Xeroderma pigmentosum – Fakten und Perspektiven

Zusammenfassung

Die Nukleotid-Exzisions-Reparatur (NER) ist für die Beseitigung von ultraviolett (UV) -induzierten DNA-Schäden und damit zur Vermeidung von Hautkrebs essenziell. Menschen mit einem genetischen Defekt in der NER, Xeroderma pigmentosum (XP) -Patienten, sind äußerst sonnenempfindlich. Sie entwickeln bereits in den ersten Lebensjahren Zeichen der vorzeitigen Hautalterung mit einem deutlich erhöhten Risiko zur Entwicklung von UV-induzierten kutanen Karzinomen. DNA-Reparaturdefektsyndrome werden vorrangig in der Klinik diagnostiziert und auf molekularer Ebene bestätigt. Für die seltene, rezessiv vererbte Erkrankung XP steht zum jetzigen Zeitpunkt leider noch keine kausale Therapie zur Verfügung, weshalb eine frühe Diagnosestellung umso bedeutsamer ist. Durch frühzeitige sowie konsequente UV-protektive Maßnahmen und eine regelmäßige Überprüfung der Haut im Zuge der Hautkrebsfrüherkennung werden sowohl die Prognose als auch Krankheitsverlauf maßgeblich verbessert.

Abstract

The Nucleotide Excision Repair (NER) removes ultraviolet (UV)-induced DNA lesions, thereby being essential for prevention of skin cancer. Individuals with a genetic defect in NER, xeroderma pigmentosum (XP) patients, are extremely sun sensitive. This results in first signs of premature skin aging at an early age with a considerably increased risk of developing UV-induced skin cancer. DNA repair defective disorders are diagnosed mainly in the clinic and confirmed on the molecular basis. At this moment, there is no treatment available for the rare, autosomal recessive disorder XP, highlighting the importance of an early diagnosis. Reduction of environmental UV exposure and regular skin cancer screenings can substantially improve prognosis as well as course of disease.

• Literatur

• 1 Lindahl T, Wood RD. Quality control by DNA repair. Science 1999; 286: 1897-1905
• 2 Wood RD, Mitchell M, Sgouros J. et al. Human DNA repair genes. Science 2001; 291: 1284-1289
• 3 Scharer OD. Nucleotide excision repair in eukaryotes. Cold Spring Harbor perspectives in biology 2013; 5: a012609
• 4 Schubert S, Lehmann J, Kalfon L. et al. Clinical utility gene card for: Xeroderma pigmentosum. Eur J Hum Genet 2014; 22 DOI: 10.1038/ejhg.2013.233.
• 5 Emmert S. Xeroderma pigmentosum, Cockayne Syndrome, and Trichothiodystrophy. In: Harper’s Textbook of Pediatric Dermatology. 2011: 135.1-135.24
• 6 Bradford PT, Goldstein AM, Tamura D. et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet 2011; 48: 168-176
• 7 Kraemer KH, Lee MM, Andrews AD. et al. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol 1994; 130: 1018-1021
• 8 Ramkumar HL, Brooks BP, Cao X. et al. Ophthalmic manifestations and histopathology of xeroderma pigmentosum: two clinicopathological cases and a review of the literature. Surv Ophthalmol 2011; 56: 348-361
• 9 Anttinen A, Koulu L, Nikoskelainen E. et al. Neurological symptoms and natural course of xeroderma pigmentosum. Brain 2008; 131: 1979-1989
• 10 Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987; 123: 241-250
• 11 Kleijer WJ, Laugel V, Berneburg M. et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair 2008; 7: 744-750
• 12 Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis 2011; 6: 70
• 13 Lehmann J, Schubert S, Emmert S. Xeroderma pigmentosum: diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches. J Dtsch Dermatol Ges 2014; 12: 867-872
• 14 Thoms KM, Baesecke J, Emmert B. et al. Functional DNA repair system analysis in haematopoietic progenitor cells using host cell reactivation. Scand J Clin Lab Invest 2007; 67: 580-588
• 15 Tamura D, DiGiovanna JJ, Khan SG. et al. Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients. Photodermatol Photoimmunol Photomed 2014; 30: 146-152
• 16 Nagore E, Sevila A, Sanmartin O. et al. Excellent response of basal cell carcinomas and pigmentary changes in xeroderma pigmentosum to imiquimod 5 % cream. BR J Dermatol 2003; 149: 858-861
• 17 Sharquie KE, Ibrahim GA. Is the skin graft immune against new malignancy?. Journal of the Saudi Society of Dermatology & Dermatologic Surgery 2011; 15: 73-75
• 18 Kraemer KH, DiGiovanna JJ, Moshell AN. et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988; 318: 1633-1637
• 19 Moshell AN. Prevention of skin cancer in xeroderma pigmentosum with oral isotretinoin. Cutis 1989; 43: 485-490
• 20 Tanaka K, Sekiguchi M, Okada Y. Restoration of ultraviolet-induced unscheduled DNA synthesis of xeroderma pigmentosum cells by the concomitant treatment with bacteriophage T4 endonuclease V and HVJ (Sendai virus). Proc Natl Acad Sci USA 1975; 72: 4071-4075
• 21 Zahid S, Brownell I. Repairing DNA damage in xeroderma pigmentosum: T4N5 lotion and gene therapy. J Drugs Dermatol 2008; 7: 405-408
• 22 Warrick E, Garcia M, Chagnoleau C. et al. Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells. Mol Ther 2012; 20: 798-807
• 23 Kraemer KH, Sander M, Bohr VA. New areas of focus at workshop on human diseases involving DNA repair deficiency and premature aging. Mech Aging Dev 2007; 128: 229-235
• 24 Kraemer KH, Rünger TM. Genome stability, DNA repair and cancer. Fitzpatrick’s Dermatology in General Medicine. 2008: 977-986