Xeroderma Pigmentosum (XP) is a rare, hereditary disease where patients experience skin hypersensitivity to ultraviolet (UV) light. It is characterized by dry skin, increased freckling as well as patches of hypo pigmentation and signs of premature aging. Affected individuals are particularly susceptible to developing actinic keratoses and squamous and basal cell carcinomas due to a defect in or lack of nucleotide excision repair (NER). Eye and neurological problems are likely to occur over time but neurological defects only develop those with the greatest impairment of DNA repair.
Squamous cell carcinoma skin cancer. Patients with XP have an extreme risk of contracting skin cancer.
There are currently 8 known complementation groups (XPA through to XPG and XPV), all with corresponding defects in their gene products. These groups differ in frequencies, with XPC being fairly common and XPE being relatively rare and severity of the disease, with XPG being severe and XPF being mild.
XP occurs worldwide, with the prevalence of 1 in 250,000 in the general population. It appears to affect men and women equally across all races. However Japan has a higher frequency of the disease with 1 in 40,000 having XP with XPA being the most common variant. The prevalence in the U.S is also 1 in 250,000.
Being a genetic disease, familial history and consanguinity increases the chance of inherited. An estimated 80% of XP sufferers will develop eye abnormalities and 30% will develop neurological disorders.
Whilst mutations occurring in any one of the XP genes can lead to the disease, splice mutations have been found to be more common in the XPA and XPC complementation groups. An estimated 1% of the Japanese population has a splice mutation in exon 3 of the XPA gene and on the other end of the scale; only 2 individuals have been reported to carry mutations in the XPE gene. XPC is the most common form of XP amongst Americans.
XP is an autosomal recessive disease, which means the individual with the disease has inherited two copies of the mutated gene (one from each parent) that causes XP. If only one XP gene is inherited then that person carries of the disease gene but is not affected by it. Having two XP genes causes skin cells to be hypersensitive to UV light, resulting in a range of symptoms.
Essentially, the symptoms are caused by faulty DNA repair mechanisms in the skin. A defect in nucleotide excision repair (NER) results in an inefficient DNA repair mechanism in XP. Sun exposure damages DNA. As the cells are unable to repair it, the DNA remains damaged, which leads to cell death or the development of cancerous cells.
XP can be separated into 8 different groups based on what and where the mutation is. Each can vary in symptoms and have different susceptibilities to developing certain symptoms. Neurological abnormalities have only been seen in XP patients with mutations in the complementation groups XPA, XPB, XPD and XPG.
DNA damage and NER in-depth
The majority of DNA damage is induced by UVB light but recently UVA rays have also been linked to the same mutations. The most common forms of DNA damage occurs via the cross linking of adjacent pyrimidines resulting in the formation of cyclobutane pyrimidine dimers (CPDs) and 6-pyrimidine-4-pyrimidone photoproducts. Mutations caused are almost always located at the interface of pyrimidine-pyrimidine interactions, characterized by C to T, C to C or T to T sequence.
NER repairs mutations caused by UV light. NER can be divided into two subtypes; global genome repair (GGR) that can function throughout the entire genome and transcription-coupled repair (TCR) that is restricted to the transcribed strand of active genes. 7 out of 8 groups of XP genes are involved with NER and if one or more of those genes are mutated, the repair process is disrupted. XPV is a variant of XP and does not affect NER. Instead, there is a defect in DNA polymerase ? which alters post replication repair. NER functions by removing and replacing damaged DNA with newly synthesized DNA. It begins with a detection phase, performed in GGR by a complex involving the product of the XPC gene and another factor. In addition, the XPA gene product has been reported to have an affinity for damaged DNA. Therefore, it is likely that XPA has a role in the damage detection phase. When DNA damage is detected, Transcription factor II H (TFIIH) helicases unwind the DNA. The XPG gene product forms an open complex called the ‘pre-incision complex’. XPB and XPD gene products are part of a 9-subunit protein complex (TFIIH) that is also needed for the open complex formation. After the assembly of the pre-incision complex, single strand incisions are made in the damaged strand by complexes involving the XPG and XPF genes which encode endonucleases. Subsequently the damaged DNA is removed and the resulting gap is filled in with new DNA by the DNA polymerases and DNA ligase.
The NER genes that encode XPB and XPD are a part of the TFIIH basal transcription factor and are essential to life.
Three stages of XP
At birth, the skin appears normal. Onset of the disease usually begins at around 6 months and generally progresses through 3 stages.
Stage 1 is usually demonstrated by about 6 months with the following signs:
- Areas exposed to the sun show diffuse erythema and freckling;
- Irregular dark spots may begin to appear;
- Xerosis and scaling may follow.
Continuous sun exposure will lead to stage 2.
Stage 2 is presented as poikiloderma, which is a result of an accumulation of actinic changes. Often, it appears at the median age of 2 and is characterized by the following:
- Solar lentigines;
- Skin atrophy and thinning;
- Patches of hypopigmentation and hyperpigmentation.
Stage 3 is the development of actinic keratoses and skin cancer. This stage may occur as early as 4-5 years or as late as adolescence.
