A rare genetic disease, xeroderma pigmentosum (XP) is expressed by hypersensitivity to ultraviolet radiation. How is the diagnosis established? What are the daily consequences of this disease? Explanations from Professor Alain Sarasin, emeritus research director at the CNRS.
A rare genetic disease, xeroderma pigmentosum (XP) was first described in 1871 by a Hungarian dermatologist, Dr. Moritz Kaposi. “However, it was only in the 1970s that the first results of genetic analysis of bacteria sensitive to ultraviolet (UV) made it possible to approach the cause of this disease. This is due to a specific defect in the repair of UV-damaged DNA. specifies Professor Alain Sarasin, emeritus researcher at the CNRS and specialist in this disease.
A mutation of 7 genes and a variant gene
XP is caused by mutations in one of the 8 genes involved in DNA repair. “Seven of them (from XPA to XPG) are classic forms, while the variant ultraviolet-induced damage to DNA.continues the researcher
Among the 7 genes identified, some of them make patients very sensitive to UV rays and others a little less. This hypersensitivity to UV rays prohibits all sun exposure to children, including when the sun is hidden by clouds. “The simple reflection of the sun is enough to cause lesions.points out Prof. Alain Sarasin.
In a sick child, both parents carry the deficient gene. More precisely, they carry one normal gene and one mutated gene. “For the child to be sick, there is a risk in 4 that the father’s mutated gene is found in the same cell as the mother’s mutated gene.explained by Prof. Alain Sarasin.
Xeroderma pigmentosum affects both boys and girls. Children are born with the disease, the first symptoms will appear from the first exposure to the sun. The disease is first expressed by classic sunburns and burning sensations. “These children will then develop increasingly significant freckles which will concern parents and lead them to consult., explains Professor Alain Sarasin. Very often, the therapeutic wandering time between different specialists, of the order of 3 to 5 years, will considerably delay the diagnosis.
Disease prevalence
Worldwide, 1 to 4 people out of 1 million in the USA and Europe are affected by xerodema pigmentosum. In the Middle East, the Maghreb and Japan, the frequency of the disease is much higher, with 1 in 100,000 children. “As soon as we observe a lot of inbreeding, the genetic mutation is transmitted more frequently”analyzes the researcher.
In Europe, the prevalence is 1 to 2 people in a million, or around a hundred cases recorded.
Skin and eye lesions
Exposure to UV rays leads to the production of free radicals, molecules that damage the DNA of exposed cells. In the general population, damaged DNA is repaired, but in these children, the damage accumulates due to a deficiency in DNA repair and leads to more or less severe skin and/or eye lesions. Ultimately, these children will be affected by skin and eye cancers. Problems with the eyelids and the cornea can indeed be observed.
The first symptoms of the disease appear in the first months. “If they are not protected, children can develop skin tumors (carcinomas or melanomas) or eye tumors from the age of 4-6”added Prof. Alain Sarasin.
In 20% of cases, neurological problems are also observed: deafness, psychomotor development disorders, coordination problems, etc. “We have not yet fully understood the origin of these neurological disorders but we know that XPA, XPD, and to a lesser extent, XPF and XPG are mutations associated with the origin of these disorders.observe Pr Alain Sarasin.
A diagnosis possible from the age of one or two years
The discovery of the genes involved in the disease dates back to the 1990s and 2000s. This has enabled tangible progress in diagnostics. Before the 1990s, DNA sequencing had not yet been developed. “To establish the diagnosis, a skin biopsy had to be carried out by taking the skin cells and culturing the fibroblasts of the patients. We irradiated these cells with UV, then we observed their sensitivity and the way in which they were able to repair the lesions. It was a long and complicated protocol that required 2 or 3 months.” says the specialist.
Today, genetic mutations are well known. From the appearance of the first clinical signs, the diagnosis is possible in a child from the age of one or two years. “If the disease is suspected, the patient’s DNA is isolated (from a blood sample), DNA sequencing is carried out and we check whether mutations are present on the XP genes. explains the specialist.
A major impact on daily life
The diagnosis of this disease disrupts the rhythm of family life as well as the life of the child and his brothers and sisters. This involves protecting the child from all daily sun exposure, summer and winter. In short, these children can only go out without protection at night. This is why this disease is also called “children of the moon disease”. It is also essential to equip living spaces with anti-UV windows and lights, whether at home, at school, in the car, in gymnasiums, etc. Children must also apply a protective sunscreen with a Very high SPF index (50+).
Founded in October 2000, the association “Les enfants de la lune” works to raise awareness of the disease and proposes concrete actions to improve the daily lives of the children affected.. “In 2015, the association developed anti-UV protection for the entire face integrating an “air conditioning” system, thus avoiding children having to protect themselves with sun cream and allowing them to to have total freedom in their sporting activities”, relate to Prof. Alain Sarasin.
If properly protected, the child enjoys a life expectancy almost identical to the general population. However, solar exposure during childhood before diagnosis plays an important role in one’s health. “During the first two or three years before diagnosis, children were exposed to the sun. Lesions may have accumulated and this can give rise, a few years later, to cancers.. In addition, as adults, some patients may feel a form of weariness with the need for daily sun protection, including with a mask. Furthermore, when faced with a difficult experience or a feeling of exclusion, psychological care may be indicated depending on the patient’s unique experience.
Management of skin tumors
To date, there is no treatment for this disease. Therapeutic trials in vitro, via gene therapy, have been attempted but they have not given the expected results. Prevention is based on protection against UV rays. Pre-cancerous skin lesions are generally treated by surgery or by applying a cream based on 5-fluorouracil (an anti-cancer molecule). As for the treatment of tumors, it is based on therapeutic means not specific to XP patients: ablation, skin grafting, chemotherapy, radiotherapy when surgical intervention is impossible. “We try to remove any lesion that seems suspicious. As these are children who are well-monitored medically, the care is generally rapid and well adapted.”summarizes Professor Alain Sarasin.
To compensate for the lack of sun exposure, vitamin D supplementation is generally considered by the dermatologist who follows the child, by means of daily, monthly or quarterly intake.
In order to treat the disease as quickly as possible and to avoid any unnecessary delay in diagnosis, it is important to react quickly to the rapid and accelerated appearance of freckles that may suggest the disease.