Xeroderma pigmentosum Made by : Khloud A.elbaset Under the supervision of Prof. Dr. Ahmad Bassiouny“It is the supreme art of the teacher to awaken joy in creative expression and knowledge.”"A teacher affects eternity he can never tell where his influence" stops. Henry Adams
Xeroderma pigmentosum:is an autosomal recessive genetic disorder of DNA repair in which the ability to repairdamage caused by ultraviolet (UV) light is deficient. In extreme cases, all exposure tosunlight must be forbidden, no matter how small. Multiple basal cell carcinomas(basaliomas) and other skin malignancies frequently occur at a young age in those with XP.In fact, metastatic malignant melanoma and squamous cell carcinoma are the two mostcommon causes of death in XP victims. This disease involves both sexes and all races, withan incidence of 1:250,000 and a gene frequency of 1:200. XP is roughly six times morecommon in Japanese people than in other groups. The most common defect in xeroderma pigmentosum is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER. If left unchecked, damage caused by ultraviolet (UV) light can cause mutations in individual cells DNA. If tumor suppressor genes or proto oncogenes are affected, the result may be cancer. Patients with XP are at a high risk for developing skin cancers, such as basal cell carcinoma, for this reason. Normally, damage to DNA in epidermal cells occurs during exposure to UV light. The absorption of the high energy light leads to the formation of pyrimidine dimers, namely cyclobutane-pyrimidine dimers and pyrimidine-6-4-pyrimidone photoproducts. In a healthy, normal human being, the damage is first excised by endonucleases. DNA polymerase then repairs the missing sequence, and ligase "seals" the transaction. This process is known as nucleotide excision repair. Xeroderma pigmentosum, a rare human skin disease, is genetically transmitted as an autosomal recessive trait. The skin in an affected homozygote is extremely sensitive to sunlight or ultraviolet light. In infancy, severe changes in the skin become evident and worsen with time. The skin becomes dry, and there is a marked atrophy of the dermis. Keratoses appear, the eyelids become scarred, and the cornea ulcerates. Skin cancer usually develops at several sites. Many patients die before age 30 from metastases of these malignant skin tumors. Ultraviolet light produces pyrimidine dimers in human DNA, as it does in E. coli DNA. Furthermore, the repair mechanisms are similar. Studies of skin fibroblasts from patients with xeroderma pigmentosum have revealed a biochemical defect in one form of this disease. In normal fibro-blasts, half the pyrimidine dimers produced by ultraviolet radiation are excised in less than 24 hours. In contrast, almost no dimers are excised in this time interval in fibroblasts derived from patients with xeroderma pigmentosum. The results of these studies show that xeroderma pigmentosum can be produced by a defect in the excinuclease that hydrolyzes the DNA backbone near a pyrimidine dimer. The drastic
clinical consequences of this enzymatic defect emphasize the critical importance ofDNA-repair processes. The disease can also be caused by mutations in eight othergenes for DNA repair, which attests to the complexity of repair processes.Aetiology:XP is an autosomal recessive disorder with 100% penetrance and can result frommutations in any one of eight genes. The products of seven of these genes (XP-Athrough G) are involved in the repair of ultravioletinducedphotoproducts in DNA by the process of nucleotide excision repair (NER) . TheXPC and XPE proteins are needed to recognise the photoproducts inDNA. XPB and XPD are part of a protein complexTFIIH, which opens up the structure of the DNA around the site of the photoproduct.XPA protein verifies that proteins are in the correct position and thenthe nucleases XPG and XPF cut the DNA on either side of the damage, so that thedamaged section can be removed and replaced with intact DNA. There are twobranches of NER, designated transcription- coupled repair, which rapidly repairs areasof DNA that are “active” and being transcribed into RNA, andglobal genome repair, which repairs damage in the rest of the genome more slowly.XPC and XPE proteins are only required for the latter branch, whereas all the otherXP proteins are required for both branches. Probably as a consequence of this,patients defective in the XPC or XPE genes do not, in general, have the extremesunburn reactions or neurological abnormalities described above. Defects in theeighth XP gene do not affect NER. Instead these so-called XP variants (XP-V) haveproblems replicating DNA containing ultraviolet-induced damage. DNA replication iscarried out by DNA polymerases. The DNA polymerases that normally replicateDNA cannot deal with damage in the DNA template and specialised polymeraseshave to be employed to get past the damage (translesion synthesis). For UVdamage, the cell uses DNA polymerase h, encoded by the gene POLH and it is thisgene that is mutated in XP-V patients . Like XP-C and XP-E patients, XP-Vpatients rarely have extreme sunburn reactions or neurologicalproblems. The genes, chromosomal locations and the functions of the protein productsare listed in Table 1. The molecular defects in XP cells result in a greatlyelevated induction of mutations in sun-exposed skin of affected individuals. Thisincreased mutation frequency probably accounts for the pigmentation changes and theskin cancers. Indeed examination of mutations in the p53 gene in tumours from XPpatients reveal p53 mutations characteristic of UV exposure in the majority oftumours . The molecular defect also results in increased UV-induced lethality, whichvaries substantially between individuals. The level of cell killing is lessin individuals mutated in the XPC and XPE genes and with some hypomorphicmutations in other XP genes, because of the residual functional DNA repair. Theseindividuals also do not show the sunburn reaction found in other groups. This has ledto the suggestion that the extreme sunburn reaction is likely to be a consequenceof cell death. The causes of the neurological abnormalities are poorly understood.They are clearly not connected with exposure to UV light. Current theories suggestthat oxidative DNA damage is generated during normal metabolismin the central nervous system, and that some types of this damage must be repaired byNER . In the absence of functional repair, the lesions persist andresult in neuronal death.
