Xeroderma pigmentosum is a rare genetic disorder that causes extreme sun sensitivity and a high risk of skin cancer. It is caused by defects in DNA repair genes that prevent the repair of UV damage to skin cells. The main symptoms are severe sunburn, freckling, dark spots on sun-exposed skin from a young age, and frequent development of skin cancers like basal cell carcinoma. There is no cure, so treatment focuses on strict sun avoidance and frequent skin screening. Advanced cases can also involve eye and neurological problems.

1. Xeroderma pigmentosum
Made by : Khloud A.elbaset
Under the supervision of
Prof. Dr. Ahmad Bassiouny
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2. Xeroderma pigmentosum:
is an autosomal recessive genetic disorder of DNA repair in which the ability to repair
damage caused by ultraviolet (UV) light is deficient. In extreme cases, all exposure to
sunlight 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 most
common causes of death in XP victims. This disease involves both sexes and all races, with
an incidence of 1:250,000 and a gene frequency of 1:200. XP is roughly six times more
common 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 cell's 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

3. clinical consequences of this enzymatic defect emphasize the critical importance of
DNA-repair processes. The disease can also be caused by mutations in eight other
genes for DNA repair, which attests to the complexity of repair processes.
Aetiology:
XP is an autosomal recessive disorder with 100% penetrance and can result from
mutations in any one of eight genes. The products of seven of these genes (XP-A
through G) are involved in the repair of ultravioletinduced
photoproducts in DNA by the process of nucleotide excision repair (NER) [5]. The
XPC and XPE proteins are needed to recognise the photoproducts in
DNA. XPB and XPD are part of a protein complex
TFIIH, 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 then
the nucleases XPG and XPF cut the DNA on either side of the damage, so that the
damaged section can be removed and replaced with intact DNA. There are two
branches of NER, designated transcription- coupled repair, which rapidly repairs areas
of DNA that are “active” and being transcribed into RNA, and
global 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 other
XP 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 extreme
sunburn reactions or neurological abnormalities described above. Defects in the
eighth XP gene do not affect NER. Instead these so-called XP variants (XP-V) have
problems replicating DNA containing ultraviolet-induced damage. DNA replication is
carried out by DNA polymerases. The DNA polymerases that normally replicate
DNA cannot deal with damage in the DNA template and specialised polymerases
have to be employed to get past the damage (translesion synthesis). For UV
damage, the cell uses DNA polymerase h, encoded by the gene POLH and it is this
gene that is mutated in XP-V patients . Like XP-C and XP-E patients, XP-V
patients rarely have extreme sunburn reactions or neurological
problems. The genes, chromosomal locations and the functions of the protein products
are listed in Table 1. The molecular defects in XP cells result in a greatly
elevated induction of mutations in sun-exposed skin of affected individuals. This
increased mutation frequency probably accounts for the pigmentation changes and the
skin cancers. Indeed examination of mutations in the p53 gene in tumours from XP
patients reveal p53 mutations characteristic of UV exposure in the majority of
tumours . The molecular defect also results in increased UV-induced lethality, which
varies substantially between individuals. The level of cell killing is less
in individuals mutated in the XPC and XPE genes and with some hypomorphic
mutations in other XP genes, because of the residual functional DNA repair. These
individuals also do not show the sunburn reaction found in other groups. This has led
to the suggestion that the extreme sunburn reaction is likely to be a consequence
of cell death. The causes of the neurological abnormalities are poorly understood.
They are clearly not connected with exposure to UV light. Current theories suggest
that oxidative DNA damage is generated during normal metabolism
in the central nervous system, and that some types of this damage must be repaired by
NER . In the absence of functional repair, the lesions persist and
result in neuronal death.

4. 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 Type
Signs and symptoms :
The disease usually progresses through 3 stages. The first stage occurs around 6
months 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 by
poikiloderma. 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, and
there is thinning of the skin.
The third stage is the development of solar keratoses and skin cancers. These may
occur as early as age 4-5 years and are more prevalent in sun-exposed areas such as
the face. The common skin cancers, basal cell carcinoma, squamous cell carcinoma,
and melanoma, occur significantly more often in people with xeroderma
pigmentosum. Other complications, including eye and neurological problems are also
apparent 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.

