Xeroderma pigmentosa

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Xeroderma pigmentosa (XP) is a rare autosomal recessive skin disease that was first discovered in the late 1800's. This autosomal recessive disease is often associated with high incidences of skin cancer as well as apoptosis of the skin, damage to the eyes, and neurological disorders. It is believed that such conditions are induced by mutations in the nucleotide excision repair mechanism that renders it defective. Without the nucleotide excision repair mechanism working properly, the individual is extremely susceptible to UV damage of their DNA. Furthermore, loss in effectiveness of this system can induce p53 damage which allows cancer to more easily proliferate in damaged tissues. Due to the rarity of this condition, there is a lack of complete understanding of the mechanism that induces the damage in the excision repair mechanisms that ultimately aids in the development of the condition. Treatment options are fairly limited due to the lack of understanding, however, individuals who avoid UV light via protective clothing and have regular skin and neurological checkups can lead fairly normal lives. Below details more on the discovery, the symptoms and the treatment options of the rare disease xeroderma pigmentosa. A diagram displaying the mechanism of autosomal recessive inheritance can be seen as well.


en. Google Images(Accessed on Nov 30,2009)


In 1880 the book Pathologie und Therapie der Hautkrankheiten in Vorlesungen für praktische Ärzte und Studierende (Pathology and Therapy of the Skin Diseases in Lectures for Practical Physicians and Students) was published. In this book, Moritz Kaposi describes the condition of XP and he is credited with the description of XP. Along with that, “The Father of Dermatology” Ferdinand Ritter von Hebra and his mentee Kaposi first described XP clinically in 1874 and described it as a syndrome of sunlight hypersensitivity, freckles and skin cancers [9]. It wasn’t until Kaposi’s book that XP got its name. A few years later in 1883 Albert Neisser was the first to notice the neurological abnormalities that occurred with XP [10]. It wasn’t until 1932 that De Sanctis and Cacchione associated XP with mental retardation, dwarfism and gonadal hypoplasia by studying three brothers that all had the same conditions. Now when XP occurs with CNS abnormalities it is sometimes referred as De Sanctis-Cacchione syndrome [10]. All of these scientists have been accredited with some type of advancement or discovery of XP that has been significant enough to the description of XP.

Symptoms of the Disease

The symptoms of XP can be mild, moderate, or severe depending upon the gene that is affected by the disease. Children with the disease are phenotypically identical to normal children at birth. Symptoms are first noted within the first 1-2 years of the afflicted child’s life, and are usually characterize by a severe sunburn that develops upon acute sunlight exposure. Many of the patients who are born with XP will develop squamal or basal cell skin cancer by age 8 [1]. Other skin conditions associated with the disease include an increased amount of freckles, xerosis (dry skin), hyper and hypopigmentation, abnormally rough skin, and painful apoptosis of the skin. The UV-exposed portions of the eye are also likely to develop cancer and may lead to full or partial blindness [3][1]. Areas of the eye that are at risk include the cornea, conjunctiva, eyelids, and iris [3]. Neurological effects associated with the disease include loss of hearing, cognitive impairment, axonal neuropathies and enlarged or thinning ventricles in the cortex [3].

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en. Google Images(Accessed on Nov 18,2009)

Mechanism of Action

Xeroderma pigmentosum is an exceedingly rare, autosomal recessive skin disease, that is characterized extreme sensitivity to both UV-radiation and acute sun exposure [1][4]. Both parents must be carriers of a defective gene for the phenotype to be passed on to their children who each have a ¼ chance of contracting the disease. Those who are born with the disease inherit a faulty nucleotide excision repair system (NES) [3]. A functional DNA nucleotide excision repair recognizes kinks in the normal DNA incurred from thymine dimers caused by UV exposure [2]. After the NES recognizes the thymine dimer, the damage is excised via endonucleases and sealed by ligase [8]. People with xeroderma pigmentosum are unable to ligate the thymine dimer out of the cellular DNA and repair damage caused by UV-light exposure before the cell divides. Individuals with xeroderma pigmentosum are therefore 1000 times more likely to develop ocular neoplasms as well as basal and squamous cell carcinoma than a person expressing the normal phenotype. Individuals with xeroderma pigmentosum who develop either type of skin cancer are more likely to contain mutations in the p53 tumor suppressor gene that is responsible for preventing genome mutation [1]. Thus, a person that has xeroderma pigmentosum and a defective p53 gene is much more likely to contract cancer and less able to prevent it from metastasizing. There are eight known types of xeroderma pigmentosum (A-H) and one variant (V) that is characterized by mutations in 9 different genes, all of which result in the same general symptoms [3][1].

