin inhibitors, immunosuppressants, excimer laser treatment, and surgical interventions. CONCLUSION: This consensus would complement current guidelines and aid both physician and patient decision-making in the treatment of vitiligo.

Eccrine Poroma Arising within Nevus Sebaceous.

Secondary neoplasms in nevus sebaceous can develop during adolescence and adulthood. Trichoblastoma and syringocystadenoma papilliferum are the most common benign neoplasms, but poroma is rarely reported. A 28-year-old female presented with an asymptomatic mass on the scalp. She has had a hairless lesion on the scalp since birth. A soft mass developed on that lesion four years prior. Physical examination revealed a localized 1 cm×2.5 cm-sized brownish, verrucous-surfaced plaque with a 1 cm×1 cm-sized pedunculated erythematous tumor on the scalp. We performed skin biopsy on both the plaque and tumor lesions. The histopathological findings demonstrated the plaque lesion consistent with nevus sebaceous and the tumor lesion consistent with eccrine poroma. Surgical mass excision was performed. The patient was eventually diagnosed with eccrine poroma arising within nevus sebaceous. To the best of our knowledge, there are only six reported cases on poroma arising within nevus sebaceous. Although rarely documented in the literature, it should be considered as a secondary neoplasm within nevus sebaceous.

Atypical maculopapular cutaneous mastocytosis showing a nevus spilus-like lesion.

A 13-year-old Korean girl presented with a 7-year history of a pruritic, light-brown patch containing multiple 0.2- to 0.5-cm brownish-to-reddish maculopapules on the left anterior chest. When her skin was rubbed, the lesion became itchy and red. Histopathologic evaluation demonstrated marked dense dermal infiltration of mast cells. We report a rare case of atypical maculopapular cutaneous mastocytosis with clinical features similar to those of nevus spilus.

Atopic labial pigmentation: a new diagnostic feature in Asian patients with atopic dermatitis.

BACKGROUND: Pigmented lesions on the lips can be caused by physiological or pathological factors, along with exogenous or endogenous factors. Many patients with atopic dermatitis (AD) and labial pigmentation are seen in clinical practice. The aim of our study was to further explore the association of labial pigmentation and AD. METHODS: We performed a retrospective chart review of patients who visited the Department of Dermatology at Kyung Hee Medical Center, Seoul, Korea, from January 1 to December 31, 2016. The study consisted of 178 patients with AD and a control group of 178 age- and sex-matched patients without AD. RESULTS: The patients with AD had both a significantly higher prevalence of labial pigmented lesions and a significantly higher number of labial pigmented lesions than was observed in the control group. Moreover, the pigmented lesions were found mainly in the middle section of the upper lip and showed multifocal distribution. The patients with AD and labial pigmentation were significantly younger at the onset of AD, showed a greater association with allergic disorder, and had a higher immunoglobulin E (IgE) level than patients without labial pigmentation. CONCLUSION: Our findings strongly suggest that labial pigmentation occurs in patients with AD. Although labial pigmentation was not present in all patients with AD, this might be a particularly helpful diagnostic feature of AD in Asian patients.

Heat shock protein 90 inhibitor enhances apoptosis by inhibiting the AKT pathway in thermal-stimulated SK-MEL-2 human melanoma cell line.

BACKGROUND: Heat shock proteins (Hsps) are chaperone proteins, which are upregulated after various stresses. Hsp90 inhibitors have been investigated as adjuvant therapies for the treatment of melanoma. Thermal ablation could be a treatment option for surgically unresectable melanoma or congenital nevomelanocytic nevi, however, there is a limitation such as the possibility of recurrence. OBJECTIVE: We evaluated apoptosis in a melanoma cell line treated with the Hsp90 inhibitor 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in hyperthermic conditions. METHODS: SK-MEL-2 cells were stimulated at 43 °C for 1 h and treated with 0, 0.1 and 1 µM 17-DMAG. We evaluated the cell viability using MTT and apoptosis with HSP 90 inhibitor. We studied the protein expression of AKT, phospho-AKT, ERK, phospho-ERK, MAPK, and phospho-MAPK, caspase 3,7,9, and anti-poly (ADP-ribose) polymerase. RESULTS: 17-DMAG significantly inhibited the proliferation of the SK-MEL-2 cells at 37 °C (0.1 µM: 44.47% and 1 µM: 61.23%) and 43 °C (0.1 µM: 49.21% and 1 µM: 63.60%), suggesting synergism between thermal stimulation and 17-DMAG. 17-DMAG treatment increased the frequency of apoptotic cell populations to 2.17% (0.1 µM) and 3.05% (1 µM) in 37 °C controls, and 4.40% (0.1 µM) and 4.97% (1 µM) in the group stimulated at 43 °C. AKT phosphorylation were activated by thermal stimulation and inhibited by 17-DMAG. CONCLUSION: Hsp90 inhibitor treatment may be clinically applicable to enhance the apoptosis of melanoma cells in hyperthermic condition.

A randomised comparative study of 1064 nm Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser and topical antifungal treatment of onychomycosis.

Conventional treatments for onychomycosis include oral and topical antifungal agents. Although Nd:YAG laser has been reported to be effective, controlled studies combined or compared with conventional treatments are needed. To evaluate the efficacy of 1064 nm Nd:YAG laser for onychomycosis and compare outcomes with those of topical antifungal treatment and combination therapy. Patients were randomly divided into three groups: Laser (L); laser with topical antifungal therapy (L + T); and topical antifungal treatment (T). Laser treatment consisted of three or four sessions at 4 week intervals. Outcomes were assessed clinically and mycologically. In 217 nails of 56 patients, 76% in the L group and 71.8% in the L + T group experienced clinical responses, and 15.2% and 22.5%, respectively, were cured at 24 weeks. The clinical and cure rates of both groups were significantly greater than those of the T group. Six patients of the L group developed new infections, as did one patient in the L + T group and two patients in the T group. 1064 nm Nd:YAG laser shows clinically good responses in onychomycosis. Addition of topical antifungal agent did not appear to improve efficacy, but may have protected against new infection.