Xeroderma pigmentosum

Management Strategy

The diagnosis of XP is based on clinical features, and can be suspected in a child with a history of freckling on sun-exposed skin before age 2 years or severe sunburn after minimal sun exposure, photophobia, or cancer of the skin or eye. Once XP is suspected UV protection should be initiated immediately. Disorders that should be excluded include porphyria, lupus, LEOPARD syndrome, Carney complex, familial melanoma, and nevoid basal cell carcinoma syndrome.

DNA testing for mutations in several XP genes is available ( www.genetests.org ). Because mutation testing may not identify all XP gene mutations, failure to identify a mutation does not rule out the diagnosis of XP.

The most critical management goal for XP is ultraviolet (UV) protection. Utilizing multiple levels of protection provides security if one measure fails. Typical levels include management of environmental exposure, topical sun block agents, and physical barriers such as clothing, glasses, and face shields.

The major source of UV is the sun. Although window glass blocks most UVB wavelengths, UVA can pass through glass. Extremely sensitive XP patients have burned through window glass. The Americans with Disabilities Act mandates that children and adults with XP be provided safe educational and working environments. Windows in rooms where XP patients will be spending substantial amounts of time, such as at home, in a car, school, and work, should be shielded from UV radiation. This can be done with clear UV protective film or by creating a consistently safe distance from windows. Schools should make accommodations for XP students to stay indoors during fire drills and physical education activities. An Individualized Educational Plan should be developed to keep them protected from UV sources while encouraging interaction with other students.

Replacing unshielded fluorescent bulbs with light-emitting diode (LED) lights or placing plastic shielding over fluorescent bulbs can substantially reduce environmental UV exposure. Halogen lights emit substantial levels of UVB and should be avoided.

Although XP patients do not repair damage from UV exposure of tissues, they react normally to visible light. Because eradicating all exposure to UV radiation may not be attainable, efforts should be directed toward providing a safer environment. Environments with high UV levels, such as outdoors during daylight hours, require the most rigorous protection and sun avoidance. However, long periods of lower levels of exposure are also damaging. We can sense differences in the intensity of visible light, but not UV. Relatively inexpensive handheld UV meters can measure UVB and UVA and can be effective tools to guide activities. Medical care can be an unintended source of UV exposure such as from lights in waiting rooms, exam rooms, or surgical suites or during medical or dental procedures. Medical instruments such as dermatoscopes, ophthalmoscopes, and otoscopes should be assessed for UV levels. Replacing halogen bulbs with LED bulbs can substantially reduce UV levels.

Protective measures should be a daily routine. These include topically applied broad-spectrum sunblock preparations with an SPF (sun protection factor) of 30 or higher with protection against both UVB (short-wavelength UV 290–320 nm) and UVA (long-wavelength UV 320–400 nm) and sun-protective lip balms and/or makeup. Daily sunblock applications should be applied to all exposed skin surface areas, and reapplied to uncovered skin (usually face, ears, neck, and hands) several times a day.

Clothing should cover as much skin surface as possible including long pants, long-sleeved shirts, socks with closed-toe shoes, hats that cover the ears, or UV-blocking face shields and hoods, and UV-blocking sunglasses with side shields. For daytime outdoor exposure gloves can be worn to protect hands. Clothing material should be tightly woven (e.g., denim) or double layered. A simple test of effective UV protection by clothing is to hold the material up to a bright light. Material that permits visible light to pass will not block UV. Commercially available clothing made from sun-blocking material is available. One alternative is a laundry additive called SunGuard, which is advertised to increase the ability of clothing to block UV.

XP patients should wear UV-blocking sunglasses. The glasses should ‘wrap around’ the eyes to protect the sides of the eyes and be large enough to fully protect both lids. Rigorous use of these measures should be initiated as soon as the diagnosis of XP is suspected to provide lifelong protection.

Medical alert bracelets ( http://www.medicalert.org/home/Homegradient.aspx ) and carrying an information card about XP can be helpful in emergencies when affected individuals may not be able to communicate their UV sensitivity.

Since vitamin D is produced in the skin by sun exposure, rigorous sun protection may lead to low levels of vitamin D in the blood and risk of bone fracture. Vitamin D–rich foods such as fish and vitamin D–supplemented milk can help maintain normal vitamin D levels along with oral supplementation and periodic monitoring of 25-hydroxyvitamin D levels in the blood.

XP patients should not use any type of tobacco product and should be protected from second-hand smoke. Carcinogens found in tobacco products induce DNA damage that is normally repaired by the NER pathway, putting the XP patient at high risk for oral and respiratory tract cancers.

