بصدد الإنجاز

The Informations

1-Definition of the disease

2- Early diagnosis of the disease

3- Xeroderma Pigmentosum in Tunisia

4- Children of the light

5- Medical follow-up

6- Photoprotection

7- Prevention

8- Social security cover

9- Future prospects

10- UV free Center

11- Social guide line

1-   Definition of the disease

Le Xeroderma Pigmentosum

Mohamed Zghal, Inçaf Mokhtar, Azza Bhoury

The Xeroderma Pigmentosum (XP) is a handicapping hereditary disease characterized by an extreme and serious cutaneous-ocular photosensitivity sometimes associated with neurological disorders. The diagnosis is clinical, but it is required at the beginning of the molecular investigations. It is based on the presence of a persistent erythema from the early months of the life associated to the photophobia. The freckles or “Pigmentosum maculae” (specific to this pathology) are settled gradually and undergo constant modification leading to an aspect “poikilodermy like” characteristic (cutaneous variegation). As of childhood, the patients affected of XP develop multiple benign and malignant skin tumors responsible for the disfiguration of the face and the loss of the sight.

3 clinical forms are distinguished to which several genetic forms correspond. The precocity of appearance of carcinomas and the melanoma as well as the importance of their number depend on severity of the clinical form. These skin cancers condition the functional and vital forecast of the disease.

In the molecular level, this pathology is characterized by a DNA repair defect of photo injury. The DNA repair capacity by the system “nucleotide excision repair“ (NER) is measurable by autoradiography investigation; it is expressed in term of UDS “unscheduled DNA-synthesis”. These techniques allow the early biological diagnosis and the antenatal diagnosis of the disease.

Seven XP genetic groups (classified from A to G) were identified, in addition to the variable XP. The responsible genes as well as the various changes were cloned and located. The PCR made it possible to identify gene and the level of change. This technique makes it possible to make the diagnosis of the disease and to recognize the operational carriers. It is important in the prevention and the reduction of the number of new cases.

The management of this pathology is heavy and expensive; it requires collaboration between the doctors of various specialties and patient’s associations. It is primarily preventive; it is based on the early diagnosis, severe photoprotection (recommending living in darkness), early detection and the treatment of all the lesions susceptible to be transformed into cancer. The treatment of skin cancer during the XP joined that of the normal subject.  The surgery, the cryosurgery and chemotherapy are often used. On the other hand the radiotherapy must be avoided because of the important risk of carcinomas radio induct this ground.  The topics anticancer and the genetics therapeutic are new promising means in the improvement of the life’s quality of these patients.

The Xeroderma Pigmentosum is an orphan disease rare in the world, relatively frequent in North Africa and certain countries of the Middle-East in connection with the high rate of consanguinity.

In Tunisia one estimates the presence of 800 cases including 338 cases followed by Dr. Zghal Mohammed. Often one finds several cases in the same family.

It is a dramatic disease, which generates a major suffering within the family and upsets their life. The affected child suffers from his disease, and has non acceptance of him self, the rejection of the entourage, school difficulties, the lack of blooming and leisure. Thus, their quality of life is entirely deteriorated.

The improvement of the life’s quality of these children, the access to the treatment, the support of the parents and the fight for the reduction of the number of new cases are the priorities of our association.

2-   Early diagnosis of the disease 

Mohamed Zghal, Inçaf Mokhtar, Azza Bhoury

 
The functional and vital prognosis of the disease depends on early diagnosis and prompt treatment.

During childhood skin is still very thin and susceptible to ultraviolet irradiation, the annexes are not yet well developed and stem cells of the skin are directly exposed to the risks of UV. At this stage, sunburn is harmful to the child and explains the development of severe skin cancer as melanoma, for example. In the normal subject Skin cancer occur 20 to 40 years after sunburn, but it takes only few months or years in the affected children by Xeroderma Pigmentosum disease.
 
