Introduction

Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis that results due to
mutations in nucleotide excision repair. The condition characteristically demonstrates severe
photosensitivity, skin pigmentary changes, malignant tumor development, and occasionally
progressive neurologic degeneration. The disease affects about 1 per million in the United States,
and the incidence in Japan is much higher at 45 per million.[1]
Dermatologist Moriz Kaposi first described xeroderma pigmentosum in 1874. Dr. Kaposi
described patients with dry skin, pigmentary changes, and the development of multiple skin
tumors at a young age. Further studies over the next several decades highlighted the importance
of severe photosensitivity in the pathophysiology of xeroderma pigmentosum. In the 1960s, Dr.
James Cleaver performed studies on cultured fibroblasts from patients with xeroderma
pigmentosum and found the fibroblasts to have defective DNA repair after UV exposure. Further
studies showed that patients with xeroderma pigmentosum with neurologic manifestations have
even less effective DNA repair after UV exposure compared to patients with XP without
neurologic manifestations.[2][3] These studies have enhanced knowledge about the connections
between UV exposure, DNA damage and repair, and the development of malignant tumors.
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Etiology
Xeroderma pigmentosum results from a mutation in nucleotide excision repair. The nucleotide
excision repair system is capable of removing ultraviolet-induced damage to DNA, such as
pyrimidine dimers and pyrimidines 6-4 pyrimidones. The progression of xeroderma
pigmentosum is due to the accumulation of unrepaired DNA damage. Eight different mutations
have been found to associate with different subtypes and clinical presentations of xeroderma
pigmentosum. Research has described the subtypes of XP A-G and XP variants, each with
varying mutations in nucleotide excision repair. A mutation in the gene XPC results in the most
common subtype in the United States.[4]
XPC gene codes for an endonuclease and is on chromosome 3p25. The mutated endonuclease is
unable to sense damage in DNA, resulting in severe sun sensitivity and malignant tumor
formation of the skin and mucous membranes. The XPC subtype of xeroderma pigmentosum has
no neurologic manifestations compared to the XPA subtype, which is the most common form in
Japan.
The XPA gene codes for DNA damage binding protein 1 (DDB1) is on chromosome 9q22.
DDB1 normally senses damage in DNA and assists in the unwinding of DNA. These patients
present with both skin and neurologic manifestations of the disease.
XPB, XPD, XPE, XPF, and XPG are all rare subtypes of xeroderma pigmentosum. The XPB
gene codes for excision-repair cross-complementing 3 (ERCC3) found on chromosome 2q21.
ERCC3 is part of a 9-subunit protein complex (TFIIH) needed for open complex formation in
DNA repair. The XPB subtype correlates with both Cockayne syndrome and
trichothiodystrophy. The XPD gene codes for ERCC2 and is on chromosome 19q13. The XPD
subtype has correlations with XP-Cockayne complex and trichothiodystrophy. The XPE gene
codes for DDB2. The XPF gene is on chromosome 16p13 and codes for ERCC4, which normally
forms an endonuclease with ERCC1 that incises damaged DNA. The XPG gene codes for
ERCC5 and is on chromosome 13q33.[5]
Mutations in the XPV gene results in the variant subtype of xeroderma pigmentosum, which
accounts for about 30% of all cases. The XPV gene product is not considered part of nucleotide
excision repair but is involved in postreplication repair. The XPV gene codes for polymerase eta
found on chromosome 6p21. There are no neurologic manifestations seen in the XPV subtype of
xeroderma pigmentosum.[1]
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Epidemiology
Xeroderma pigmentosum is a rare autosomal recessive genodermatosis that affects about 1 per
million in the United States, and the incidence in Japan is much higher at 45 per million. The
incidence in Western Europe is estimated to be 2.3 cases per million. Cases of XP have also
appeared in North Africa and the Middle East.[6] The most prevalent subtype seen in the United
States, Africa, and Europe is XPC. The most common subtype seen in Japan is XPA. The XP
variant (XPV) accounts for about 30% of all cases of xeroderma pigmentosum. The subtypes
XPA, XPC, and XPV, make up about 75% of all cases of XP worldwide. Both men and women
are affected equally by xeroderma pigmentosum.[1]
Most patients present in the first few years of life with severe sun sensitivity and after developing
severe sunburns despite minimal sun exposure. Infants may develop erythema and bullae in sun-
exposed areas. Patients typically present with ephelides and other pigmentary changes before the
age of two. The median age for the development of their first non-melanoma skin cancer is about
nine, and the median age for the development of their first malignant melanoma is about 22.[1]
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History and Physical

The various subtypes of xeroderma pigmentosum may have differing clinical history and
physical findings. All patients with xeroderma pigmentosum will present with skin changes
secondary to severe sun sensitivity. Patients may also present with oral, ophthalmologic, and/or
neurologic manifestations of the disease. Given that XP inheritance is in an autosomal recessive
pattern, patients do not typically have a family history of XP, and the parents are healthy. History
of consanguinity may be present.
