Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Xeroderma Pigmentosum

  • Author: Linda J Fromm, MD, MA, FAAD; Chief Editor: William D James, MD  more...
 
Updated: Jun 10, 2016
 

Background

Xeroderma pigmentosum (XP) was first described in 1874 by Hebra and Kaposi. In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin. Xeroderma pigmentosum is a rare disorder transmitted in an autosomal recessive manner. It is characterized by photosensitivity, pigmentary changes, premature skin aging, and malignant tumor development.[1] These manifestations are due to a cellular hypersensitivity to ultraviolet (UV) radiation resulting from a defect in DNA repair.

The Medscape Pediatric Dermatology Resource Center and Skin Cancer Resource Center may be helpful.

Next

Pathophysiology

The basic defect in xeroderma pigmentosum is in nucleotide excision repair (NER), leading to deficient repair of DNA damaged by UV radiation.[2] This extensively studied process consists of the removal and the replacement of damaged DNA with new DNA. Two types of NER exist: global genome (GG-NER) and transcription coupled (TC-NER).[3] The last decade has seen the cloning of the key elements of NER, and the process has been reconstituted in vitro.

Seven xeroderma pigmentosum repair genes, XPA through XPG, have been identified. These genes play key roles in GG-NER and TC-NER. Both forms of NER include a damage-sensing phase, performed in GG-NER by the product of the XPC gene complexed to another factor. In addition, the XPA gene product has been reported to have an affinity for damaged DNA. Therefore, XPA likely also plays a role in the damage-sensing phase.

Following detection of DNA damage, an open complex is formed. The XPG gene product is required for the open complex formation. The XPB and XPD gene products are part of a 9-subunit protein complex (TFIIH) that is also needed for the open complex formation. Subsequently, the damaged DNA is removed. The XPG and XPF genes encode endonucleases; however, the XPF gene product functions as an endonuclease when complexed to another protein. The resulting gap is filled in with new DNA by the action of polymerases.

A xeroderma pigmentosum variant has also been described. The defect in this condition is not in NER, but is instead in postreplication repair. In the xeroderma pigmentosum variant, a mutation occurs in DNA polymerase η.[4, 5]

Seven complementation groups, XPA through XPG, corresponding to defects in the corresponding gene products of XPA through XPG genes, have been described. These entities occur with different frequencies (eg, XPA is relatively common, whereas XPE is fairly rare), and they differ with respect to disease severity (eg, XPG is severe, whereas XPF is mild) and clinical features. Cockayne syndrome can rarely occur with XPB, XPD, and XPG.[6]

The continued presence of repair proteins at sites of DNA damage may also contribute to the pathogenesis of cutaneous cancer, as has been shown in XPD.[7]

In addition to the defects in the repair genes, UV-B radiation also has immunosuppressive effects that may be involved in the pathogenesis of xeroderma pigmentosum.[8] Although typical symptoms of immune deficiency, such as multiple infections, are not usually observed in patients with xeroderma pigmentosum, several immunologic abnormalities have been described in the skin of patients with xeroderma pigmentosum. Clinical studies of the skin of patients with xeroderma pigmentosum indicate prominent depletion of Langerhans cells induced by UV radiation. Various other defects in cell-mediated immunity have been reported in xeroderma pigmentosum. These defects include impaired cutaneous responses to recall antigens, decreased ratio of circulating T-helper cells to suppressor cells, impaired lymphocyte proliferative responses to mitogen, impaired production of interferon in lymphocytes, and reduced natural killer cell activity.

In addition to their role in DNA repair, xeroderma pigmentosum proteins also have additional functions. For example, Fréchet et al[9] have shown that matrix metalloproteinase 1 is overexpressed in dermal fibroblasts from patients with XPC.[10] They also demonstrated accumulation of reactive oxygen species in these fibroblasts in the absence of exposure to UV. They concluded that the XPC protein has roles in addition to NER. Matrix metalloproteinase 1 overexpression has been shown to occur in both aging of skin and carcinogenesis.

