eMedicine Specialties > Dermatology > Photo-Related Diseases
Xeroderma Pigmentosum
Updated: Oct 7, 2008
Introduction
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.
Pathophysiology
The basic defect in xeroderma pigmentosum is in nucleotide excision repair (NER), leading to deficient repair of DNA damaged by UV radiation. 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). 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 έ.2
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.3
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.4
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. 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 al5 have shown that matrix metalloproteinase 1 is overexpressed in dermal fibroblasts from patients with XPC. 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.6
With respect to neurodegeneration seen in some cases of xeroderma pigmentosum, it may be associated with TC-NER rather than GG-NER.7
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.
Mortality/Morbidity
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. 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.
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.
Clinical
History
A history of severe persistent sunburn can be found in many patients. The history should focus on the relationship of the eruption to sun exposure, with a careful determination of its time course and morphology.
As with most autosomal recessive disorders, usually no family history is present; the parents, being heterozygotes, are healthy. Additionally, a history of consanguinity may be elicited.
Physical
The disease typically passes through 3 stages. The skin is healthy at birth. Typically, the first stage appears after age 6 months. This stage is characterized by diffuse erythema, scaling, and frecklelike areas of increased pigmentation (see Media File 1). These findings, as would be expected from the pathophysiologic basis for the disease, are seen over light-exposed areas, appearing initially on the face. With progression of the disease, the skin changes appear on the lower legs, the neck, and even the trunk in extreme cases. While these features tend to diminish during the winter months with decreased sun exposure, as time passes, these findings become permanent.
The second stage is characterized by poikiloderma. Poikiloderma consists of skin atrophy, telangiectasias, and mottled hyperpigmentation and hypopigmentation, giving rise to an appearance similar to that of chronic radiodermatitis (see Media File 2). Although telangiectasias also occur in the sun-exposed areas, they have been reported to arise in unexposed skin and even buccal mucosa.
The third stage is heralded by the appearance of numerous malignancies, including squamous cell carcinomas, malignant melanoma, basal cell carcinoma, and fibrosarcoma. These malignancies may occur as early as age 4-5 years and are more prevalent in sun-exposed areas.
- Photosensitivity should be suspected and evaluated in any patient with intermittent or persistent abnormalities on light-exposed areas.
- Photosensitivity in xeroderma pigmentosum is variable, but it generally occurs in the range of 290-320 nm. The minimal erythema dose is lower than normal at most wavelengths.
- In xeroderma pigmentosum, the photosensitivity is acute in nature. The action spectrum for elicitation of the photosensitivity may be suggested by the seasonal or diurnal variability of the eruption and by any protective effect of window glass or sunscreens.
- Ocular problems8 occur in nearly 80% of individuals with xeroderma pigmentosum.
- The initial problems include photophobia and conjunctivitis.
- Eyelid solar lentigines occur during the first decade of life, and they might transform into malignant melanoma.
- Ectropion, symblepharon with ulceration, repeated conjunctival inflammation, infections, and scarring might develop in these patients. In addition, vascular pterygia; fibrovascular pannus of the cornea; and epitheliomas of the lids, the conjunctivae, and the cornea can occur.
- Finally, the propensity for malignancies, such as squamous cell carcinoma, basal cell carcinoma, sebaceous cell carcinoma, and fibrosarcoma, can also involve the eyes of patients with xeroderma pigmentosum.
- Neurologic problems8 are seen in nearly 20% of patients with xeroderma pigmentosum, more commonly in groups XPA and XPD. The severity of these problems is proportional to the sensitivity of xeroderma pigmentosum fibroblasts to UV radiation.
- The problems include microcephaly, spasticity, hyporeflexia or areflexia, ataxia, chorea, motor neuron signs or segmental demyelination, sensorineural deafness, supranuclear ophthalmoplegia, and mental retardation. The neurologic problems might overshadow the cutaneous manifestations in some patients with xeroderma pigmentosum.
- De Sanctis-Cacchione syndrome refers to the combination of xeroderma pigmentosum and neurologic abnormalities (including mental retardation and cerebellar ataxia), hypogonadism, and dwarfism.
- The eMedicine Neurology article Xeroderma Pigmentosum may be of interest.
Causes
See Pathophysiology.
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| References |
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References
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Further Reading
Keywords
xeroderma pigmentosum, skin cancer, XP, photosensitivity, pigmentary changes, premature skin aging, malignant tumors, defective nucleotide excision repair, NER, defect in DNA repair, defective DNA repair