Patients born with xeroderma pigmentosum are born with normal skin; however, with increased
sun exposure, the patients develop pigmentary changes that typically start before the age of two.
Patients usually present with hyperpigmented and hypopigmented macules over the face, neck,
chest, and dorsal hands and forearms. They also present with other skin changes secondary to
actinic damage such as telangiectasias and actinic keratoses and also develop progressive
premature aging of the skin, including atrophy, xerosis, and wrinkling.
The median age for the development of their first non-melanoma skin cancer is about 9.[7] Basal
cell carcinomas (BCC) present, as they would in any other patient, as a pearly pink to
hyperpigmented papule with “rolled” borders, telangiectasias, and often central ulceration.
Squamous cell carcinomas (SCC) typically present as a scaly to hyperkeratotic erythematous
macule or papule. These non-melanoma skin cancers may present as a non-healing or easily
traumatized wound. Patients may also present with keratoacanthoma-SCC type skin cancers.
Keratoacanthomas typically present with rapid onset and growth over days to weeks.
Keratoacanthomas present as the typical round skin-colored to erythematous papule or plaque
with a central hyperkeratotic plug. The median age for the development of their first malignant
melanoma is about 22.[7] Malignant melanoma typically presents as an irregular and changing
brown-to-black macule or patch. Given the wide variation of clinical presentation of various skin
cancers, patients with xeroderma pigmentosum must be followed closely for regular total body
skin exams by a dermatologist.
Patients with xeroderma pigmentosum may also present with oral malignant tumors, especially
of the anterior tongue. Patients with XP have been found to develop squamous cell carcinomas of
the anterior tongue.[7]
Additionally, patients with xeroderma pigmentosum typically present with multiple
ophthalmologic manifestations of their disease. Patients typically complain of progressive eye
symptoms over several years. Patients may have photophobia or dry eye symptoms. Patients with
XP may develop hyperpigmentation of the eyelid and/or conjunctiva. Patients may also develop
telangiectasias, as well. Patients with XP can also present with an ectropion, corneal
vascularization, or opacification. Patients can also present with both benign and/or malignant
ocular and periocular lesions, including benign lid papillomas, basal cell carcinomas of the
eyelid, or malignant melanoma.[8]
Some subtypes of xeroderma pigmentosum also present with progressive neurologic symptoms.
These symptoms are most commonly seen in XP subtypes XPA and XPD and occur in about
20% of patients with XP. Neurologic symptoms are progressive over the patient’s life regardless
of sun exposure. Neurologic manifestations are secondary to loss of neurons, cortical atrophy,
and dilation of the ventricles. Neurologic symptoms may include neurodevelopment deficiency
and/or sensorineural deafness. Additionally, patients may also present with microcephaly,
hyporeflexia, spasticity, or ataxia.[9]
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Evaluation
While there currently are no routine laboratory tests or imaging that can be performed to confirm
a diagnosis of xeroderma pigmentosum, the diagnosis can be confirmed by either unscheduled
DNA synthesis techniques (UDS) or by gene sequencing.