5. Exams and Tests
The doctor will perform a physical exam and ask if you have a family history of
xeroderma pigmentosa.
An eye exam may show:
Clouding of the cornea
Keratitis
Lid tumors
Blepharitis
The 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 baby
in the womb (uterus). It is usually done in a doctor's office or medical center. You do
not 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, the
medicine is given through a shot in the skin on the belly area. The health care
provider inserts a long, thin needle through your belly and into the womb. A small
amount of fluid is removed from the sac surrounding the baby.
2.Chorionic villous sampling
3.Culture of amniotic cells
The following tests can help diagnose the disorder after the birth of the child:
Culture of skin fibroblasts
Skin biopsy

6. Treatment :
There is no cure for xeroderma pigmentosum. The main goal of treatment is to protect
oneself from UV exposure and thus prevent the damaging effects it can have on the
skin. Xeroderma pigmentosum patients should follow these general precautionary
measures:
Sun avoidance methods
o Wear protective clothing (long sleeves and pants, shirts with collars,
tightly woven fabrics that don't 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. Some
xeroderma pigmentosum patients who have had many skin cancers may be prescribed
isotretinoin. This is a vitamin A derivative that may prevent formation of new
cancers.
Limbal stem cell deficiency and xeroderma pigmentosum:
(http://www.nature.com) :
To report limbal stem cell deficiency in a case of xeroderma pigmentosum that was
successfully managed by limbal transplantation and penetrating keratoplasty.
Case report
A healthy 28-year-old male diagnosed with xeroderma pigmentosum presented with
diminished vision in both eyes, of several years duration. There was no prior history
of exanthematous fever. He had been treated elsewhere for malignant lesions of the
skin and nose. In the left eye, his best visual acuity was 20/400. An adherent leucoma
was present in the lower one-third of the cornea with 120° conjunctivalization (Figure
1a). In the right eye, his vision was reduced to accurate projection of rays due to a
dense vascularized corneal scar. Both eyes had normal lids, conjunctiva, and adequate
tear meniscus. Dense corneal scars precluded the view of the remaining anterior and
posterior segments. Systemic examination revealed no abnormalities other than hyper-
and depigmented lesions of the skin in exposed areas. The differential diagnosis in the

7. left eye included ocular surface squamous neoplasia and partial stem cell deficiency.
Impression cytology revealed goblet cells in the inferior quadrant (Figure 2a) with
squamous metaplasia in other areas of the cornea (Figure 2c). Adequate goblet cells
were noted on the conjunctival surface (Figure 2b). There was no evidence of
dysplasia in the epithelial cells. He was diagnosed as having partial limbal stem cell
deficiency, and was advised a living-related conjunctival limbal allograft. His
unaffected father volunteered to be the donor. After informed consent, the donor
tissue was transplanted inferiorly over 0600 h. Histopathology of the excised pannus
confirmed conjunctivalization of the cornea and excluded dysplastic changes (not
shown). We followed the immunosuppressive regimen described by Tsubota.4 After 3
months 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 was
20/40. The corneal graft was clear and the inferior limbal graft has been accepted (
Figure 1
figure 2
Conclusion
In xeroderma pigmentosum, there is a deficiency of the enzymes responsible
for repairing UV light-induced DNA damage.Persistence of unrepaired DNA results
in somatic mutations, leading to neoplasias. The manifestation of limbal stem cell
deficiency in this patient prompted us to speculate that exposure of the limbal stem
cells to UV radiation might lead to permanent damage or dysfunction of these cells, or
alteration 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 cell
deficiency could result in a failed corneal graft; therefore, we decided to do a limbal
transplant, followed by penetrating keratoplasty. Partial LSCD can be managed
conservatively, by repeated mechanical debridement, or amniotic membrane
transplantation.However, the success of these procedures is determined by the
presence of healthy residual limbal stem cells. In a patient of xeroderma pigmentosum
with high susceptibility to UV radiation-induced damage we anticipated a permanent
damage to the residual limbal stem cells and therefore preferred a living-related

8. conjunctival limbal allo-transplant. We support the belief that a penetrating
keratoplasty after restoration of ocular surface stability is more beneficial, as has been
advocated earlier. A simultaneous procedure may result in delivery of less antigenic
load to the recipient by utilizing the same donor for both limbal and corneal
transplants, and in preservation of the transient amplifying cells. The poor long-term
outcome following simultaneous limbal transplantation and penetrating keratoplasty
has prompted the recommendation of a staged procedure with a 1-year gap. Though a
stable ocular surface and good vision have been attained following these surgeries, the
inherent pathology remains. Photoprotective measures have been advocated and the
patient has been cautioned about the possible development of ocular or cutaneous
manifestations of XP described earlier. Indefinite immunosuppression remains
necessary to ward off limbal allograft rejection. The patient is on low doses of
cyclosporine ensuring serum trough levels of 50 ng/ml, regular assessment of renal
and 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 of
xeroderma pigmentosum, necessitating a high degree of suspicion and early surgical
intervention to prevent visual disability.
Researchers in the United States and throughout the world are learning aboutX P and
trying to correct the DNA r e p a i rdefect in laboratory-grown cells frompatients with
XP. The genes causing mosttypes of XP have been identified. Manylaboratories in the
US, Europe, andJapan are studying XP genes and tryingto understand what they do.
Clinical studies on skin cancer prevention with oralmedications and evaluating
patients withunusual features are also being conducted at the National Institutes of
Health.