Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by sensitivity to sunlight and predisposition to cutaneous malignancies. There are various types, including the Variant type, which does not manifest with acute sunburn reactions. This results to the development of multiple malignancies that are often discovered at late stages, making management more challenging. This is a case of a 54-year-old Filipino female presenting with multiple basal cell carcinomas (BCCs) on several areas of the face and advanced cutaneous squamous cell carcinoma (cSCC) on the right zygomatic area, treated with imiquimod 5% cream and external beam radiation therapy, respectively. There was an excellent response of the BCCs to imiquimod 5% cream and good tumoral response of the SCC to radiation therapy, with tolerable side effects, highlighting the use of these palliative treatment modalities for XP patients with multiple, unresectable, or difficult-to-treat cutaneous malignancies.

Human ; Female ; Middle Aged: 45-64 Yrs Old ; Xeroderma Pigmentosum ; Carcinoma, Basal Cell ; Carcinoma, Squamous Cell ; Imiquimod ; Radiation Therapy ; Radiotherapy

PURPOSE: To discuss the clinical course and diagnosis of corneal dysplasia in a xeroderma pigmentosum patient based on a genetic evaluation. CASE SUMMARY: A 42-year-old female visited our clinic for decreased left visual acuity and corneal opacity. She had undergone several surgeries previously due to the presence of basosquamous carcinoma in the left lower eyelid, neurofibroma, and malignant melanoma of the facial skin. The patient showed repeated corneal surface problems, with a suspicious dendritic lesion; however, antiviral therapy was ineffective, and herpes simplex virus polymerase chain reaction results were negative. Despite regular follow-ups, the patient showed neovascularization around the corneal limbus and an irregular corneal surface. We performed corneal debridement with autologous serum eye drops for treatment. The patient's visual acuity and corneal surface improved after the procedure. The impression cytology result was corneal dysplasia. In whole exome sequencing, two pathogenic variants and one likely pathogenic variant of the POLH gene were detected. CONCLUSIONS: This is the first genetically identified xeroderma pigmentosum case with ophthalmological lesions of the eyelid and cornea in Korea. Debridement of the irregular corneal surface and autologous serum eye drop administration in xeroderma pigmentosum could be helpful for improving visual acuity.
Adult ; Carcinoma, Basosquamous ; Cornea ; Corneal Opacity ; Debridement ; Diagnosis ; Exome ; Eyelids ; Female ; Follow-Up Studies ; Humans ; Ichthyosis ; Korea ; Limbus Corneae ; Melanoma ; Neurofibroma ; Ophthalmic Solutions ; Polymerase Chain Reaction ; Simplexvirus ; Skin ; Visual Acuity ; Xeroderma Pigmentosum

BACKGROUND: Non-melanoma skin cancers (NMSC) consists of  basal-cell carcinomas (BCC) and squamous-cell carcinomas (SCC).Certain populations are predisposed to develop  NMSC,  including  patients  with  previous  history  of  NMSC.Systemic  retinoids  have  shown  promising  results  in chemoprevention of recurrence of NMSC in other high-risk populations (xeroderma pigmentosum and renal-transplant patients).We  assessed  the  efficacy  and  safety  of  low-dose  systemic  retinoids  compared  with  placebo,  as  a  chemopreventive agent for NMSC in patients with previous NMSC.
METHODOLOGY: Electronic  databases  were  systematically searched for this study. Participants in the studies selected must have had a biopsy-proven NMSC, over 18 years of age, with  no  exclusion  of  other  demographic  characteristics. All  types  of  systemic  retinoids  were  included  with  no restriction on dosage. Two authors independently performed standardized  eligibility  assessment  and  data-extraction.Differences in opinion were resolved by consensus with the third author. Statistical analysis was done using the Review Manager 5 software.
RESULTS: Eleven full-text studies were assessed for eligibility out of 178 studies found. Five studies were excluded because of the different population, while the two articles used topical retinoids. Four articles were included. The interventions were 10.0 mg isotretinoin, 25,000IU retinol and 25.0 mg acitretin,compared with placebo. Meta-analysis produced RR of 0.94 (95% CI, 0.89-1.00), with moderate heterogeneity (34%) due to the difference in interventions used. There are significantly more  adverse  events  in  the  retinoids  group,  especially  in the  incidence  of  mucocutaneous  adverse  events,  and deranged lipid profile and liver enzymes.
CONCLUSION: There is insufficient evidence to support the use of low-dose systemic retinoids as chemoprevention for patients with previous NMSC. Furthermore, adverse events may limit their use. Topical preparations with less side-effects may be investigated.