XP normally presents early after birth, with it extreme sun sensitivity being detected at the age of 1-2 years. Freckling from sun exposure typically occurs in young children with XP which rarely occurs in normal children. The accumulation of DNA damage results in many other symptoms including:
- Diffuse redness
- Sunburn from minimal sun exposure
- Dry, scaly skin
- Thin skin
- Patches of discolored skin
Individuals with XP have a 1,000 fold risk of developing skin cancer then the normal population. It will typically manifest before the age of 20 and is common in XP. Skin cancers are more prevalent in sun exposed patches of skin such as the face, neck and forearms. There is also a 10 – 20 fold increase in the likelihood of developing cancer or tumors affecting internal organs.
Any structure of the eye can develop abnormalities from UV exposure. Many individuals experience:
- Photophobia – pain/discomfort from light
- Loss of vision
- Loss of eyelashes
- Blepharitis – inflammation of the eyelids
- Keratits – inflammation of the cornea
Patients also have an increased risk of developing cancerous or non cancerous growths in the eye
Neurological disorders mainly occur due to neuronal degeneration and are only seen in particular subsets of XP with symptoms varying in severity. The most common abnormality is a loss of high-frequency hearing. Other neurological defects include poor co-ordination, decreased reflex responses (hyporeflexia), progressive mental retardation, seizures and spasticity.
The NER pathway involves many genes including the XP genes. Because of this, other rare disorders that have defects in NER such as Trichothiodystrophy (TTD) and Cockayne syndrome (CS) can be mistaken for XP and vice versa. The clinical features of these patients have some similarities and but also have marked differences. While XP patients have 1000-fold increase in risk of developing to skin cancer, TTD and CS patients don’t. Several of the genes involved in NER also affect somatic growth and developments, meaning some patients have growth retardation and immature sexual development. Progressive loss of hearing is also a feature of XP and CS. Neurological abnormalities in XP are primarily due to neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the neurons in the brain which are unrelated to sun exposure but could be due to faulty DNA repair mechanisms.
Being a genetic disorder there is no curative treatment. Preventative therapy must begin immediately upon diagnosis, which is usually in childhood. This means minimal exposure to the sun where possible and using a combination of UV protection such as complete coverage from the sun with clothing and hats, UV-protective glasses and constant application of sunscreen (SPF30+ or above is recommended).
Manifestations of the condition are treatable but there is no guarantee that the symptoms will not recur. Larger areas of sun damaged skin may be removed by dermabrasion to remove the superficial layers of skin. This allows for regeneration of the population of skin cells that were not affected by UV rays.
Avoidance of the sun is crucial in preventing the symptoms seen in the skin. However, XP progresses to skin cancer then standard anti-cancer therapies would be used such as topical 5-fluorouracil, freezing with liquid nitrogen or surgical excision of the cancerous cells. If other malignancies develop they would be treated in the same manner as cancer patients without XP. Physicians may also prescribe medications such as high-dose oral Isotretinoin to prevent new cancers from forming, but there are toxic side effects to this treatment.
It is also recommended that frequent skin examinations are performed in order for early detection of any new lesions and monitor any growths for changes in shape, color and size.
Corneal transplantation has been successful in restoring vision to those with corneal opacities and severe keratitis, however immunosuppressive therapy is necessary in order to prevent rejection and can increase the chance of infections. Abnormal growths in the eye and tissue surrounding the eye would be treated surgically.
Neurological treatment is restricted due to lack of known treatments as well as fact that many drugs cannot get into to brain or they would cause too many unwanted side effects. Drug use for these symptoms is limited to anticonvulsants such as Phenytoin to prevent seizures.
Recently novel enzyme and gene therapies have been developed based on the etiology of XP. T4N5, a bacteriophage T4 endonuclease 5 has been utilized for topical therapy in a liposomal lotion. It is able to diffuse into the nucleus without a nuclear localization sequence and enables NER to recognize and cleave CPDs using light energy. This lotion holds significant promise for those with XP, receiving a Fast Track designation from the FDA.
Gene therapy using recombinant retroviruses carrying additional DNA repair genes to correct damaged cells and restore the capacity of NER are still being developed with aims of validating the procedure.
Due to its genetic basis, XP cannot be prevented. Carriers of the disease are asymptomatic and need not worry. Preventative therapy can slow down the progression of the disease and must begin immediately upon diagnosis, which is usually in childhood by the age of 2. This means minimal exposure to the sun where possible and using a combination of UV protection such as complete coverage from the sun with clothing and hats, UV-protective glasses and constant application of sunscreen (SPF30+ or above is recommended).
As individuals with XP have cells that are hypersensitive to environmental mutagens, cigarette smoke and alcohol should be avoided. It has also been reported that some individuals with XPV are sensitive to caffeine and it increases the amount of defective DNA repair.
Many patients with XP die at an early age from skin cancers and less than 40% will live past the age of 20. However, if a person is diagnosed early, does not have severe neurological symptoms and takes all the precautionary measures to avoid exposure to UV light, they may survive beyond that age.
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