Disorder Subdivisions Xeroderma Pigmentosum, Type A, I, XPA, Classical Form Xeroderma Pigmentosum, Type B, II, XPB Xeroderma Pigmentosum, Type C, III, XPC Xeroderma Pigmentosum, Type D, IV, XPD Xeroderma Pigmentosum, Type E, V, XPE Xeroderma Pigmentosum, Type F, VI, XPF Xeroderma Pigmentosum, Type G, VII, XPG Xeroderma Pigmentosum, Dominant TypeSigns and symptoms :The disease usually progresses through 3 stages. The first stage occurs around 6months after birth (skin appears normal at birth) with the following signs: Areas exposed to the sun such as the face show a reddening of the skin with scaling and freckling. Irregular dark spots may also begin to appear. These skin changes progress tthe neck and lower legs. In severe cases the trunk may be involved. Over the winter months these changes may diminish.Continued sun exposure will lead to the second stage, which is characterised bypoikiloderma. This is where there are irregular patches of lightened or darkened skin,a spider web-like collection of blood spots and vessels are seen through the skin, andthere is thinning of the skin.The third stage is the development of solar keratoses and skin cancers. These mayoccur as early as age 4-5 years and are more prevalent in sun-exposed areas such asthe face. The common skin cancers, basal cell carcinoma, squamous cell carcinoma,and melanoma, occur significantly more often in people with xerodermapigmentosum. Other complications, including eye and neurological problems are alsoapparent in patients with xeroderma pigmentosum.Eye problems occur in nearly 80% of xeroderma pigmentosum patients. Eyes become painfully sensitive to the sun (photophobia). Eyes easily irritated, bloodshot and clouded. Conjunctivitis may occur. Non-cancerous and cancerous growths on the eyes may occur.Neurological problems occur in about 20% of xeroderma pigmentosum patients. These can be mild or severe and include spasticity, poor coordination, developmental delay, deafness, and short stature. May develop in late childhood or adolescence. Once they do occur they tend to worsen over time.
Exams and TestsThe doctor will perform a physical exam and ask if you have a family history ofxeroderma pigmentosa.An eye exam may show: Clouding of the cornea Keratitis Lid tumors BlepharitisThe following tests can help diagnose the condition in a baby before the birth:1.Amniocentesis :Amniocentesis removes a small amount of fluid from the sac that surrounds the babyin the womb (uterus). It is usually done in a doctors office or medical center. You donot need to stay in the hospital. You will probably have a pregnancy ultrasound first.This helps your health care provider find out exactly where the baby is in your womb.Numbing medicine is then rubbed onto part of the your belly. Sometimes, themedicine is given through a shot in the skin on the belly area. The health careprovider inserts a long, thin needle through your belly and into the womb. A smallamount of fluid is removed from the sac surrounding the baby.2.Chorionic villous sampling3.Culture of amniotic cellsThe following tests can help diagnose the disorder after the birth of the child: Culture of skin fibroblasts Skin biopsy
Treatment :There is no cure for xeroderma pigmentosum. The main goal of treatment is to protectoneself from UV exposure and thus prevent the damaging effects it can have on theskin. Xeroderma pigmentosum patients should follow these general precautionarymeasures: Sun avoidance methods o Wear protective clothing (long sleeves and pants, shirts with collars, tightly woven fabrics that dont let light through), hats (wide-brimmed) and eyewear (specifically made to protect from UV rays) o Use sunscreens with SPF of 30 or greater: apply to all exposed areas o Outdoor activities should be avoided and kept to a minimum if at all necessary o Restrict outdoor activities to night time Undergo frequent skin examinations by someone who has been taught to recognise signs of skin cancer. Report to your doctor any suspicious spots or growths immediately. Examination by a dermatologist at least every 3 to 6 months. Any suspicious growths can be biopsied. Skin cancers are usually excised. Frequent eye examinations by an ophthalmologist. Yearly testing (through to age 20) for potential neurological problems.Solar keratoses may be treated by cryotherapy or 5-fluorouracil cream. Somexeroderma pigmentosum patients who have had many skin cancers may be prescribedisotretinoin. This is a vitamin A derivative that may prevent formation of newcancers.Limbal stem cell deficiency and xeroderma pigmentosum:(http://www.nature.com) : To report limbal stem cell deficiency in a case of xeroderma pigmentosum that wassuccessfully managed by limbal transplantation and penetrating keratoplasty.Case reportA healthy 28-year-old male diagnosed with xeroderma pigmentosum presented withdiminished vision in both eyes, of several years duration. There was no prior historyof exanthematous fever. He had been treated elsewhere for malignant lesions of theskin and nose. In the left eye, his best visual acuity was 20/400. An adherent leucomawas present in the lower one-third of the cornea with 120° conjunctivalization (Figure1a). In the right eye, his vision was reduced to accurate projection of rays due to adense vascularized corneal scar. Both eyes had normal lids, conjunctiva, and adequatetear meniscus. Dense corneal scars precluded the view of the remaining anterior andposterior segments. Systemic examination revealed no abnormalities other than hyper-and depigmented lesions of the skin in exposed areas. The differential diagnosis in the