Human ; Male ; Female ; Aged ; Middle Aged ; Adult ; Vitamin A ; Acitretin ; Xeroderma Pigmentosum ; Isotretinoin ; Incidence ; Kidney Transplantation ; Carcinoma, Basal Cell ; Carcinoma, Squamous Cell ; Chemoprevention ; Biopsy ; Lipids ; Liver

PURPOSE: Xeroderma pigmentosum (XP) is rare autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. We reported the first molecularly confirmed Korean patient of XP by targeted exome sequencing. The prevalence of XP included all subtype and carrier frequency of XP-A the using public data were estimated for the first time in South Korea. MATERIALS AND METHODS: We described a 4-year-old Korean girl with clinical diagnosis of XP. We performed targeted exome sequencing in the patient for genetic confirmation considering disease genetic heterogeneity and for differential diagnosis. We verified a carrier frequency of c.390-1G>C in XPA gene known as mutational hot spot using Korean Reference Genome Data Base. We estimated the period prevalence of all subtypes of XP based on claims data of the Health Insurance Review and Assessment Service in South Korea. RESULTS: We identified homozygous splicing mutation of XPA (c.390-1G>C) in the patient. The carrier frequency of risk for XPA (c.390-1G>C) was relatively high 1.608 e-03 (allele count 2/1244). The prevalence of XP in South Korea was 0.3 per million people. CONCLUSION: We expect that c.390-1G>C is hot spot for the mutation of XPA and possible founder variant in South Korea. However, the prevalence in South Korea was extremely low compared with Western countries and Japan.
Child, Preschool ; Diagnosis ; Diagnosis, Differential ; DNA Repair ; Exome ; Female ; Genetic Heterogeneity ; Genome ; Heredodegenerative Disorders, Nervous System ; High-Throughput Nucleotide Sequencing ; Humans ; Ichthyosis* ; Insurance, Health ; Japan ; Korea* ; Prevalence ; Ultraviolet Rays ; Xeroderma Pigmentosum*

BACKGROUND: Approximately 90%~99% of ultraviolet A (UVA) ray reaches the Earth's surface. The deeply penetrating UVA rays induce the formation of reactive oxygen species (ROS), which results in oxidative stress such as photoproducts, senescence, and cell death. Thus, UVA is considered a primary factor that promotes skin aging. OBJECTIVE: Researchers investigated whether pretreatment with ferulic acid protects human dermal fibroblasts (HDFs) against UVA-induced cell damages. METHODS: HDF proliferation was analyzed using the water-soluble tetrazolium salt assay. Cell cycle distribution and intracellular ROS levels were assessed by flow cytometric analysis. Senescence was evaluated using a senescence-associated β-galactosidase assay, while Gadd45α promoter activity was analyzed through a luciferase assay. The expression levels of superoxide dismutase 1 (SOD1), catalase (CAT), xeroderma pigmentosum complementation group A and C, matrix metalloproteinase 1 and 3, as well as p21 and p16 were measured using quantitative real-time polymerase chain reaction. RESULTS: Inhibition of proliferation and cell cycle arrest were detected in cells that were irradiated with UVA only. Pretreatment with ferulic acid significantly increased the proliferation and cell cycle progression in HDFs. Moreover, ferulic acid pretreatment produced antioxidant effects such as reduced DCF intensity, and affected SOD1 and CAT mRNA expression. These effects were also demonstrated in the analysis of cell senescence, promoter activity, expression of senescent markers, and DNA repair. CONCLUSION: These results demonstrate that ferulic acid exerts protective effects on UVA-induced cell damages via anti-oxidant and stress-inducible cellular mechanisms in HDFs.
Aging ; Animals ; Antioxidants ; Catalase ; Cats ; Cell Aging ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Death ; Complement System Proteins ; DNA Repair ; Fibroblasts* ; Humans* ; Luciferases ; Matrix Metalloproteinase 1 ; Oxidative Stress ; Reactive Oxygen Species ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Skin Aging ; Superoxide Dismutase ; Ultraviolet Rays ; Xeroderma Pigmentosum