Unscheduled DNA synthesis involves exposing the patient’s cultured fibroblasts to UV radiation
and then assessing their ability to repair DNA. DNA repair after UV exposure is different than
DNA synthesis during normal cell replication and is therefore called unscheduled DNA
synthesis. The amount of UDS after irradiation is quantifiable by determining the number of
nucleotides incorporated into DNA. Nucleotide incorporation into DNA is determined using one
of the following methods: fluorescence assay, autoradiography, or liquid scintillation counting. If
the patient’s level of UDS is low following UV exposure, the diagnosis of xeroderma
pigmentosum is confirmed.[5]
For the variant subtype of XP, cultured fibroblasts do not show severe sun sensitivity, as seen in
subtypes XP A-G. The cultured fibroblasts from XPV patients require incubation with caffeine
for sensitization to UV exposure. The fibroblasts are incubated with caffeine for several days
following UV radiation and are then compared to normal fibroblasts to determine any deficiency
in UDS. UV sensitivity, when cultured with caffeine, confirms the diagnosis of the variant
subtype of xeroderma pigmentosum.
Prenatal diagnoses of xeroderma pigmentosum can also be confirmed by either performing UDS
on cultured amniotic fluid cells or by performing gene sequencing on chorionic villus cells or
amniotic fluid cells.
Following confirmation of xeroderma pigmentosum, further tests can be performed to confirm
the gene mutation for that given patient. One method to determine the gene complementation
group is by performing a complementation analysis. Cultured fibroblasts from the patient get
fused with each of the different XP subtypes. If the fused cells do not regain UDS and remain at
a low level of UDS, the gene complementation group is confirmed, and the specific subtype of
xeroderma pigmentosum can be diagnosed. Additionally, the patient can undergo gene
sequencing to determine the mutated gene and subtype of XP.
Patients with XP will need multiple skin biopsies throughout their lifetime to diagnose or rule
out various skin cancers. Histologic examination of the skin biopsies will be necessary for
diagnosis. If the patient presents with neurologic symptoms, a neurologist may perform
electroencephalography.
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Treatment / Management
The goal of the management of patients with xeroderma pigmentosum is to decrease the number
of malignant tumors the patient develops, early detection and treatment of malignant tumors, and
to improve the patient’s quality of life as much as possible. The most effective method of
decreasing the number of malignant tumors in patients with XP is strict sun avoidance and
protection. Patients and their caregivers should be educated on all strategies to keep UV radiation
exposure to a minimum. Patients should avoid going outside of their homes during daytime
hours. If they must go outside during the day, patients should be covered head to toe with
sunscreen. Broad-spectrum sunscreen requires application every two hours. Patients should also
use a lip balm with sunscreen. Patients should wear sun-protective clothing with long sleeves and
pants. They should also wear a hat and sunglasses with side shields. All windows of the home,
car, and school should have a covering with a UV-blocking film. Patients should also avoid
exposure to fluorescent, metal halide, and halogen lighting, which can emit UV radiation.
Given the strict sun protection and avoidance, patients should take vitamin D supplementation
regularly. Patients can also obtain vitamin D by consuming vitamin D-rich foods such as fish,
eggs, mushrooms, and fortified foods.
Regular total body skin exams should be performed by a dermatologist as well as by caregivers.
Patients should see a dermatologist at a minimum every three months throughout the patient’s
life. Caregivers should perform daily skin exams at home and receive education on changes to
bring to the attention of the patient’s dermatologist. Actinic keratoses should be treated as early
as possible after the presentation to decrease progression to squamous cell carcinoma. These
precancerous lesions are treatable with cryotherapy in the dermatology office. A shave biopsy
should be a consideration for any lesions that are changing, new, or clinically suspicious. Basal
cell carcinomas, squamous cell carcinomas, and other non-melanoma skin cancers typically get
treated with Mohs micrographic surgery or excision. Radiation therapy is to be avoided in
patients with xeroderma pigmentosum. Malignant melanoma should have treatment with wide
local excision with possible sentinel lymph node biopsy. Patients with metastatic disease should
obtain a referral to hematology/oncology for further workup and treatment.
