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Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder. There is an impairment of the skin's ability to repair damage from ultraviolet (UV) light, leading to early skin changes, early sunburn, dry skin and a vastly increased tendency to develop skin tumours and eye damage from UV light.
Xeroderma pigmentosum (XP) is very rare but appears to be present throughout the world and in every ethnic group. There are currently approximately 100 diagnosed cases in the UK. The incidence in the USA is estimated as 1 in 1 million. Some areas such as Japan and the Middle East have higher rates of XP.
Types of xeroderma pigmentosum
Seven forms have been described, denoted by letters (XPA-XPG). There is an 8th type known as xeroderma pigmentosum (XP) variant (XPV). Each has a different genetic characteristic. XPV was formerly known as pigmented xerodermoid.
Previously, an individual with XP with any neurological abnormality was said to have the De Sanctis-Cacchione syndrome. Now that the spectrum of XP disease is better understood, this term is reserved for XP with severe neurological disease, dwarfism and immature sexual development (rare).
XP-Cockayne syndrome (XP-CS) includes facial freckling and early skin cancers typical of XP, with some features of Cockayne's syndrome.
The main presenting features of xeroderma pigmentosum (XP) are photosensitivity, skin changes and a high incidence of skin cancer at very young age. Skin changes occur first over the areas most exposed to light, initially on the face.
- Typically, there is marked freckling of sun-exposed areas in a child before the age of two years (rare in normal children).
- Photosensitivity - approximately 50% of XP patients show acute sun sensitivity, ie sunburn occurs after minimal sun exposure, often noticed in infancy.
- However, in some forms of XP (especially XPC), patients lack this acute sun sensitivity; they tan and freckle without burning. In these patients, the presence of skin cancers may be the first indication that the child has XP.
- Xerosis (dry skin).
- Poikiloderma (comprising irregular patches of hyperpigmentation and hypopigmentation, telangiectasia and atrophy).
- Skin cancers develop early; the median age is 8 years (although this is prevented by good protection - see treatment under 'Management' section, and 'Prognosis' section). These are: solar keratoses (premalignant), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and malignant melanoma. BCC and SCC occur most frequently. They may occur as early as age 4 or 5 years old and are more prevalent in areas exposed to sun. The anterior tongue is also vulnerable.
Eye features occur in the anterior, exposed part of the eye:
- Conjunctival inflammation and keratitis. Severe keratitis can lead to corneal opacification and vascularisation.
- Tumours of conjunctiva and eyelids - benign or malignant.
- Eyelids may be pigmented, may lose lashes, or may atrophy - leading to ectropion or entropion.
30% of affected individuals have neurological manifestations, including acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment.
- Neurological problems occur in 20-30% of XP sufferers. They can be mild or severe.
- Possible features are: hyporeflexia, sensorineural deafness, spasticity, poor co-ordination, seizures, acquired microcephaly or progressive intellectual impairment.
- These seem to be unrelated to UV exposure, but tend to occur in those whose skin is most severely affected by UV.
- The De Sanctis-Cacchione syndrome is XP with severe neurological involvement, including dwarfism and delayed sexual development.
- There are other causes of photosensitivity, e.g congenital erythropoietic porphyria.
- Other genetic conditions with photosensitivity due to defective DNA repair. eg Cockayne's syndrome (CS), the XP-CS complex, trichothiodystrophy (TTD), the XP-TTD complex, cerebro-oculo-facio-skeletal (COFS) syndrome, and the UV-sensitive syndrome.
Referral of suspected cases
The initial diagnosis is clinical, based on skin, eye, and neurologic manifestations. Note:
- Early diagnosis is important to prevent complications. Babies and children with photosensitivity should be referred to a dermatologist.
- Marked freckling of sun-exposed areas under age 2 years is unusual in normal children and should raise the suspicion of xeroderma pigmentosum (XP).
- Skin cancer in children is rare and merits investigation for an underlying cause.
- The diagnosis is made by skin biopsy with fibroblast culture. Functional tests on living cells can be used to screen for abnormalities in DNA repair.
- Genetic testing is available for XPA and XPC types. Molecular genetic testing for other types is on a research basis only.
- Prenatal diagnosis is usually possible.
Currently, there is no specific treatment for xeroderma pigmentosum (XP). Management involves preventing damage and dealing with damaged tissues at an early stage.
In the UK, Guy's and St Thomas' Hospital has been designated the national centre for treating children with XP, in collaboration with the photobiology unit at Ninewells Hospital, Dundee, and the diagnostic laboratory service at the University of Sussex. Their aim is a department where specialists in dermatology, neurology, ophthalmology and other relevant fields work together to support XP patients and their doctors UK-wide.
Total protection from UV light greatly improves the prognosis and reduces skin changes and cancers. This is achieved by:
- Restricting outdoor activities to night time. If outdoors during the day, cover the skin completely.
- Clothing: long opaque clothes, sunhats, UV protective sunglasses with side shields, and long hairstyles; custom-made face shields are also available.
- Protective film on windows (normal glass filters some, but not all, UV light).
- As some indoor lighting emits UV, light sources may need to be changed or protected. Standard incandescent light bulbs do not emit UV. Further information about suitable/unsuitable light bulbs is available on the XP Society's website.
- Frequent application of high-factor sunscreen, even indoors.
- Dermatologist reviews 3-monthly for skin cancer surveillance. Photographs can be helpful in monitoring lesions.