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by xerosis, ultraviolet light sensitivity, and cutaneous dyspigmentation. Due to defects in their DNA repair mechanism, genetic mutations and carcinogenesis inevitably occurs in almost all patients. In these patients, reconstruction of cutaneous malignancies in the head and neck area is associated with some challenges such as likelihood of recurrence and an aggressive clinical course. The aim of this study is to discuss the therapeutic options and challenges commonly seen during the course of treatment. METHODS: Between 2005 and 2015, 11 XP patients with head and neck cutaneous malignancies were included in this study. Demographic data and treatment options of the patients were evaluated. RESULTS: The mean age of the patients was 32 years (range, 10-43) (4 males, 7 females). The most common tumor type and location were squamous cell carcinoma (6 patients) and the orbital region (4 patients), respectively. Free tissue transfer was the most commonly performed surgical intervention (4 patients). The average number of surgical procedures was 5.5 (range, 1-25). Six patients were siblings with each other, 5 patients had local recurrences, and one patient was lost to follow-up. CONCLUSIONS: Although genetic components of the disease have been elucidated, there is no definitive treatment algorithm. Early surgical intervention and close follow-up are the gold standard modalities due to the tendency toward rapid tumor growth and possible recurrence. Treatment must be individualized for each patient. In addition, the psychological aspect of the disease is an important issue for both patients and families.
Carcinogenesis ; Carcinoma, Squamous Cell ; DNA Repair ; Follow-Up Studies ; Free Tissue Flaps ; Head and Neck Neoplasms ; Head* ; Humans ; Ichthyosis* ; Lost to Follow-Up ; Male ; Neck* ; Orbit ; Recurrence ; Siblings ; Skin Neoplasms ; Ultraviolet Rays ; Xeroderma Pigmentosum*

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by xerosis, ultraviolet light sensitivity, and cutaneous dyspigmentation. Due to defects in their DNA repair mechanism, genetic mutations and carcinogenesis inevitably occurs in almost all patients. In these patients, reconstruction of cutaneous malignancies in the head and neck area is associated with some challenges such as likelihood of recurrence and an aggressive clinical course. The aim of this study is to discuss the therapeutic options and challenges commonly seen during the course of treatment. METHODS: Between 2005 and 2015, 11 XP patients with head and neck cutaneous malignancies were included in this study. Demographic data and treatment options of the patients were evaluated. RESULTS: The mean age of the patients was 32 years (range, 10-43) (4 males, 7 females). The most common tumor type and location were squamous cell carcinoma (6 patients) and the orbital region (4 patients), respectively. Free tissue transfer was the most commonly performed surgical intervention (4 patients). The average number of surgical procedures was 5.5 (range, 1-25). Six patients were siblings with each other, 5 patients had local recurrences, and one patient was lost to follow-up. CONCLUSIONS: Although genetic components of the disease have been elucidated, there is no definitive treatment algorithm. Early surgical intervention and close follow-up are the gold standard modalities due to the tendency toward rapid tumor growth and possible recurrence. Treatment must be individualized for each patient. In addition, the psychological aspect of the disease is an important issue for both patients and families.
Carcinogenesis ; Carcinoma, Squamous Cell ; DNA Repair ; Follow-Up Studies ; Free Tissue Flaps ; Head and Neck Neoplasms ; Head* ; Humans ; Ichthyosis* ; Lost to Follow-Up ; Male ; Neck* ; Orbit ; Recurrence ; Siblings ; Skin Neoplasms ; Ultraviolet Rays ; Xeroderma Pigmentosum*