In a small study of five patients with XP, high doses of oral 13-cis retinoic acid (isotretinoin) was
shown to decrease the number of skin cancers these patients developed dramatically. Patients
received 2 mg/kg/day of oral isotretinoin. All patients developed xerostomia and xerophthalmia.
Some patients developed side effects such as elevated triglycerides and liver function tests and
even skeletal abnormalities. Despite multiple side effects of the medication, this study
demonstrated the significant benefit of chemoprevention of oral retinoids for patients with
xeroderma pigmentosum.[10]
Ophthalmologic manifestations of XP are almost as common as the skin manifestations.
Symptoms are progressive and often include photophobia and conjunctival injection. Patients
may develop cataracts, conjunctivitis, blepharitis, pigmentary changes of the eyelids or
conjunctiva, ectropion, corneal vascularization, xerophthalmia, and corneal scarring. Patients
may also develop skin lesions of the eyelid, which may include benign lid papillomas, basal cell
carcinomas, and malignant melanoma. Patients have also been found to develop melanomas of
the anterior chamber of the eye. Patients should be followed regularly by an ophthalmologist for
eye exams and management of ophthalmologic manifestations of XP.[8]
For patients with XP that develop neurologic manifestations, they should obtain a referral to a
neurologist for workup and management. Unfortunately, neurologic symptoms are progressive
and not slowed by sun protection.
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Differential Diagnosis
There are several other syndromes and conditions in the differential diagnosis for xeroderma
pigmentosum. Along with XP, these syndromes have revealed information about the various
proteins and genes involved in nucleotide excision repair.
Cockayne syndrome is due to a mutation in either CSA or CSB genes, which results in defects in
nucleotide excision repair. Patients with Cockayne syndrome present with microcephaly, retinal
degeneration, deep-set eyes, prominent ears, sensorineural hearing loss, kyphoscoliosis, and gait
abnormalities. Patients with Cockayne syndrome also have photosensitivity but are not at
increased risk of developing skin cancers or pigmentary changes, as seen in XP.
There is a Cockayne-XP overlap syndrome (CS-XP), which has features of both Cockayne
syndrome and xeroderma pigmentosum. This condition results in multi-system degeneration and
is characterized by photosensitivity, degenerative neurologic manifestations, joint contractures,
and short stature. Patients with CS-XP develop the same cutaneous manifestations as patients
with xeroderma pigmentosum. After achieving some initial developmental milestones, these
patients reach a plateau in their development and eventually reach a period of decline. Cockayne-
XP overlap syndrome is extremely rare, with only 43 cases reported in the literature.[11]
Another condition to consider in the differential diagnosis of XP is trichothiodystrophy (TTD).
Trichothiodystrophy has a characteristic presentation of photosensitivity, brittle hair, ichthyosis,
short stature, low fertility, and developmental delay. Despite patients with TTD having
photosensitivity, these patients do not carry the same increased risk of skin malignancies and
pigmentary changes as patients with xeroderma pigmentosum. There have been some cases of a
trichothiodystrophy-xeroderma pigmentosum overlap syndrome (TTD-XP) reported.
Cerebro-oculofacial-skeletal syndrome (COFS) is another condition that has overlapping features
with xeroderma pigmentosum. Patients with COFS present with characteristic facial dysmorphic
features, including a prominent nasal root and an upper lip, which hangs over the lower lip.