XPG has been shown to form a stable complex with the transcription factor TFIIH, as mentioned above. Some manifestations of XPG/Cockayne syndrome in patients may therefore be due to abnormal transcription.[11]

With respect to neurodegeneration seen in some cases of xeroderma pigmentosum, it may be associated with TC-NER rather than GG-NER.[12]

Previous
Next

Epidemiology

Frequency

United States

The frequency in the United States is approximately 1 case per 250,000 population. Group XPC is the most common form in the United States.

International

The frequency in Europe is approximately 1 case per 250,000 population. In Japan, it is higher, 1 case per 40,000 population. Groups XPA and XPC are the most common. Group XPA is the most common form in Japan.

Race

Cases of xeroderma pigmentosum are reported in persons of all races.

Sex

An equal prevalence has been reported in males and females.

Age

The disease is usually detected at age 1-2 years.

Previous
Next

Prognosis

Less than 40% of patients survive beyond age 20 years. Individuals with milder disease may survive beyond middle age. Individuals with this disease develop multiple cutaneous neoplasms at a young age. Two important causes of mortality are metastatic malignant melanoma and squamous cell carcinoma.[13] Patients younger than 20 years have a 1000-fold increase in the incidence of nonmelanoma skin cancer and melanoma. The mean patient age of skin cancer is 8 years in patients with xeroderma pigmentosum, compared with 60 years in the healthy population. Actinic damage occurs between ages 1 and 2 years.

Previous
Next

Patient Education

Constant education of the patient is the most important objective in the management of xeroderma pigmentosum. The need for adequate solar protection cannot be overemphasized and should be reinforced at every visit.

Sunblocks should be used, even in winter months and during evening and early morning hours. The exposed surfaces of the skin should be shielded with protective, double-layered clothing and broad-brimmed hats. The eyes should be shielded with UV-absorbing sunglasses with side shields.

Even unlikely sources of illumination can prove hazardous and should be pointed out to patients; for example, fluorescent lights that emit radiation below 320 nm can be dangerous.

The Xeroderma Pigmentosum Society provides information for individuals who are affected, their families, and the public. It also provides peer support for patients and their families.

Previous
 
 
Contributor Information and Disclosures
Author

Linda J Fromm, MD, MA, FAAD Private Practice, Fromm Dermatology at Health Concepts, Rapid City, South Dakota

Linda J Fromm, MD, MA, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Craig A Elmets, MD Professor and Chair, Department of Dermatology, Director, Chemoprevention Program Director, Comprehensive Cancer Center, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine

Craig A Elmets, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American College of Physicians, American Federation for Medical Research, Society for Investigative Dermatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: University of Alabama at Birmingham; University of Alabama Health Services Foundation<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ferndale Laboratories<br/>Received research grant from: NIH, Veterans Administration, California Grape Assn<br/>Received consulting fee from Astellas for review panel membership; Received salary from Massachusetts Medical Society for employment; Received salary from UpToDate for employment. for: Astellas.

A Hafeez Diwan, MD, PhD Associate Professor, Department of Pathology, University of Texas MD Anderson Cancer Center

A Hafeez Diwan, MD, PhD is a member of the following medical societies: College of American Pathologists, Southern Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Marcelo Horenstein, MD, to the development and writing of this article.

References
  1. English JS, Swerdlow AJ. The risk of malignant melanoma, internal malignancy and mortality in xeroderma pigmentosum patients. Br J Dermatol. 1987 Oct. 117(4):457-61. [Medline].

  2. DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J Invest Dermatol. 2012 Mar. 132(3 Pt 2):785-96. [Medline]. [Full Text].

  3. Warrick E, Garcia M, Chagnoleau C, Chevallier O, Bergoglio V, Sartori D, et al. Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells. Mol Ther. 2011 Nov 8. [Medline].

  4. Gratchev A, Strein P, Utikal J, Sergij G. Molecular genetics of Xeroderma pigmentosum variant. Exp Dermatol. 2003 Oct. 12(5):529-36. [Medline].

  5. Ortega-Recalde O, Vergara JI, Fonseca DJ, Ríos X, Mosquera H, Bermúdez OM, et al. Whole-exome sequencing enables rapid determination of xeroderma pigmentosum molecular etiology. PLoS One. 2013. 8(6):e64692. [Medline]. [Full Text].