left eye included ocular surface squamous neoplasia and partial stem cell deficiency.Impression cytology revealed goblet cells in the inferior quadrant (Figure 2a) withsquamous metaplasia in other areas of the cornea (Figure 2c). Adequate goblet cellswere noted on the conjunctival surface (Figure 2b). There was no evidence ofdysplasia in the epithelial cells. He was diagnosed as having partial limbal stem celldeficiency, and was advised a living-related conjunctival limbal allograft. Hisunaffected father volunteered to be the donor. After informed consent, the donortissue was transplanted inferiorly over 0600 h. Histopathology of the excised pannusconfirmed conjunctivalization of the cornea and excluded dysplastic changes (notshown). We followed the immunosuppressive regimen described by Tsubota.4 After 3months when the ocular surface was stable (Figure 1b), a corneal transplant was done.At the last visit, a year following penetrating keratoplasty, his best visual acuity was20/40. The corneal graft was clear and the inferior limbal graft has been accepted ( Figure 1figure 2Conclusion In xeroderma pigmentosum, there is a deficiency of the enzymes responsiblefor repairing UV light-induced DNA damage.Persistence of unrepaired DNA resultsin somatic mutations, leading to neoplasias. The manifestation of limbal stem celldeficiency in this patient prompted us to speculate that exposure of the limbal stemcells to UV radiation might lead to permanent damage or dysfunction of these cells, oralteration of the stromal microenvironment.Our patient had features of partial LSCD with 120° conjunctivalization inferiorly.Since ocular surface squamous neoplasia is frequently noted in XP patients,impression cytology aided in exclusion of this entity. The presence of stem celldeficiency could result in a failed corneal graft; therefore, we decided to do a limbaltransplant, followed by penetrating keratoplasty. Partial LSCD can be managedconservatively, by repeated mechanical debridement, or amniotic membranetransplantation.However, the success of these procedures is determined by thepresence of healthy residual limbal stem cells. In a patient of xeroderma pigmentosumwith high susceptibility to UV radiation-induced damage we anticipated a permanentdamage to the residual limbal stem cells and therefore preferred a living-related
conjunctival limbal allo-transplant. We support the belief that a penetratingkeratoplasty after restoration of ocular surface stability is more beneficial, as has beenadvocated earlier. A simultaneous procedure may result in delivery of less antigenicload to the recipient by utilizing the same donor for both limbal and cornealtransplants, and in preservation of the transient amplifying cells. The poor long-termoutcome following simultaneous limbal transplantation and penetrating keratoplastyhas prompted the recommendation of a staged procedure with a 1-year gap. Though astable ocular surface and good vision have been attained following these surgeries, theinherent pathology remains. Photoprotective measures have been advocated and thepatient has been cautioned about the possible development of ocular or cutaneousmanifestations of XP described earlier. Indefinite immunosuppression remainsnecessary to ward off limbal allograft rejection. The patient is on low doses ofcyclosporine ensuring serum trough levels of 50 ng/ml, regular assessment of renaland hepatic parameters, and on close follow-up in conjunction with an internist.In summary, limbal stem cell deficiency may be one of the ocular manifestations ofxeroderma pigmentosum, necessitating a high degree of suspicion and early surgicalintervention to prevent visual disability.Researchers in the United States and throughout the world are learning aboutX P andtrying to correct the DNA r e p a i rdefect in laboratory-grown cells frompatients withXP. The genes causing mosttypes of XP have been identified. Manylaboratories in theUS, Europe, andJapan are studying XP genes and tryingto understand what they do.Clinical studies on skin cancer prevention with oralmedications and evaluatingpatients withunusual features are also being conducted at the National Institutes ofHealth.