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The term xeroderma pigmentosum (XP) designates a heterogenic range of rare, autosomal, recessive disorders characterised by:
– cutaneous and ocular sensitivity, poikiloderma and the onset, in a short time frame of numerous skin tumours, i.e. benign tumours (actinic keratoses, keratoacanthomas) and especially, skin cancers (squamous and basal cell carcinomas, melanomas) in the areas exposed to UV radiation. Ocular lesions, i.e. conjunctival and palpebral tumours, are common and characterised by early onset and may lead to blindness. Concomitant neurological abnormalities are observed in approximately 20 p. 100 of cases;
– a deficiency in the enzyme system responsible for the repair of DNA damaged by the effects of UV light;
– the incidence of the disease varies significantly worldwide, i.e. 1 per million births in Metropolitan France against 10 per million births in North Africa and Japan and 50 per million births in the Comoros including Mayotte.
The nucleotide excision repair genes implicated in the classic forms of xeroderma pigmentosum are the XPA to XPG genes. In the variant type of xeroderma pigmentosum, the genetic defect results from mutations in the POLH gene that encodes a DNA polymerase (Polη) capable of relatively consistently replicating damage caused by UV light. Patients with the classic form of XP present their first skin tumours at 4 to 5 years of age on average whereas the clinical manifestations of the variant form of XP are less severe and patients generally do not consult until they are adults.
Clinical diagnosis of the disease is usually not a problem for experienced dermatologists except for variant XP which may be confused with different forms of photosensitivity with no apparent genetic cause. Diagnosis is confirmed by laboratory testing demonstrating the presence of a defect in the DNA repair mechanism in the patient’s cells (fibroblasts obtained by skin biopsy or circulating lymphocytes) after UVC irradiation in a laboratory setting. Determination of the complementation group may be achieved in vitro by fusing the cells of the patient to be tested with XP cells of known complementation groups. Sequencing of one of the 8 implicated genes makes it possible to know exactly which mutation the patient is carrying. The disease may be diagnosed prenatally from the tenth week of pregnancy by trophoblast biopsy in families where XP has already been characterised genetically or by laboratory tests.
Nucleotide excision repair (NER) may be divided into two different subpathways: transcription coupled repair (TCR) where UV-induced damage is repaired only on transcribed DNA strands and global genomic repair. The two subpathways differ in how they recognize DNA damage. With TCR, RNA polymerase II stalls at a DNA lesion and the blocked polymerase thus serves as a damage signal. Conversely, global genomic repair is not dependant on transcription and damage, which modifies the native structure of the DNA, is detected by the XPC and XPE binding proteins. Once the damage has been detected, a key protein complex, TFIIH, the activity of which is to repair and transcribe, intervenes. The complex comprises two DNA helicase subunits (XPB and XPD), which help unwind the DNA at the site of the damage. The rest of the repair process involves the factor XPA and two endonucleases, XPF and XPG, which cut the damaged DNA strand on the 5’ and 3’ sides, respectively. Once the lesion has been removed, the DNA strand is reconstructed by replication using DNA polymerase and DNA ligase.
XP-E and XP-C patients (the most common group worldwide) have global genomic repair deficiencies but their TCR activity is normal. This means they are very sensitive to solar UV light and they therefore develop tumours very rapidly if they don’t take total sun protection measures. However, because their TCR activity is normal, they do not present any development or neurological abnormalities. Conversely, patients from the other groups have deficiencies in both DNA repair subpathways and present with progressive neurological abnormalities which often lead to premature death.
XP variant patients show normal NER activity, but their cells are specifically sensitive in vitro to UV light in the presence of caffeine. However, the deficiency in Polη, which is a translesion DNA polymerase capable of relatively consistently and effectively replicating damage principally caused by UV light, leads to longer blocking of DNA replication in DNA strands with lesions. Due to the deficiency in Polη, another translesion polymerase is used for the replication of lesions but the latter polymerase is less consistent and induces mutations opposite the replicated lesions and the development of cancers in the long term. Polη is also used in B cells during somatic hypermutation and immunoglobulin class switching.
A few novel treatment options have been proposed in addition to total sun protection and surgical removal of skin tumours, which are indisputable measures. However, data in the literature are very fragmented and most often refer to a few isolated cases or to very limited series of uncontrolled clinical trials. Quasi 100% protection from the sun and other light sources which give off UV radiation (such as certain white lamps) allows patients to keep their skin looking virtually normal and, particularly, prevents them from developing skin tumours. XP-C and XP-E patients generally follow a normal school curriculum and they can readily integrate themselves into the working world. However, for patients belonging to the other complementation groups, progressive neurological disorders significantly limit the social dimension.
An increase in the risk of developing internal tumours, particularly tumours of the central nervous system from the youngest age, has been described for the classic form of XP. As very few patients are concerned, the risk is difficult to quantify from a statistical perspective.
Treatment of a patient with xeroderma pigmentosum entails familial counselling. The parents of patients need to be reassured and may even need to come to terms with feelings of guilt. They also need help finding a compromise between the preventive measures required by their child’s health and an overprotective attitude. They need to be informed of the possibility of diagnosing the disease prenatally in cases of future pregnancies.
Xeroderma pigmentosum has a major cosmetic impact because of the poikiloderma, the multiple tumours and sometimes disfiguring treatments. It is therefore also important to be able to respond to cosmetic requests, made mostly by young girls, which might sometimes seem frivolous in comparison with the seriousness of the disease.
Evidently, the disease also has a major psychological impact on patients given its disfiguring nature, its seriousness and the social exclusion it results in from patients not being able to attend school. The rest of the family may also be affected psychologically, i.e. parents, brothers and sisters, and family psychological counselling may be required.
INFORMATION FOR PARENTS
The pathophysiological bases of the disease and treatment must be explained to the patient or the patient’s parents.
The problem may be broached as follows:
“You (or your child) have (has) a genetic disorder. There is currently no cure for the disease. Your cells are unable to normally repair the damage caused by the sun’s ultraviolet rays to the DNA contained in the nuclei of your cells. That explains why your skin is so sensitive to sunlight. Cumulative UV exposure is extremely dangerous for your skin: it causes serious burns, pigmented spots and significantly increases the risk of developing skin cancer and eye disorders.”
“In order to limit theses problems, you must protect yourself as much as possible from the sun’s rays and certain white lights which may also give off UV radiation. You must also regularly see a dermatologist in the aim of detecting any cancers or precancerous lesions as early as possible.”
Parents of children with XP should be informed of the 25 p. 100 probability of having a second child with xeroderma pigmentosum and of the possibility of diagnosing the disease through prenatal tests and of terminating the pregnancy if they so wish. The physician may also need to broach the subject of the risk of children with XP that might be born to brothers and sisters of the XP patient who might marry a member of the family or someone from their original village (concept of coancestry).
An association was founded in France several years ago by parents of children with xeroderma pigmentosum (Association des Enfants de la Lune – Association of the Children of the Moon). The association has an internet site, www.asso.orpha.net/AXP that patients are encouraged to visit, where they may find useful practical information and for those that need it, essential psychological support. Patients may register with the association and receive aids for their UV protective measures. Summer camps are organised annually for XP children and their families. Special suits, specifically designed to completely protect patients against UV light are currently being manufactured at the initiative of the association.
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