A child with XP (especially that of severe genetic form (group A, C, G) who received high doses of ultraviolet during the first Children suffer enormously whatever the quality of care adopted thereafter. Hence the importance of recognizing and protecting the child reaches early.

One year of adequate photoprotection during early childhood makes us win at least 10 years of slowdown in the evolution of the disease and a significant gain in the life quality.

The first events are Ophthalmic: photophobia, intolerance to light. The child closes his eyes as they approach the window with onset of chronic tearing without apparent cause.

The facial redness (erythema) appear from the first minimal (example: walking outside during a few minutes) exposure to sunlight.  It appears few hours after exposure to the sun (12 to 24 hours) and persists for several days. For prolonged exposure time, 2nd degree burns may be appear.
 

Do not confuse between persistent erythema and face redness of which can be seen in babies during the abrupt change in temperature but it can be present only during a few minutes or erythema in atopic that is accompanied by other suggestive signs.

These only two symptoms : (persistent redness and photophobia) can evoke the diagnosis before the age of 12 months especially in families at risk or in countries where the disease is common.

At this stage the diagnosis could be confirmed by the evaluation DNA repair capacity of the patient (UDS) or by PCR (when the gene and the mutation in the family has been identified)

One year of adequate photoprotection during early childhood makes us win at least 10 years of slowdown in the evolution of the disease and a significant gain in quality of life.

  Some months later (between the ages of 1 to 3 years depending on the genetic form and the photoprotection quality) appear pigmented spots at the level of the areas (pigmentosum macula) specific to this disease. In this stage the diagnosis can be easily established.
 

3-   Xeroderma pigmentosum in Tunisia 

Mohamed Zghal, Inçaf Mokhtar, Azza Bhoury

The exact number of the affected children with Xeroderma Pigmentosum is unknown. It is estimated between 600 and 800 cases, this if one takes into account patients followed by Dr. Zghal and extrapolation starting from the genetic trees. There is still several families affected unidentified and patients who never consulted in a specialized service, and the number of cases may require more than 1000 cases.

Among the association target, the participation in the census of the patients in order to offer them assistance, relieve the families and reduce the number of new case.

The highest concentration in sick is most often seen in the North West and south of the country where marriages blood exceed 30%.

Most of affected children are from poor families, helpless, poorly educated. The parents fail to understand neither disease to their child nor the preventive modalities.

It is difficult to persuade parents or even the doctors that the UV rays, not visible, are responsible for the destruction of the skin and the emergence of skin cancer especially those people that are often followed in an unprotected milieu.

The ignorance of parents that despite the presence of several skin tumors and the destruction of the skin and eyes, the child continues to live exposed to solar rays during the day without any photoprotection. For them it’s their “fate”.

In these families, the number of genes carrier of the disease is very high. Despite the increased risk of having affected children, many risky subjects continue to marry between them and entrust their fate to "the good god."
 

Most patients live in houses known as Arab (patio with open sky). They are very exposed to ultraviolet rays in a country already very sunny.

A medical and social cooperation is required. Our success depends on the resources, commitment of our partner but also the presence of doctors motivated, competent, dedicated, aware that agree to allow sufficient time for these children.

We have before us a long journey to do and efforts to be done to change the mentality and behavior of these families.

4-   Children of the light 

Mohamed Zghal, Inçaf Mokhtar, Azza Bhoury

Several nicknames were awarded to this disease. 

The oldest is the children of the night because the night is considered the ideal time to travel without protection and without risks. Unfortunately in our environment there are increasingly artificial sources emitting enough ultraviolet to harm the health of these children (neon tubes, fluorescent lamps called economic, ultraviolet type A sources in the nightclubs, the net equipped fluorescent light, and the cameras’ flashes ....). In addition darkness is a source of anxiety and depression for children and parents whose life’s quality is profoundly altered.

These patients are also called children of the moon. « Au Clair de la Lune » is very romantic children and parents prefer these nicknames. The light of the moon is low and it does not harm the health of these children. During the summer especially in camps for sick children, they try to have fun and play with the moon. They have a light for them. Unfortunately the moon is ephemeral; it is present only a few days per month and is visible only in good weather. In addition to that, may I add the nightlife and its disadvantages?