  6. Nouspikel T. Nucleotide excision repair and neurological diseases. DNA Repair (Amst). 2008 Jul 1. 7(7):1155-67. [Medline].

  7. Boyle J, Ueda T, Oh KS, Imoto K, Tamura D, Jagdeo J, et al. Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. Hum Mutat. 2008 Oct. 29(10):1194-208. [Medline].

  8. Bowden NA, Beveridge NJ, Ashton KA, Baines KJ, Scott RJ. Understanding Xeroderma Pigmentosum Complementation Groups Using Gene Expression Profiling after UV-Light Exposure. Int J Mol Sci. 2015 Jul 14. 16 (7):15985-96. [Medline].

  9. Fréchet M, Warrick E, Vioux C, Chevallier O, Spatz A, Benhamou S, et al. Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients. Oncogene. 2008 Sep 4. 27(39):5223-32. [Medline].

  10. Parlanti E, Pietraforte D, Iorio E, Visentin S, De Nuccio C, Zijno A, et al. An altered redox balance and increased genetic instability characterize primary fibroblasts derived from xeroderma pigmentosum group A patients. Mutat Res. 2015 Oct 23. 782:34-43. [Medline].

  11. Ito S, Kuraoka I, Chymkowitch P, Compe E, Takedachi A, Ishigami C, et al. XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne syndrome in XP-G/CS patients. Mol Cell. 2007 Apr 27. 26(2):231-43. [Medline].

  12. Niedernhofer LJ. Tissue-specific accelerated aging in nucleotide excision repair deficiency. Mech Ageing Dev. 2008 Jul-Aug. 129(7-8):408-15. [Medline].

  13. Schaffer JV, Orlow SJ. Radiation Therapy for High-Risk Squamous Cell Carcinomas in Patients with Xeroderma Pigmentosum: Report of Two Cases and Review of the Literature. Dermatology. 2011 Oct 21. [Medline].

  14. Sethi M, Lehmann AR, Fawcett H, Stefanini M, Jaspers N, Mullard K, et al. Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions. Br J Dermatol. 2013 Jul 25. [Medline].

  15. Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis. 2011 Nov 1. 6:70. [Medline]. [Full Text].

  16. Lasso JM, Yordanov YP, Pinilla C, Shef A. Invasive basal cell carcinoma in a xeroderma pigmentosum patient: facing secondary and tertiary aggressive recurrences. J Craniofac Surg. 2014 Jul. 25 (4):e336-8. [Medline].

  17. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 1987 Feb. 123(2):241-50. [Medline].

  18. Kleijer WJ, van der Sterre ML, Garritsen VH, Raams A, Jaspers NG. Prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy in 76 pregnancies at risk. Prenat Diagn. 2007 Dec. 27(12):1133-7. [Medline].

  19. Alapetite C, Benoit A, Moustacchi E, Sarasin A. The comet assay as a repair test for prenatal diagnosis of Xeroderma pigmentosum and trichothiodystrophy. J Invest Dermatol. 1997 Feb. 108(2):154-9. [Medline].

  20. Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988 Jun 23. 318(25):1633-7. [Medline].

  21. Giannotti B, Vanzi L, Difonzo EM, Pimpinelli N. The treatment of basal cell carcinomas in a patient with xeroderma pigmentosum with a combination of imiquimod 5% cream and oral acitretin. Clin Exp Dermatol. 2003 Nov. 28 Suppl 1:33-5. [Medline].

 
Previous
Next
 
Face of a toddler with xeroderma pigmentosum, representative of an early stage of the disease. Note the freckling and the scaling. Courtesy of Neil S. Prose, MD, Duke University Medical Center, Durham, North Carolina.
Back of an adolescent with xeroderma pigmentosum, representing a later stage of the disease. Note the mottled hyperpigmentation and atrophy. Courtesy of Neil S. Prose, MD, Duke University Medical Center, Durham, North Carolina.
Histologic features of actinic keratosis in an individual with xeroderma pigmentosum. Note the atypia of the keratinocytes and the parakeratosis.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.