ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Jennifer O. Black declares she has no conflict(s) of interest to disclose. Xeroderma Pigmentosum: An Insight into DNA Repair Processes Jennifer O. Black, MD Assistant Professor Division of Pediatric Pathology and Laboratory Medicine Children’s Hospital Colorado University of Colorado Anschutz Medical Campus Aurora, Colorado Introduction: Xeroderma Pigmentosum Xeroderma Pigmentosum (XP): • Initially described 1874 • Rare autosomal recessive disorder • Prevalence: 1-45/million, variable ethnic frequency • UV radiation sensitivity disorder characterized by: • Severe skin burning following minimal sun exposure • Early freckling (before 2 years of age) • Skin cancer at an early age Kraemer KH, DiGiovann JJ. Photochemistry and Photobiology 91:452-459, 2015 Introduction: Xeroderma Pigmentosum XP Clinical Spectrum: • Skin Changes: o Early freckling and subsequent checkered pigmentation o Thin, dry, contracted skin o Telangiectasias o Skin cancers: o Squamous cell carcinoma o Basal cell carcinoma o Melanoma Courtesy Dr. Bahig M. Shehata, Children’s Healthcare of Atlanta Introduction: Xeroderma Pigmentosum Squamous Cell Carcinoma Robbins and Cotran Pathologic Basis of Disease. Lazar, Alexander J.F.; Murphy, George F. Pages 1141-1178 Introduction: Xeroderma Pigmentosum Basal Cell Carcinoma Robbins and Cotran Pathologic Basis of Disease. Lazar, Alexander J.F.; Murphy, George F. Pages 1141-1178. Introduction: Xeroderma Pigmentosum Melanoma Pigment Cell & Melanoma Research Volume 27, Issue 3, pages 454-464 Introduction: Xeroderma Pigmentosum Ocular Manifestations of Disease OCULAR ABNORMALITIES Structural Eyelid Abnormalities: Entropion Ectropion* Lagophthalmos Blepharitis Keratinization Loss of Eyelashes Neoplasms of the Ocular Surface Squamous Cell Carcinoma and Eyelids: Basal Cell Carcinoma Ocular Surface Disease and Conjunctivitis Inflammation: Melanosis* Xerosis Corneal Abnormalities: Neovascularization Pterygium Scarring Brooks et al. Ophthalmology. 2013 Jul; 120(7): 1324–1336. Opacification Other: Photophobia * More frequent in patients with non-burning phenotype Introduction: Xeroderma Pigmentosum Neurologic Manifestations of Disease • 24% XP Patients • Progressive Neurologic Degeneration: o Cognitive deterioration o Impaired hearing o Abnormal speech o Areflexia o Progressive ataxia o Spasticity o Peripheral neuropathy • Brain tumors: Glial tumors • Pontine glioma, glioblastoma, spinal cord astrocytoma Anttinen, et al. Brain. 2008 Aug;131:1979-89 Xeroderma Pigmentosum: Disease Pathophysiology Xeroderma Pigmentosum: Pathophysiology BER: Base excision repair NER: Nucleotide excision repair DSBR: Double stranded break repair MMR: Mismatch repair Xeroderma Pigmentosum: Pathophysiology Historical Studies: • XP cells demonstrate UV radiation hypersensitivity (Gartler 1964) • Deficient excision repair observed in cultured XP skin fibroblasts (Cleaver 1968) • Stable DNA photoproducts identified following UV radiation (Setlow 1962), not removed by XP cells ( Setlow 1969, Cleaver and Trosko 1970) • Defective excision repair in XP cells demonstrated in vitro (Reed 1969) and in vivo (Epstein 1970) • Cell fusion studies demonstrated heterogeneity of XP molecular defects ( De Weerd-Kastelein 1972) Fusion of fibroblasts from different XP patients form heterokaryons that demonstrate corrected DNA repair mechanisms. Characterization of different complementation groups, A-G (Kramer 1975, Arase 1979, Keijer 1979) Xeroderma Pigmentosum: Complementation Groups Complementation Gene Normal Protein Function Disease Characteristics Group Protein that assists with DNA unwinding Photosensitivity, poikiloderma, lentigines, skin cancer, XP-A XPA neurodegeneration Helicase involved with DNA unwinding Photosensitivity, poikiloderma, lentigines, skin cancer, XP-B XPB/ERCC3 neurodegeneration XP-C XPC Protein recognizing global genome defects Photosensitivity, poikiloderma, lentigines, skin cancer Helicase involved with DNA unwinding Photosensitivity, poikiloderma, lentigines, skin cancer, XP-D XPD/ERCC2 neurodegeneration, brain tumors Protein recognizing global genome defects Photosensitivity, poikiloderma, lentigines, skin cancer, XP-E XPE/DDB2 neurodegeneration Forms an endonuclease together with ERCC1 that Photosensitivity, poikiloderma, lentigines, skin cancer, XP-F XPF/ERCC4 incises damaged DNA for repair neurodegeneration, brain tumors Endonuclease that incise damaged DNA Photosensitivity, poikiloderma, lentigines, skin cancer, XP-G XPG/ERCC5 neurodegeneration DNA-polymerase eta (pol-eta) which performs Milder photosensitivity and poikiloderma XP-Variant XPV/POLH trans-lesion DNA synthesis past ultraviolet (UV) Xeroderma Pigmentosum: Pathophysiology Nucleotide Excision Repair Pathway DiGiovanna. J Invest Dermatol. 