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en. Google Images(Accessed on Nov 18,2009)

Early Detection and Treatment Options

To detect xeroderma pigmentosa a doctor may first perform a number of preliminary examinations to determine if one is susceptible to developing the disease provided it can run in families. One way in which doctors may screen for this rare disease is through an eye examinination. Indications related to the eye, which can be attributed to this disease, include clouding of the cornea, keratitis, lid tumors and blepharitis. Furthermore, doctors can also perform a variety of examinations to determine if the condition resides in a baby prior to birth. Such tests include amniocentesis, chronic villous sampling, and culture of amniotic cells. Post birth culture of skin fibroblasts as well as skin biopsies can be performed to further test for the presence of the disease. Overall, this disease is generally diagnosed in the first of second year of infancy. [5]

Being that it is quite a rare disease, there is currently no treatment option for xeroderma pigmentosa that completely cures this ailment. Furthermore, provided the ailment is so rare, one of the only true techniques that could offer a cure would be gene therapy provided the disease is based on through alleles. However, gene therapy is expensive and still a complex and not fully understood field. Provided gene therapy is not a true cure to those who suffer xeroderma pigmentosa, the main aim of the current treatment options is to protect oneself from UV exposure and thus prevent the damaging effects it can have on the skin. Some ways in which those suffering from xeroderma pigmentosa is to avoid sun exposure through a number of different means. Some of the ways of avoidance include wearing protective clothing such as long sleeves, pants, shirts with collars, tightly woven fabrics, hats and eye wear. Individuals should also use sunscreens with an SPF of 30 or greater, and should apply it to all exposed areas of the body. Furthermore, if possible, outdoor activities should be avoided and kept to a minimum, or the outdoor activities should be carried out at night rather than in the daylight. Lastly, protective film should be placed on the windows, and standard incandescent light bulbs should be used indoors provided they do not emit UV as some other common household light bulbs do. [6]

Beyond wearing protective clothing and monitoring the amount of sun exposure when performing outdoor activities, xeroderma pigmentosa patients should also undergo frequent skin examinations about every three months by dermatologists to recognize signs of skin cancer. Patients should also undergo frequent eye examinations by an ophthalmologist. Yearly testing, up through adolescence, is another part of the treatment for the disease as a way to monitor potential neurological problems. Furthermore, individuals who suffer this disease should also take vitamin D supplements given that restricted sun exposure induces a vitamin D deficiency. [5]

In situations in which dermatological harm has already taken place due to the disease, various therapies can be utilized. Cryptherapy or 5-flurouracil cream for example can treat solar keratoses. In cases where the xeroderma pigmentosa patient has suffered from many skin cancers, they may be prescribed isotretinoin, which is a vitamin A derivative that may be able to prevent formation of new cancers. [5]

Below is a picture showing the latest protective clothing available to those who suffer from xeroderma pigmentosa. As can be seen there are optional full body protective suits (A) or facial masks (B)


en. Google Images(Accessed on Nov 18,2009)


The prognosis for the disease is slightly dismal provided it is a rare disease. Given its rarity, its mechanism of action is not well enough understood to allow medical professionals to offer cures for the ailments it induces, rather only medicinal remedies to help alleviate those aliments. For those who have the disease, it is often difficult to treat the variety of skin cancer that develops. Most patients who suffer xeroderma pigmentosa die at an early age from skin cancer, yet if diagnosed early enough, the individual has a smaller risk of suffering several neurological symptoms as well as overcoming cancer. Overall , with avoidance of UV rays and early detection of cancer, a relatively normal life span can ensue. [7]