The substantial lifestyle adjustment necessary to provide a safer UV environment can be a challenge for the family. Outdoor activities should be avoided during daylight hours, particularly between 10 a.m. and 2 p.m. Identifying appropriate indoor play and sports activities for the affected XP child, while continuing to meet the needs of the unaffected family members, can be difficult. Emotional support for the entire family is essential.

The need for frequent painful procedures and hospitalizations for more extensive surgeries can lead to posttraumatic stress disorder–type symptoms in some patients and families. It is important to consider pain management and stress reduction appropriate for the developmental level of the XP patient when planning care. The emotional and economic stability of the family is often affected and, as with any chronic illness, the family and patient will need to go through a period of adjustment to the lifestyle changes. Studies of XP patients in England found that families and patients who were able to incorporate the UV protective regimen into their normal routines were best able to effectively institute UV protection. In family situations with psychosocial pathologies (e.g., substance abuse or domestic violence), or if the family is having extreme difficulty coping with the diagnosis, referral to social services or a therapist may be advisable. The patients may be eligible for Social Security Disability Insurance or other medical assistance.

XP support groups help patients connect with other affected families and minimize social isolation; these groups also sponsor UV-safe family activities. These include the XP Family Support Group, http://www.xpfamilysupport.org ; and the Xeroderma Pigmentosum Society, http://www.xps.org in the United States; and the Xeroderma Pigmentosum Support Group UK, http://xpsupportgroup.org.uk . There are also support groups in Germany, Japan, and the Middle East.

Genetic considerations are important for XP management. XP is a recessive disorder, with probands having two mutated alleles, and clinically normal parents (heterozygotes) carrying one mutated allele. The risk of having another affected child is 1 in 4 for each subsequent pregnancy. Prenatal diagnosis may be possible, and consultation with a genetic counselor and Fetal Maternal Specialist can address genetic risks in future pregnancies.

Teaching patients and families to look for premalignant and malignant lesions can enable earlier identification and removal of small tumors. Depending on the rate of new tumor development, full skin examinations should be scheduled regularly (every 3–6 months). Baseline whole-body photographs and close-up photos of lesions with a ruler in the image for size comparison can help track changes. Digital images can be given to the family for use at home and also kept in the medical record.

Premalignant lesions including actinic keratoses can be treated with cryotherapy, topical 5-fluorouracil (5-FU), or topical imiquimod . Care needs to be taken to ensure that existing skin cancers are adequately treated. When using topical 5-FU or imiquimod as field treatments there is a risk of treating the superficial areas of skin cancer but leaving deeper areas of tumor untreated. Well-controlled studies of topical field treatments in XP patients have not been published. Because of the known DNA damage produced by ultraviolet alone and with porphyrin, we would not recommend use of photodynamic treatment with daylight nor other light source.

Dermabrasion or dermatome shaving has been used to remove the superficial photodamaged epidermal layers. Theoretically, these procedures allow replacement of severely damaged epidermal cells with cells arising from the deeper, less UV-damaged adnexal structures. Newer techniques using laser methodology for resurfacing have also been used in a few XP patients. For patients developing many new lesions, chemoprevention with oral retinoids (isotretinoin or acitretin) has been used. A longitudinal study of a small number of XP patients performed at the National Institutes of Health found oral isotretinoin was effective in decreasing the number of new non-melanoma skin cancers. However, there were many side effects in these patients, especially at the higher drug dosages. Vismodegib (Erivedge) has also been used in a few XP patients who were experiencing multiple basal cell carcinomas. There was a good response while on treatment; however, this therapy is associated with multiple side effects. Early and adequate treatment of skin cancers is extremely important. All suspected tumors should be biopsied and removed. Standard techniques, including electrocurettage and desiccation, surgical excision, or cryosurgical ablation, can be used for small superficial lesions. Due to the extensive poikilodermatous changes and scarring in XP patients, it can be difficult to differentiate recurrent from new lesions. Mohs micrographic surgery is optimal for combining effective tumor removal with tissue sparing. Several factors complicate skin cancer treatment in XP patients. Cancers may develop in a ‘field’ of extreme actinic damage, often with little normal-appearing skin either visibly or histologically. This complicates the goal of clear margins. A more practical goal would be a tumor-free margin. In addition, the quality of actinically damaged skin in XP differs from the non-XP skin cancer patient. The non-XP cancer patient typically has damage to both the epidermis and dermal connective tissue (collagen, elastic tissue, etc.) from high doses of UV exposure that result in lax, wrinkled skin. In contrast, damage in XP patients is caused by unrepaired DNA in the epidermis and the total dose of UV they have received is generally insufficient to cause typical solar elastosis, lax skin, and wrinkling. As a result they develop skin atrophy, with very tight skin, which limits tissue movement for surgical repair. Movement of tissue with flaps can be complicated because of the presence of precancers or small skin cancers in the severely damaged surrounding skin. Skin cancer removal with minimal margins is also necessary to preserve tissue for future surgeries. Despite their hypersensitivity to UV, many XP patients have demonstrated a normal response to X-ray therapy when it is used to treat recurrent skin and eye cancers or brain and spinal cord neoplasms.