Other names have been used to describe this condition as "children of obscurity", "children of darkness" ... but these aggressive words are misunderstood by these families. To spare the susceptibility of the affected children and their families, it is better to abandon these terms.

The major enemy of these children is the sun. Sunlight is considered harmful to these children. Meaning often misunderstood and misinterpreted even by specialists.
 

The sun emits different radiations (gamma rays, X-rays, ultraviolet rays (C, B and A), visible light, infrared and radio waves). Some of these rays are not compatible with life. Fortunately the atmospheric layer surrounding the Earth, composed mostly of ozone (pollution can destroy this layer) eliminates all harmful rays.

           On the earth surface, solar spectrum composed by ultraviolet type B (290 to 320 nm, the most harmful and which are responsible for the genesis of skin cancer in the subject and in normal children with XP) , Ultraviolet Type A (from 320 to 400 nm, considered less dangerous than the B), visible light (400 to 700 nm, essential for life, these rays have no negative impact on the skin , Source of life, light and the antidepressant), infrared and radio waves.

          Ultraviolet rays called often "invisible light." In fact it is more radiation rather than light. The retina (the sensitive film of the eye) composed of sticks and cones do not detect these rays. For these reasons it makes more sense to reserve the term "light" only to visible light. This precision is very important in the management of the disease.

For a balanced life, happens, children suffering from XP need visible light. They can therefore be called "children of the light”.

XP patients have no problem with visible light. They need this light for a balanced and fulfilling life. That is why the term "children of light" proposed by a patient is more compatible with this disease, it offers more hope and will to live.

Just provide an free UV light environment for these children lead a life quite normal.

To do this, offer a free UV space is our first concern.
 

	Installation of stop UV films in the house of  two affected  children

     5- medical follow-up

        Within the framework the management of this disease, the patient must be followed at the same time by the family doctor or the podiatrist (every 2 months) and by a well trained dermatologist (minimum twice per year). 

        The periodic visits are very significant even in the absence of new lesions or skin cancers. 

For this disease, we insist on the importance of the collaboration between all the implied actors:  the patient, the attending doctor, the specialist doctors, the school doctor, the psychologist, the teacher, the welfare officer, parents, the related, entourage and associations. 

The parents must be implied and formed well in the detection of the suspect lesions such as: 

- A pigmented task which changes of the color, which increases by size, which bleeds or which becomes asymmetrical. 

- Visible rough lesions or not

- A nodular, scale or scared mass

- The parents must learn how to palpate the ganglion area.

- To evaluate the evolution of the intelligence of their child...

It is significant that the parents hold a personal file on which are noted:  Received antecedents, vaccinations, diseases, treatments, dates of appearance of the first signs of the disease and dates of each medical and surgical act sudden. 

Once the diagnosis carried out, it is significant to identify the genetic group and the level of the change.  This examination confirms the diagnosis, makes it possible to have an idea forecasts and allows the realization of a possible antenatal diagnosis in the event of pregnancy in the family. 

The genetic Council:  the attending doctor or the geneticist, and within the medical framework of education, could inform the family on the modes of transmission of the disease and give councils in order to avoid the birth of new sick children. 

It is significant that the whole of the family (aunt, uncle...) are informed of the disease and on its mode of transmission because they are individuals who are likely to transmit the disease to their offspring.  Currently, in Tunisia, it is possible to identify the normal subjects (hétérozygotes) carrying genes of the disease.

The XP is a hereditary disease with recessive autosomic transmission.   If one enters the children of several families of patient, we will find that 25% of the children are reached, 25% normal children non carrying gene and 50% children normal but carrying genes.  The limitation of the size of the family makes it possible to reduce the number of the children reached in the families at the risks.  In the same way the identification of the children carrying gene makes it possible to avoid the marriages at the risks. 