Xeroderma pigmentosum (XP) is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patient-specific induced pluripotent stem cells (iPSCs) harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells (NSCs) or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clarify the molecular mechanisms of neurological abnormalities in the XP patients.
DNA Damage ; DNA Repair ; DNA-Binding Proteins ; genetics ; metabolism ; Female ; Humans ; Induced Pluripotent Stem Cells ; metabolism ; pathology ; Male ; Models, Biological ; Mutation ; Neural Stem Cells ; metabolism ; pathology ; Xeroderma Pigmentosum ; genetics ; metabolism ; pathology

Ultraviolet light(UV)-sensitive disorders refer to a group of diseases due to damages to the nucleotide excision repair mechanism which cannot effectively repair DNA damage caused by ultraviolet radiation. The inheritance pattern of such diseases, mainly including xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, is autosomal recessive and known to involve 13 genes. As proteins encoded by such genes are involved in DNA repair and transcription pathways. There is overlap between the symptoms of such diseases, and their genotype - phenotype correlations are quite complex. To facilitate genetic and prenatal diagnosis for such diseases, a summary of the research progress is provided, which mainly focused on mutation research and genotype - phenotype correlation studies. We also propose a strategy for their genetic diagnosis based on recent findings of our group.
Biomedical Research ; methods ; trends ; Cockayne Syndrome ; genetics ; DNA Damage ; DNA Repair ; genetics ; Genetic Predisposition to Disease ; genetics ; Humans ; Skin ; metabolism ; pathology ; radiation effects ; Trichothiodystrophy Syndromes ; genetics ; Ultraviolet Rays ; Xeroderma Pigmentosum ; genetics

OBJECTIVETo explore the relationship of polymorphisms in the xeroderma pigmentosum group D (XPD) gene and the glutathione-S transferees M1 (GSTM1) gene with susceptibility to primary hepatic carcinoma (PHC) in Tibetans from the Qinghai region.

METHODSThis case-control study compared equal groups (n=102 each) of patients with PHC and healthy individuals recruited from Qinghai, Tibet.PCR and denaturing high-performance liquid chromatography (DHPLC) was used to detect each participant's genotypes for the XPD and GSTM1 genes.Non-conditional logistic regression modeling was used in multivariate analysis to evaluate the predictive value for PHC, to compare the risk of different genotypes for PHC, and to assess the risk of gene polymorphisms and environmental factors for PHC.

RESULTSSix factors, including smoking, carnivorous diet, alcohol consumption, hepatitis B virus (HBV) infection, immediate family members with HBV infection and immediate family members with history of PHC, were included in the logistic regression model (alpha =0.05).The XPD751C mutation genotype distribution frequencies were significantly higher in the cases than in the controls (21.6% vs. 10.8%, P=0.036). The risk of PHC increased 2.275 times (95% CI, 1.04-4.98). The frequencies of the GSTM1 genotype were remarkably higher in the cases than in the controls (60.4% vs. 39.6%, P=0.017), suggesting this as an exposure factor. Individuals with the GSTM1 genotype had 1.963 times higher risk of PHC than individuals without the GSTM1 genotype (95% CI, 1.124-3.428). With both the XPD751C mutation and the GSTM1 genotype as exposure factors, the risk incidence increased to 3.030 times (95% CI, 1.165-7.881), indicating that the combined genotypes have a synergistic effect.Application of unconditioned logistic stepwise regression analysis of the genotypes and environmental risk factors showed an interaction between the XPD751C mutation and HBV infection, alcohol consumption and immediate family members with history of PHC. In addition, an interaction between the GSTM1 genotype and HBV infection was found.

CONCLUSIONAlcohol consumption, HBV infection and the presence of immediate family members with HBV infection are the main environmental risk factors of PHC in Qinghai Tibetans.Qinghai Tibetans who carry the XPD751C gene mutation and the GSTM 1 genotype are at increased risk of PHC, compared to individuals carrying only one or the other.The XPD751C mutation may increase risk of PHC when combined with the environmental factors.

Alcohol Drinking ; Carcinoma, Hepatocellular ; genetics ; Case-Control Studies ; Genetic Predisposition to Disease ; Genotype ; Glutathione ; Glutathione Transferase ; genetics ; Humans ; Incidence ; Liver Neoplasms ; genetics ; Logistic Models ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Risk Factors ; Smoking ; Tibet ; Xeroderma Pigmentosum Group D Protein ; genetics