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Xeroderma Pigmentosum
- 2. Contents Introduction Causes Aetiology Signs and Symptoms Diagnosis Treatment Prognosis Prevention Conclusion 2
- 3. Xeroderma Pigmentosum (XP) is a rare genetic disorder that occurs worldwide in all races and ethnic groups. First described by Hebra and Kaposi in 1874 the disorder is characterised by marked photosensitivity and premature onset of all major types of skin cancer. Definition: It is characterised by inability of a cell to repair damage caused by UV leading to genetic instability and skin cancer. 3
- 4. Incidence: Usually found at very young age(1-2yrs). XP affects approximately one in 1,00,000 individuals worldwide. One in 250,000 persons in the United States and Europe (2) Six times more common in Japanese people than in any other groups (3) 4
- 5. NORMAL CONDITION WITHOUT XP Exposure to UV light Thymine dimer DNA damage NER No replication of DNA strand 5
- 6. SKIN The POL H gene (encoded DNA polymerase eta (Pol η)) Protecting cells from UV rays Repairing of DNA damage Xeroderma pigmentosum UV 9/10/2017 Pharmacology Division 6 ABNORMAL
- 7. Causes of XP Autosomal recessive genetic disorder Nucleotide excision repair(NER) enzymes are mutated Reduced or eliminated number of NER enzymes Metastatic malignant melanoma Squamos cell carcinoma 9/10/2017 Pharmacology Division 7
- 9. Autosomal Recessive Genetic Disorder In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease. 9
- 10. Aetiology • The products of seven of XPgenes (XP-A through G) are involved in the repair of ultraviolet-induced photoproducts in DNA by the process of nucleotide excision repair (NER)5. • The XPC and XPE proteins are needed to recognise the photoproducts in DNA. • XPB and XPD are part of a protein complex TFIIH, which opens up the structure of the DNA around the site of the photoproduct. • XPA protein verifies that proteins are in the correct position and then the nucleases XPG and XPF cut the DNA on either side of the damage, so that the damaged section can be removed and replaced with intact DNA. 10
- 12. • Patients defective in the XPC or XPE genes do not, in general, have the extreme sunburn reactions or neurological abnormalities. • Defects in the eighth XP gene do not affect NER . • The DNA polymerases that normally replicate DNA cannot deal with damage in the DNA template and specialised polymerases have to be employed to get past the damage (translesion synthesis). • For UV damage, the cell uses DNA polymerase η, encoded by the gene POLH and this gene is mutated in XP-V patients . • Like XP-C and XP-E patients, XP-V patients rarely have extreme sunburn reactions or neurological problems. 12
- 13. Signs and Symptoms of Xeroderma Pigmentosum • Severe sunburn. • Development of many freckles at an early age. • Rough-surfaced growths (solar keratoses), and skin cancers. • Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot and clouded. • Blistering or freckling on minimum sun exposure. 13
- 14. CONTINUED… • Spider Veins • Limited growth of hair on chest and legs • Scaly skin • Dry skin • Irregular dark spots on the skin • Corneal ulcerations 14
- 15. 9/10/2017 Pharmacology Division 15 Bloodshot blister freckles Scaly skin
- 16. Diagnosis Before birth: Amniocentesis Chorionic villous sampling After birth: Severe sunburn after first exposure to the sunlight Based on clinical findings and family history, skin, eye, and nervous system By measuring the DNA repair factor from skin or blood sample 16
- 17. Treatment of XP Cryotherapy Removal of heat from the body. Fluorouracil Pyrimidine analogue used to treat cancer Reduced exposure to sun’s UV rays 17
- 18. 18 Protection from UV Eye and skin exam Prompt removal of cancerous tissue Neurological exam Psychososial care
- 19. prognosis Many patients die at an early age from skin cancers but if a person is diagnosed early, does not have severe neurological symptoms and takes all the precautionary measures to avoid exposure to UV light, they may survive beyond middle age. Less than 40% of individuals with the disease survive beyond age 20. Some with less severe cases manage to live well up to 40 years. 19
- 20. References 1) Halpern, J.; Hopping, B.; Brostoff, J. (2008)“Photosensitivity, corneal scarring and developmental delay: Xeroderma Pigmentosum in a tropical country”.. Cases journal. 1:254.doi:10.1186/1757-1626-1-254.PMC 2577106. PMID 18937855 2) Robbins JH, Kraemer KH, Lutzner MA, Festoff BW, Coon HG: Xeroderma pigmentosum: an inherited disease with sun-sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Annals Internal Med 1974, 80:221- 248. 3) Lehmann AR, McGibbon D, Stefanini M (2011). Xeroderma pigmentosum. 2011 ;Orphanet J Rare Dis. 6: 70. Nov 1;6:70. doi: 10.1186/1750-1172-6- 70. 4) Stefanini M, Kraemer KHK: Xeroderma pigmentosum. In Neurocutaneous Diseases Edited by: Ruggieri M, Pascual-Castroviejo I, Di Rocco C 2008, Chapter 51:771-792. 20
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