The antenatal diagnosis is possible by various techniques of which certain realizable in Tunisia.  However, it is significant to plan this invaluable pregnancy with the dermatologist, the gynecologist and the geneticist. 

       6-   Photoprotection

          The children reached of XP can live in the presence of the visible light provided that it is not contaminated by the ultraviolet rays.  It is the stake of the prevention and protection.  They do not need to live in the darkness, for this reason one should not any more call them "children of the darkness" or "children of the night ". They need rather a space of life free UV.  We combine our efforts to ensure this space without UV to them.

             a- Life space free UV

¨     UV Stop Film

At the house, at the school, in the leisure or sports halls, club of Internet, the means of transport or other place attended by the children reached of XP, the panes of the windows must be equipped with UV stop films.

 Association begins to help the parents to equip their hearths by the film stop UV

¨     Pure light from artificial source

There or are the children reached of XP, the artificial sources of light must emit pure light without UV. 

For this reason, only incandescent lamps (traditional lamps with filament) and the LED emit visible light not contaminated by the ultraviolet rays will be used in the life places of the patients.

The other sources such as the neon’s tubes, the fluorescent lamps known as economic, the spots, the flash of camera which emits a more or less significant quantity of ultraviolet rays of the type A and B must be avoided. 

It is advised not to use these sources in the places where these patients are present.  To do it, it has no possibility significant to fix these sources at a distance higher than 3 meters of the place where the patient is and to protect these sources by suitable cages of protection and UV stop film.

Association places at the disposal of the patients average specific equipment to check the absence of ultraviolet rays in their space of life

           b- Time photoprotection

The time photoprotection is of primary importance.  It consists in avoiding sun light between 8:00 hours and 18:00 hours, especially during the summer season.  For these children, it is strongly misadvised being out door, between 10:00 hours and 16:00

During day times, activities (sporting, professional...) in the open air “out door” were prohibiting for XP patients.

The maintenance of night social activities is essential for the psychic balance of these patients. 

        c-  Cloth photoprotection

The wearing of long clothing, covering all the parts of the body (head, face, neck, low neckline, arm, before arm, thigh, leg and feet), of gloves, hat on broad board, and broad sunglasses completely covering the eyes with UV filter is essential. 

Association places knowledge and apparatus at the disposal of the patients for controlling the quality of fabric used and the safety of their sunglasses. 

         d- Sun cream   

The choice of the sun creams relates to high quality products, certified, with the highest photo protection index confirmed by the in vitro studies on the XP cells and by clinical trials. 

The use of stick photo protectors on the lips is also significant.

The parents and the patients must be informed on the practical methods of the use of these products:  the cream or milk photo protector must be applied in thick layer to the face and the photo exposed area (neck cut off, hands and before arm).  The spreading out of the cream with the fingers is made interior towards outside to avoid the arrival of these products on the ocular mucous membranes which they can irritate it, without omitting to apply sufficient product to the nose.

 The application of these creams must be renewed every 2 hours, at least 4 times per day.  These products must be applied even if the child remains inside the house (the total ousting of the ultraviolet rays inside the hearth being practically difficult to realize in particular in the very sunny countries like Tunisia).

The addition of moisturizer cream applied the evening is strongly recommended considering the importance of the skin xerosis among these patients. 

            e- Vitamin D

The vitamin D is essential in the normal development of the bone.  The addition of vitamin D (or rich food in vitamin D) constitutes an auxiliary treatment of the photoprotection to avoid the rickets.

         7-   Prevention

The prevention is a capital time in the assumption of the management of this disease. 

                  -   Prevention of the appearance again a new cases

                  -   The deceleration of the natural evolution of the disease 

            a- New cases reduction policy

Thanks to the medical advances in knowledge, the presence in Tunisia of doctors and qualified biologists and with the efforts of the state as regards health, It would not be acceptable any more to still see several children reached in the same family. 