COFS patients also present with photosensitivity, microcephaly, developmental delay, congenital
cataracts, and joint contractures.[12]
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Prognosis
Patients with xeroderma pigmentosum typically present before the age of two with severe sun
sensitivity. Patients may develop erythema and bullae after minimal sun exposure. Skin changes
secondary to sun exposure progressively develop over the course of the patient’s life with the
progressive development of pigmentary changes, telangiectasias, and actinic keratoses. The
median age for the development of their first non-melanoma skin cancer is about 9. Patients may
develop dozens to hundreds of non-melanoma skin cancers per year. Patients with xeroderma
pigmentosum have a more than 10000 fold risk of developing non-melanoma skin cancer
compared to the general population. The median age for the development of their first malignant
melanoma is about 22. Patients with XP have a more than 2000 fold risk of developing
malignant melanoma compared to the general population. Patients will need regular total body
skin exams by a dermatologist and routine and early treatment of precancerous lesions and skin
malignancies.[7]
The life expectancy for patients with xeroderma pigmentosum varies with the different subtypes
of XP. Patients with neurologic manifestations of XP typically live a shorter life compared to
patients with XP that do not have neurodegeneration. The median age of death in patients with
XP without neurodegeneration is about 37 years old. The median age of death in patients with
XP with neurodegeneration is younger at about 29 years old. Patients with the XP variant
subtype typically have longer-term survival compared to patients with XP with other subtypes.
While the most common cause of death amongst patients with XP is metastatic malignant
melanoma or invasive squamous cell carcinoma, the second most common cause is due to
neurodegeneration.
Patients with xeroderma pigmentosum are also at an increased risk of developing malignancies
of other organs of the body. They may develop cancers of the anterior tongue or ocular
surface. Patients with XP that smoke cigarettes are also at increased risk of developing lung
cancer compared to the general population. Also, patients with XP have a more than 50-fold risk
of developing tumors of the central nervous system such as spinal cord astrocytoma,
schwannoma, medulloblastoma, and glioblastoma.[7]
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Complications
There are many complications of xeroderma pigmentosum, which this activity discussed
previously. The median age for the development of their first non-melanoma skin cancer is about
9. Patients may develop dozens to hundreds of non-melanoma skin cancers per year. Patients
with xeroderma pigmentosum have a more than 10000 fold risk of developing non-melanoma
skin cancer compared to the general population. The median age for the development of their
first malignant melanoma is about 22. Patients with XP have a more than 2000 fold risk of
developing malignant melanoma compared to the general population.[1]
The median age of death in patients with XP without neurodegeneration is about 37 years old.
The median age of death in patients with XP with neurodegeneration is younger at about 29
years old. While the most common cause of death amongst patients with XP is metastatic
malignant melanoma or invasive squamous cell carcinoma, the second most common cause is
due to neurodegeneration.
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Deterrence and Patient Education

Given the significantly increased risk of developing malignant tumors, patients and their
caretakers should have regular education and reinforcement of the many steps that are necessary
to minimize the development of malignant tumors and shorten the time between clinical
presentation, diagnosis, and treatment of malignant tumors as they develop.
The most effective method of decreasing the number of malignant tumors in patients with XP is
strict sun avoidance and protection. Patients and their caregivers should be educated on all
strategies to keep UV radiation exposure to a minimum. Patients should avoid going outside of
their homes during daytime hours. If they must go outside during the day, patients should be
covered head to toe with sunscreen. Broad-spectrum sunscreen requires application every two
hours. Patients should also use a lip balm with sunscreen. Patients should wear sun-protective
clothing with long sleeves and pants. They should also wear a hat and sunglasses with side
shields. All windows of the home, car, and school should have a covering with a UV-blocking
film. Patients should also avoid exposure to fluorescent, metal halide, and halogen lighting,
which can emit UV radiation.
Regular total body skin exams should be performed by a dermatologist as well as by caregivers.
Patients should visit a dermatologist at least every three months throughout the patient’s life.
Caregivers should perform daily skin exams at home and receive educated on changes that
require the attention of the patient’s dermatologist.
Patients with XP that smoke cigarettes are also at increased risk of developing lung cancer
compared to the general population and, therefore, should be educated on strict smoking
avoidance or cessation.
Patients and their caretakers should also receive information for xeroderma pigmentosum
support groups.
Gene Function
XPA Pre-incision complex assembly
damaged DNA binding
XPB DNA unwinding damage verification
XPC DNA damage recognition
XPD
XPE
XPF 5’ endonuclease
XPG Pre-incision complex assembly associates
XPV Replication bypass of CPD’S