Continuing Education Activity

Xeroderma pigmentosum is a rare autosomal recessive genodermatosis that results due to mutations in nucleotide excision repair. The condition is characterized by severe photosensitivity, skin pigmentary changes, malignant tumor development, and occasionally progressive neurologic degeneration. This activity describes the evaluation and management of xeroderma pigmentosum and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Describe the etiology of xeroderma pigmentosum.
• Review the clinical presentation of the patient with xeroderma pigmentosum.
• Outline the management considerations for patients with xeroderma pigmentosum.
• Explain the importance of improving care coordination amongst the interprofessional team to improve outcomes for patients affected by xeroderma pigmentosum.

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.

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]

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]

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]

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.

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.

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]

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]

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.

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.

Enhancing Healthcare Team Outcomes

An interprofessional team is essential in the management of patients with xeroderma pigmentosum. Given their significantly increased risk of developing malignant tumors, multiple providers are needed for the diagnosis and management of these tumors to provide the best clinical outcome and quality of life for each patient. Pediatricians need to recognize early manifestations of the disease and obtain a prompt referral to a dermatologist. Patients need regular total body skin exams by a dermatologist and treatment of precancerous and malignant tumors. Patients may need a referral to a general surgeon and/or plastic surgeon for the management of tumors that are not treatable under local anesthesia in a dermatology clinic. Patients should be followed regularly by an ophthalmologist for eye exams and management of ophthalmologic manifestations of XP. For patients with XP that develop neurologic manifestations, these patients should get referred to a neurologist for workup and management. The pharmacist should educate the patient on retinoids for chemoprevention but also inform them about the potential side effects. In addition to medical care, patients and their caretakers should receive information for a xeroderma pigmentosum support group. Close communication between the interprofessional team is necessary to avoid the high morbidity of XP.