Xeroderma Pigmentosum (XP)

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, where there is an impairment of the skin's ability to repair damage from ultraviolet light. Affected individuals appear to age more rapidly and develop dryness of the skin. More importantly, they have a vastly increased tendency to develop skin tumours and eye damage from ultraviolet (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 international incidence is around 1 in 250,000. Some areas such as Japan and the Middle East have higher rates of XP.²

Seven forms have been described, denoted by letters (XPA - XPG). There is an 8th type known as XP variant (XPV). Each has a different genetic characteristic.

XP variant was formerly known as pigmented xerodermoid.

DeSanctis-Cacchione syndrome

In the past, XP with any neurological abnormality was classified as DeSanctis-Cacchione syndrome. Currently, this syndrome refers to XP with severe neurological disease. The complete syndrome is very rare, but individuals with XP may have one or more of its neurological features (see below).

The main features of XP are photosensitivity and a high incidence of skin cancer at very young age. Presenting features are:

Skin features

• Sunburn occurs after minimal sun exposure, often noticed in infancy.
• Skin changes - which occur in 3 stages:
  1. Dry or scaly skin, freckling and irregular areas of hyperpigmentation.
  2. Poikiloderma (comprising irregular patches of hyper- and hypo-pigmentation, telangiectasia and atrophy).
     • These changes are seen first over the areas most exposed to light, initially on the face.
     • Later, lesions may develop on unexposed skin.
  3. Skin cancers and develop early; the median age is 8 years (though this is prevented by good protection - see treatment and prognosis sections). These are: solar keratoses (premalignant), squamous cell carcinoma, basal cell carcinoma and malignant melanoma. 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 features³

Eye features occur in the anterior, exposed part of the eye:

• Photophobia.
• Conjunctival inflammation and keratitis.
• Tumours of conjunctiva and eyelids - benign or malignant.
• Atrophy of eyelids leading to ectropion or entropion.

Neurological features

• Neurological problems occur in 20% of XP sufferers.⁴ They can be mild or severe.
• Possible features are: hypo-reflexia, 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 DeSanctis-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.¹
• There are several other genetic conditions with photosensitivity due to defective DNA repair.²

• 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 XP.
• Skin cancer in children is rare and merits investigation for an underlying cause.
• The diagnosis is made by skin biopsy with fibroblast culture. The fibroblasts can be tested for DNA repair, UV sensitivity and unscheduled DNA synthesis.
• Genetic testing is available for XPA and XPC types.
• Prenatal diagnosis is usually possible.

Currently, there is no specific treatment for XP. Management involves preventing damage and dealing with damaged tissues at an early stage.

Avoidance of UV light^1,5,6

Total protection from UV light greatly improves the prognosis and reduces skin changes and cancers. This is achieved by:

• Restrict 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, long hairstyles; custom made face shields are also available.
• Protective film on windows (normal glass filters some but not all UV light).
• Some indoor lighting emits UV: light sources may need to be changed or protected. Standard incandescent light bulbs do not emit UV.
• Frequent application of high-factor sunscreen, even indoors.

Surveillance^1,2

• Dermatologist reviews 3-monthly for skin cancer surveillance.
• 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.

Drug treatments

• Vitamin D supplements may be needed, since sunlight (a major source of vitamin D) is excluded.^1,2
• Moisturisers: skin emollients and artificial tear preparations (soft contact lenses may also protect against dry eyes).²
• Oral retinoids can reduce the incidence of skin cancer, but side-effects limit their use.^2,7
• A possible development is T4N5 lotion. This contains a bacterial enzyme, T4 endouclease. which repairs some DNA defects. In one small trial, it reduced the development of solar keratoses in XP patients. However, it is not yet licensed.⁸

Treatment of neoplasms²

• Premalignant lesions, e.g. 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.

Other treatments²

• Genetic counselling if parents are considering further pregnancies. Prenatal diagnosis may be possible.
• Support and counselling for patients and families, because of the severe lifestyle restrictions involved.
• Avoid tobacco.
• Siblings should be protected from UV until XP can be excluded.

• 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.
• Some patients with XP are hypersensitive to X-rays, so a small test dose is advised before therapeutic X-radiation.⁹
• 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 same DNA repair defect in combination with other toxins.

The prognosis varies with the severity of the genetic disorder, the success in avoiding UV light and vigilance of screening. It also depends on neurological involvement.^10,4

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.^1,6

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 xeroderma pigmentosum in 1969,¹¹ it provided the first clear understanding of the central role played by DNA mutation in cancer.