- Relatives can be taught to do skin checks between appointments.
- Ophthalmology examinations annually.
- Early surgical removal of skin lesions.
- Regular neurological review and hearing tests.
- Monitoring of vitamin D levels.
- Vitamin D supplements may be needed, since sunlight (a major source of vitamin D) is excluded.
- Emollients for dry skin.
- Artificial tears for dry eyes.
- High-dose oral isotretinoin may prevent new neoplasms, although side-effects limit its use.
- T4N5 lotion - this contains a bacterial enzyme, T4 endonuclease V, which repairs some DNA defects. In one small trial, it reduced the development of solar keratoses and BCCs in XP patients.
Treatment of neoplasms and eye complications
- Premalignant lesions, eg actinic keratoses: topical 5-fluorouracil or cryotherapy. Larger areas can be treated by dermabrasion or dermatome shaving.
- Skin and eye tumours are treated in the same way as for those without XP, but with caution to conserve undamaged skin (because of the likely need for further procedures).
- Large areas with skin tumours can be grafted using unexposed skin.
- Corneal transplantation for severe keratitis.
- Genetic counselling (see 'Genetic counselling and risk to relatives' below).
- Support and counselling for patients and families, because of the severe lifestyle restrictions involved.
- Avoid smoking, because cells from individuals with XP are also hypersensitive to environmental mutagens, such as benzo(a)pyrene found in cigarette smoke.
- Skin and eye tumours, as above. The risk of these is approximately a thousand times normal.
- Vitamin D deficiency (and its complications) have been reported, although a small study from Germany found that not all xeroderma pigmentosum (XP) patients were vitamin D deficient.
- Some patients with XP are hypersensitive to X-rays, so a small test dose is advised before therapeutic X-radiation. Most patients with XP have a normal response to therapeutic X-radiation.
- There may be increased tobacco sensitivity. Lung cancer at a relatively young age has been reported in XP patients who smoke.
- Other cancers:
- There seems to be an increased risk of buccal cancer (probably due to UV in the oral cavity).
- There may be a higher rate of internal cancers, perhaps due to the underlying DNA repair defect combined with other toxins. Case reports suggest an increased susceptibility to lung cancer in smokers.
- The inheritance is autosomal recessive.
- If parents are considering further pregnancies, prenatal diagnosis is often possible.
- Where XP is suspected, siblings should be protected from UV light until XP can be excluded.
- Recent investigations of heterozygotes with one of four xeroderma pigmentosum (XP) genes (XPA, XPC, ERCC2, or ERCC5) have reported an increased risk of skin cancer, lung cancer, or altered response to certain chemotherapeutic agents.
The prognosis varies with the severity of the genetic disorder, the success in avoiding UV light and vigilance of screening. It also depends on the extent of any neurological involvement.
Previously, the prognosis was a reduced life expectancy due to skin cancers or neurological complications. However, more recent information suggests that a normal lifespan is possible for patients without neurological problems who are fully protected from UV.
Xeroderma pigmentosum (XP) was first described in 1870 by Hebra and Kaposi. The disease has a unique place in medical history: when Cleaver identified the basis of XP in 1969, it provided the first clear understanding of the central role played by DNA mutation in cancer.
Further reading & references
- Xeroderma Pigmentosum, St John's Institute of Dermatology; institute is linked with St Thomas' Hospital London, the national centre for XP.
- Xeroderma Pigmentosum, Online Mendelian Inheritance in Man (OMIM)
- Diwan AH; Xeroderma Pigmentosum, eMedicine, Oct 2008
- Webb S; Xeroderma pigmentosum. BMJ. 2008 Feb 23;336(7641):444-6.
- Kraemer KH. Xeroderma Pigmentosum. In: Gene Reviews, updated May 2008. (Detailed overview of xerorderma pigmentosum)
- European Dermatology Guideline for the photodermatoses - Genomic Instability diseases. Accessed December 2010.
- Xeroderma pigmentosum, DermNet NZ, July 2010
- 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.
- XP Support Group UK; Support group for patients and families in the UK
- Xeroderma Pigmentosum Society. Information for patients, research, patient programs.
- Querings K, Reichrath J; A plea for the analysis of Vitamin-D levels in patients under photoprotection, Cancer Causes Control. 2004 Mar;15(2):219.
- 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 Jun 23;318(25):1633-7.
- Yarosh D, Klein J, O'Connor A, et al; Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet. 2001 Mar 24;357(9260):926-9.
- Bath-Hextall F, Leonardi-Bee J, Somchand N, et al; Interventions for preventing non-melanoma skin cancers in high-risk groups. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005414.
- Hoesl M, Dietz K, Rocken M, et al; Vitamin D levels of XP-patients under stringent sun-protection. Eur J Dermatol. 2010 Jul-Aug;20(4):457-60. Epub 2010 May 21.
- Arlett CF, Plowman PN, Rogers PB, et al; Clinical and cellular ionizing radiation sensitivity in a patient with xeroderma pigmentosum. Br J Radiol. 2006 Jun;79(942):510-7.
- 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.
- Cleaver JE; Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proc Natl Acad Sci U S A. 1969 Jun;63(2):428-35.
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|Original Author: Dr Naomi Hartree||Current Version: Dr Naomi Hartree|
|Last Checked: 18/03/2011||Document ID: 1719 Version: 23||© EMIS|