As of the discovery of the disease, if the parents wish to have other children, they must plan the pregnancy with their attending practitioner.  The antenatal diagnosis is currently realizable in Tunisia thanks to collaboration between Dr. Zghal Mohamed (hospital Habib Thameur) with Dr. Sonia Abdelhak (Institute Pasteur Tunis) and other doctors and scientists. 

We advise the limitation of the number of children in the families at the risk, the ideal would be not to exceed 3 children per family.

Currently, it is also possible to identify the subject’s normal but carrying genes of the disease. 

In order to break this transmission chain of the disease we propose to the parents:  cousins of patient XP to make specific biological tests necessary to the identification of the operational carriers and that with an aim of not training new families at the risk. 

b- To delay the natural evolution of the disease

In the absence of protection and the basic treatment of the XP disease, the patients finish in a dramatic state.  Various types of cancers will invade the skin, which will be atrophied, scared, become sclerotic with losses of substances, mutilations and patients becomes blind. 

Fortunately, one can prevent and avoid this serious evolution by observing certain rules: 

- A life in a free UV space associated with an adapted photo protection. 

- To avoid the artificial sources emitting UV

- To avoid the places rich in radioactive products (not to work or remain a long time exposed in the places where the radioactive x-rays or products are used or to approach certain mines with radioactive potential....)

- A continues monitoring (every 2 months) by an experienced dermatologist and an ophthalmologist. 

- Fast destruction of any suspect lesion. 

- To avoid the radiotherapy. 

- To avoid certain drugs which are likely to deteriorate the DNA (some antibiotics, products of general anesthesia, chemotherapy...)

- A balanced food rich in iron and vitamin D.

All these precautions make it possible to transform this severe, major and serious handicap in a light handicap compatible with a normal life. 

         8- Social security cover

The law allows to the children reached xeroderma pigmentosum to obtain the chart of handicap (Decree n° 2005-3086 of November 29 2005). 

The parents of the patient can profit from the one of mode of Social Security cover: 

- Card of indigence

- CNAM

While being covered of the one of these modes associated to the handicap card, the subjects reached are dealt with free in the public medical structures (consultation, hospitalization, care and drugs).

However the sun creams, the UV stop films, clothing and the sunglasses are not dealt with. 

Negotiations with the CNAM to improve the assumption of responsibility of these patients east incur. 

Certain parents profit from a complementary insurance which can deals with all the means of photoprotection. 

 Association helps the parents for obtaining the handicap card for their children and facilitates their fast access in the various public care centers of.  Contact us in the event of difficulty. 

       9-  Future prospects

The preventive measures have their limit in the management of the XP.  Research in the therapeutic field is directed towards the development of treatments etiologic aiming.

Several ways of research are in hand: 

-  The use of the NER proteins in the cream, but these products are unstable at the ambient temperature and require several applications per day.  Each protein is specific of a genetic group.  It is a specific treatment of only one genetic group but whose action is limited. 

-  The synthesis of the skin starting from the repaired patient keratinocytes by genetic engineering.  But the stability of the repaired keratinocytes is dubious.  It is necessary to change the whole skin of the child, which is very heavy, not easily realizable and not stripped of risk. 

- The introduction of repaired gene, transported by vectors shuttles contained in creams is in the course of in vitro evaluation.

- The graft skin taken from the normal subject (heterograft).  This technique has been just started in Egypt.  However, the change of the skin of the face is a heavy treatment.  In addition the use of the heterogeneous skin requires the addition of the immuno suppressors who are not indicated on this disease, because this product exhibit to the development of the skin cancers, it can be responsible for the appearance of a high number of carcinomas during the XP. 

- The fetal stem cells stocks constitute a new way of very interesting research.  Because, if one does not manage to completely solve the problem of these patients, an improvement partial of the quality of the dermal is possible what will make it possible to guarantee the skin stability and the integrity of the vision. 

Despite everything the difficulties, these techniques are promising. 

        10- Free UV Centers

As we carry out the investigations and the checking of different places, we inform the parents of the places where their children are in safety measures like degrees of vigilance. 

11- Social guide line

Under development

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