Current Research

Current research for XP is now focused on curing the disease rather than treatment. The only available treatment for XP is UV exposure avoidance. Some research for XP is looking into gene therapy as a cure for XP patients. As of right now the studies using gene therapy are still in pre-clinical trials but are showing promise into becoming clinical trials. The gene therapy currently being looked at is one that uses the skin to deliver the genetic material to the affected cells. The way the skin is used is by applying a topical treatment that targets the proteins involved in DNA repair with DNA repair enzymes known as liposomes [11]. Along with this retrovirus or recombinant retroviral vectors can be used effectively to introduce the gene missing in XP patients, with the gene being produced and expressed for generations later in the cells [11]. In trying to reproduce skin in vitro test were used in testing the keratinocytes and with the gene being introduced and being expressed it was found that the keratinocytes corrected themselves and produced skin cells [11]. This is really important because it shows that with the gene missing and then being introduced and expressed the keratinocytes responded positively, showing a possible chance in them repairing damaged skin cells in XP patients. For in vivo lentiviruses can be used to deliver the needed genes without causing a high immune response by the host [11]. This is important so that the virus isn’t destroyed before it can affect all cells. Along with that lentiviruses can affect cells that are not dividing, which is important because with XP all cells needed to be treated due to a single cells ability to cause cancer [11]. Lentiviruses haven’t been used in XP test but in HIV testing carrying the same genes to cells as those needed in XP and these test have shown promise for a future in helping XP [11]. A more promising virus has been found to help correct skin damage and produce resistance to UV light in XP cells at levels of wild type [11]. Adenoviruses are the type of virus that produces this positive feedback and an even more promising thing is that adenoviruses have been used in pre-clinical trials with mice and the mice treated with adenoviruses have shown the same skin damage being repaired and a produced resistance to UV light [11].

There is one treatment that has found to be effective at reducing the amount of new developed skin lesions and cancers in XP patients. This treatment uses T4 endonuclease V as a bacterial DNA repair enzyme, this enzyme increases the repair of sunlight damaged cells [12]. In this experiment T4N5 lotion was given to 20 people and a placebo was given to 10 others, these patients were told to apply the lotions daily for the next year with three month checkups [12]. The three month checkups were used to measure new actinic keratoses and basal-cell carcinomas, which were removed each visit [12]. The study found that in those who used the T4N5 lotion showed a significant decrease in new actinic keratoses and basal-cell carcinomas compared to those that took the placebo lotion [12]. The decrease for new actinic keratoses was 68% and 30% in the basal-cell carcinomas in the T4N5 lotion users compared to the placebo users [12].

More current research is being conducted on the DenV T4 endonuclease, a DNA repair enzyme derived from becateria that is currently under developement for use as topical liposome-containing preparation. DenV T4 has been reported to reduce the frequency of new keratoses and basal cell carcinomas in individuals with XP [3]. This treatment is not yet approved by the US Food and Drug Administration.


[1] Copeland NE, Hanke CW, Michalak JA. “The molecular basis of xeroderma pigmentosum”. Department of Dermatology, Indiana University. 1997 Jun;23(6):447-55.

[2] Klar, Essen LO. “Light-driven DNA repair by photolyases”. Cell Mol Life Sci. 2006 Jun;63(11):1266-77.

[3] Kraemer, H. Kenneth, “ Xeroderma Pigmentosum”. Center for Cancer Research, National Cancer Institute. Apr. 22, 2008.

[4] Josephy, P. David and Mannervik, Bengt. Molecular Toxicology, 2nd Edition. Oxford University Press, 2006.

[5] NZDSI. Xeroderma pigmentosum. 2009. <http://dermnetnz.org/systemic/xeroderma-pigmentosum.html>

[6] Plus, Patient. Xeroderma Pigmentosum (XP). 2009. <http://www.patient.co.uk/doctor/Xeroderma-Pigmentosum.htm#at>

[7] Xeroderma pigmentosa. 2009. <http://www.nlm.nih.gov/medlineplus/ency/article/001467.htm>

[8] Stine, E. Karen and Brown, M. Thomas. Principles of Toxicology, 2nd Edition. CRC Press, 2006.

[9] Anttinen, Anu et al.Neurological symptoms and natural course of xeroderma pigmentosum. June 21, 2008. <http://brain.oxfordjournals.org/cgi/content/full/awn126v1>

[10] Hedera, Peter. Xeroderma Pigmentosum. Jan 8, 2009. <http://emedicine.medscape.com/article/1177889-overview>

[11] M. Menck. “On the Search for Skin Gene Therapy Strategies of Xeroderma Pigmentosum Disease.” Current Gene Therapy, v. 7 issue 3, 2007, p. 163-174.

[12] Yarosh, Daniel. “Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study.” Lancet, v. 357 issue 9260, 2001, p. 926-929.