Xeroderma Pigmentosum

It is often abbreviated to XP

Xeroderma pigmentosa is a very rare autosomal recessive disorder. Seven forms have been described, each with further subgroups with a slightly different genetic characteristic. The mutations of the different forms are on different chromosomes. They are often abbreviated with an alphabetical suffix to be called XPA, XPC, XPD, etc. An 8th form of the disease may have a dominant form of inheritance, although doubts have been expressed that this is truly a form of XP.

People with XP have an impairment of their ability to repair damage to their skin from ultraviolet radiation. Affected individuals appear to age more rapidly and develop dryness of the skin. More importantly, they also have an increased tendency to develop skin tumours due to DNA transcription errors. Xeroderma pigmentosa has a unique place in medical history in that when Cleaver identified the basis of xeroderma pigmentosa in 1969¹ it provided the first clear understanding of the central role played by DNA mutation in cancer.

Xeroderma pigmentosa (XP) is very rare but appears to be present throughout the world and is represented in every ethnic group. There are currently approximately 100 diagnosed cases in the UK. Worldwide, the commonest groups are XPA and XPC. The international incidence is around 1 in 250,000 but in Japan it is as high as 1 in 40,000 with XPA being the commonest variety. It affects both sexes equally.

Both parents are usually unaffected but there may be consanguinity.
It usually presents in childhood with unusually severe and persistent sunburn after the first exposure to the sun. The disease passes through 3 stages.

• The skin is healthy at birth but after the age of 6 months there is diffuse erythema, scaling, and freckled areas of increased pigmentation. They are seen over the areas most exposed to light, appearing initially on the face. As the disease progresses, the skin changes appear on the lower legs, the neck, and even the trunk in extreme cases. These features tend to diminish during winter, with decreased sun exposure, but as time passes, they become permanent.
• In the second stage there is poikiloderma. These changes consist of skin atrophy, telangiectasias, and mottled hyperpigmentation and hypopigmentation. Telangiectasias occur mostly in areas exposed to sun but they have been reported in unexposed skin and even buccal mucosa.
• The third stage is characterised by numerous malignancies, including squamous cell carcinomas, malignant melanoma, basal cell carcinoma, and fibrosarcoma. These malignancies may occur as early as age 4 or 5 years old and are more prevalent in areas exposed to sun.

Other features to be noted at various stages may include:

• Unusually thin, dry skin.
• Benign skin lesions more usually associated with ageing skin, including solar keratoses.
• Malignant tumours of the mouth such as carcinoma of tongue.²
• Benign and malignant ophthalmic tumours.³
• Corneal opacities possibly leading to blindness. Some form of ocular problem occurs in 80%.
• Neurological damage occurs in 20% of XP sufferers⁴ and can include deafness, developmental delay and spasticity.This appears to be unrelated to UV exposure, but seems to occur in those whose skin is most severely affected by UV exposure
• Depression or psychological disorder as a result of disfigurement or lifestyle restrictions

De Santis Cacchione syndrome⁵ shares many features with XP, but may also be associated with neurological abnormalities, mental retardation, dwarfism and hypogonadism. Progeria can produce similar skin changes. Extreme photosensitivity may occur with porphyria and systemic lupus erythematosis.

There is no simple and easy laboratory test.

Definitive diagnosis of XP is made by studies of DNA from affected cells. The XP complementation groups can be determined by using cell-fusion techniques followed by assessment of DNA repair or by gene sequencing.

There is no specific treatment for XP and management relies on preventing damage where possible, and dealing with damaged or aberrant tissues at an early stage :

• Avoidance of UV light as much as possible.
• Restrict outdoor activities to night time.
• The use of very high factor sun block creams and UV filtering clothing including hats.
• Use of optical UV protection.
• Regular dermatology, ophthalmology and neurology examinations including hearing tests.
• Early surgical removal of skin lesions.
• Oral retinoids can reduce the incidence of skin cancer but overdose causes irreversible calcification of ligaments and tendons and must be avoided.⁶
• 5 fluouracil and other creams may be useful for actinic keratosis.
• Pre-natal screening is possible for parents who already have one affected child, but is not carried out routinely.
• Genetic counselling should be arranged for parents of an affected child if they are considering further pregnancies.
• Psycho-social counselling may be required due to problems brought about by physical appearance or restrictions brought about by the disease.

• Actinic damage occurs between 1 and 2 years old.
• The mean age of skin cancer in these patients is 8 years old,⁴ compared with 60 in the general population.
• There is an increased risk of many malignancies including internal malignancies and brain tumours.²
• Death is often from malignant melanoma or squamous cell carcinoma.

The prognosis varies with the severity of the genetic disorder and the success in avoiding UV light and vigilance of screening. Despite all efforts, many sufferers will die as a result of a malignancy. A small sample found that death related to neurological involvement was common.⁷ A few with milder disease may survive to middle age but fewer than 40% of patients survive beyond age 20 years.

Antenatal diagnosis is possible by amniocentesis or chorionic villus sampling. Unscheduled DNA synthesis is the classic method for diagnosis. A faster technique is the alkaline comet assay.⁸

The condition was first described in 1874 by Hebrew and Kaposi. In 1882, Kaposi coined the term xeroderma pigmentosum to reflect the characteristic dry, pigmented skin. The skin is very susceptible to the changes caused by the sun including photosensitivity, pigmentary changes, premature aging, and malignant tumours. There is a defect in DNA repair.

The basic defect is in repair of DNA damaged by ultraviolet light. Nucleotide excision repair (NER) normally removes DNA damaged by UV radiation and replaces it with new DNA. There are two types of NER: global genome (GG-NER) and transcription coupled (TC-NER).

Seven XP repair genes have been identified and named XPA through to XPG. These genes are fundamental to both GG-NER and TC-NER. They detect damaged DNA as well as repairing it.

The 7 complementation groups, named XPA to XPG, corresponding to defects in the production of XPA-XPG genes. The rarity varies. XPA is relatively common, whilst XPE is very rare. Disease is severe in XPG but milder with XPF. Cockayne syndrome can rarely occur with XPB, XPD, and XPG.

UV-B radiation also has immunosuppressive effects. Typical features of immune suppression, such as multiple infections, are not usually seen with XP but immunological abnormalities have been described in the skin of patients. There is depletion of Langerhans cells induced by UV radiation. Other defects in cell-mediated immunity have been reported. These defects include impaired cutaneous responses to recall antigens, decreased circulating T-helper cells-to-suppressor cells ratio, impaired lymphocyte proliferative responses to mitogen, impaired production of interferon in lymphocytes, and reduced natural killer cell activity.