2012 Mar; 132(3): 785–796. Xeroderma Pigmentosum: Pathophysiology DiGiovanna. J Invest Dermatol. 2012 Mar; 132(3): 785–796. Xeroderma Pigmentosum: Overlap Syndromes Gene Normal Protein Function Clinical Syndrome Disease Characteristics XPB/ERCC3 Helicase involved with DNA unwinding XP-B, CS, TTD Photosensitivity, poikiloderma, lentigines, skin cancer, neurodegeneration XPD/ERCC2 Helicase involved with DNA unwinding XP-D, TTD, COFS, CS Photosensitivity, poikiloderma, lentigines, skin cancer, neurodegeneration, brain tumors XPF/ERCC4 Forms an endonuclease together with ERCC1 that incises XP-F, XFE progeroid Photosensitivity, poikiloderma, lentigines, skin cancer, damaged DNA for repair syndrome, Fanconi anemia neurodegeneration, brain tumors ERCC1 Forms an endonuclease together with XPF/ERCC4 that XP, CS, COFS Photosensitivity, poikiloderma, lentigines, skin cancer, incises damaged DNA for repair neurodegeneration CSA/ERCC8 DNA excision repair protein involved in the TCR pathways CS Growth failure, impaired neurodevelopment, photosensitivity, eye disorders, premature aging CSB/ERCC6 DNA excision repair protein involved in the TCR pathway CS, COFS Growth failure, severely impaired neurodevelopment, photosensitivity, eye disorders, premature aging GTF2H5 TTDA protein stabilizes the DNA/protein complex during TTD Brittle hair, intellectual impairment, photosensitivity unwinding of DNA strand for repair TTDN1/C7orf11 Regulates mitosis and cytokinesis TTD Non-photosensitive TTD CS = Cockayne Syndrome; TTD = Trichothiodystrophy; COFS = Cerebro-Oculo-Facio-Skeletal Syndrome Xeroderma Pigmentosum: Overlap Syndromes Trichothiodystrophy (TTD): • Features: • Photosensitivity (with XPD, XPB, TTDA but not TTDN1 mutations) • Abnormal hair • Decreased fertility • Short stature • Ichthyosis • Normal skin pigmentation • Intellectual impairment without neurodegeneration • Neuroimaging: demyelination, cortical heterotopia, partial agenesis of the corpus callosum, perimedullary fibrosis of the spinal cord, intracranial calcifications DiGiovanna. J Invest Dermatol. 2012 Mar; 132(3): 785–796. Xeroderma Pigmentosum: Overlap Syndromes Cockayne Syndrome (CS) • Results from mutations in the CSA and CSB genes of the NER pathway • Features: • Short stature • Microcephaly • Pigmentary retinal degeneration • Kyphoscoliosis • Gait defects • Sensorineural deafness • Distinct facial features (deep-set eyes, prominent ears, “wizened appearance”) • Neurodegenerative Features; Demyelination (increased DTRs), • Neuroimaging: cerebral atrophy, ventricular dilation, calcification of basal ganglia and cortex, neuronal loss • Multiple Types: • Type I: moderate phenotype, normal prenatal development, abnormalities evident in first 2 years of life • Type II: Severe phenotype, growth failure at birth, death first decade • Type III: Mild symptoms, late onset; photosensitivity with normal pigmentation, no increased risk of cutaneous malignancy Laugel. Mechanisms of Ageing and Development 134 (2013) 161–170 Xeroderma Pigmentosum: Overlap Syndromes Cerebro-Oculo-Facio-Skeletal Syndrome (COFS): • Autosomal recessive disorder\ • Mutations involve CSB, XPD, XPG, and ERCC1 genes • Features: • Microcephaly • Congenital cataracts • Arthrogryposis • Severe developmental delay • Severe postnatal growth failure • Photosensitivity • Facial dysmorphism (prominent nasal root and overhanging upper lip) Laugel. J Med Genet 2008;45:564-571 Xeroderma Pigmentosum Disease Course Xeroderma Pigmentosum: Long Term Survival Leading Cause of Death: Skin cancer and metastasis Lifetime Cancer Risk: • 33% XP patients do not develop cancer • Squamous Cell and Basal Cell Carcinoma: o Median age at first cancer = 9 years (range 1-32 years) o XP patients have 58-year reduction in age at first non-melanocytic skin cancer o 10,000 fold lifetime risk compared to general population • Melanoma: o Median age at first cancer = 22 years (range 2-47 years) o XP patients have a 33-year reduction in age at first non-melanocytic skin cancer o 2,000 fold lifetime risk compared to general population o PTEN mutations more common (53%) compared to general population (16%) • Other Cancer: • Increased risk of lung cancer in XP smokers • Brain tumors Neurodegeneration: • More common in XPA, XPB, XPD, XPF, XPG (Rare in XPC, XPE) • Associated with decreased median age of death compared to XP patients without neurodegeneration (29 vs 37 years) • Second leading cause of death in XP patients