Recently, several case reports have been published on the use of PD-1 antibody chemotherapy for XP patients with widely metastatic melanoma. The patients’ melanomas regressed with treatment as did many of their squamous cell carcinomas. Although the patients in the case reports did well with initial treatment, the papers did not report on long-term follow-up. This class of drugs can have very profound side effects including immune-mediated pneumonitis, nephritis, hepatitis, and immune-mediated dermatologic conditions including Stevens–Johnson syndrome. Long-term evaluations on XP patients have yet to be reported.

Several studies have noted that a few naturally occurring substances such as polypodium leucotomos, afamelanotide, and carotenoids may be useful as adjuvant therapies for lessening the effects of UVB exposure. However, none of these agents have been systematically studied in XP patients and should not be relied upon for UV protection.

XP patients have a substantially increased risk for developing cancers of the lips and squamous cell carcinoma of the tip of the tongue, and these areas should be regularly evaluated. Telangiectasia on the tip of the tongue is an early UV-induced change.

Ophthalmologic care is extremely important. Most ophthalmologic problems in XP patients occur in the anterior, UV-exposed surface structures of the eye and may begin in childhood as photophobia and conjunctivitis. Precancerous and cancerous lesions can arise on the cornea, sclera, lids, conjunctiva, and supporting tissues. UV damage on the cornea can lead to ‘dry eye,’ keratitis, and conjunctival inflammation. Ectropion of the lids, resulting in defects of eye closure, can occur secondary to eyelid atrophy and surgical removal of malignancies from the periocular skin. Ectropion exacerbates eye dryness and, if left untreated, can lead to corneal ulceration, scarring and opacification of the cornea, and blindness. Corneal transplants have been performed but frequently have led to rejection from vascularization of the area. A thorough ophthalmologic examination at least yearly can include the Schirmer test for dry eye and assessment of lid closure. Eye lubricants are recommended along with lubricating ointments at night, especially if lid closure is poor.

In the United States and Europe approximately 25% of XP patients develop progressive neurologic disease. The rate of symptom progression varies greatly among patients, with the most severe patients developing symptoms in early childhood (De Sanctis–Cacchione syndrome). Routinely testing reflexes during skin examinations and performing annual audiograms can help identify XP patients at risk for neurologic disease. Loss of deep tendon reflexes, most notably in the lower extremities, may be the first manifestation of neurodegeneration and may be the only symptom for years. Some patients may have microcephaly. Progression includes hearing loss, cognitive decline, dysarthria, dysphagia, mobility difficulties with ataxia, and falls; eventually a wheelchair may be needed. Magnetic resonance imaging shows progressive dilation of the ventricles and loss of gray matter of the brain. Death may occur from aspiration pneumonia or other complications of severe debilitation. In a National Institutes of Health (NIH) study of 106 XP patients, the median age at death in XP patients with neurodegeneration (29 years) was significantly younger than those XP patients without neurodegeneration (37 years).

Progressive sensorineural hearing loss in XP patients may be diagnosed early, in the first decade of life, and may first be suspected secondary to inattentiveness in school. Audiology examinations provide a sensitive method for early detection. The hearing loss can be helped with hearing aids, and assisted hearing systems may be used in the classroom.

Some XP patients appear to have an increased risk for developing internal malignancies, including an approximately 50-fold increased risk of developing primary central nervous system tumors. These may respond to standard X-ray therapy with normal skin reaction. However, because some XP cell lines have increased sensitivity to X-radiation, a small test dose might be advised before full-dose exposure. In addition, XP patients have been reported with myelodysplasia, acute lymphoblastic leukemia, lymphoma, and thyroid cancer.

With improved healthcare and better protective measures, XP patients are living longer and more active lives, marrying, and having children. However, some adult women with XP, particularly those with mutations in the XPC gene, have developed premature menopause in their twenties and thirties. When a patient discusses contemplating a pregnancy, referral for preconceptual genetic counseling is recommended.

Optimal management of XP patients is a multidisciplinary process involving several medical specialties and active cooperation and input from the patient and family.