Are You Confident of the Diagnosis?
What you should be alert for in the history
Xeroderma pigmentosum (XP) is a rare genetic disease characterized by a spectrum of clinical phenotypes ranging from mild almost asymptomatic disease to severe sensitivity to ultraviolet radiation and neurological deficits. Typically, patients with XP develop significant sun damage to sun exposed areas of the skin starting at a very early age leading to premature skin aging and the development of numerous skin malignancies. Many patients may concurrently have neurological abnormalities (unrelated to sun exposure) as well as ophthalmological pathologies.
XP is the result of defective nucleotide excision repair and is classified into 8 different subtypes or complementation groups (XP-A, XP-B, XP-C, XP-D, XP-E, XP-F, XP-G and XP-variant) based on the gene involved. They differ with respect to disease severity and frequency (see below and (Table I) for a more extensive discussion of the genetic basis of the disease). For example, XP-A and XP-C are the most common types, whereas XP-E is rare. XP-G is severe, whereas XP-F is mild.
Characteristic findings on physical examination
The dermatological manifestations of XP typically clue in the physician to its diagnosis. Most patients have noticeable skin changes within the first year of life over light-exposed areas (face, neck, arms, and legs). Babies may develop a severe sunburn with minimal exposure to the sun that may last for an extended period of time. Diffuse erythema, blister formation, scaling and dyspigmentation of the skin may be seen.
Over time, the skin becomes poikilodermic from actinic damage that is characterized by erythema, dyspigmentation, scarring, telangiectasias, atrophy and xeroderma (xerosis). Beginning in early childhood (with a mean age of 8 years), numerous skin tumors develop over the UV-radiation exposed surfaces of the body and include actinic (solar) keratoses, keratoacanthomas, squamous cell carcinomas, basal cell carcinomas and melanomas. The numerous skin malignancies may lead to severe disfigurement.
One large study of 830 XP patients found that 18% of them had neurological abnormalities with mental retardation present in 80% of those with neurological impairments. Other neurological deficits include nerve deafness (high-frequency hearing loss), microcephaly, abnormal motor activity (spasticity, ataxia, chorea, spasticity, difficulty swallowing) and progressive neural degeneration. These neurological impairments are particularly prominent in patients with XP-A and XP-D, and when present are progressive and irreversible.
Approximately half of all XP patients have ophthalmological abnormalities. The effects of UV light are particularly pronounced on the eyelids, the conjunctiva and cornea. Problems such as photophobia, chronic conjunctivitis, corneal clouding, fibrovascular pannus formation, loss of eyelashes, corneal ulcers, blepharitis and ectropion can all cause impaired vision in XP patients. Ocular neoplasms including basal cell carcinoma and squamous cell carcinoma of the eyelid, conjunctiva and cornea is increased 2000-fold.
Expected results of diagnostic studies
XP can be diagnosed from a careful and comprehensive history and physical exam. A history of increased photosensitivity (severe sunburn with very minimal sun exposure), neurological features such as nerve deafness, mental retardation, spasticity, ataxia, along with clinical findings of dyspigmented skin, multiple precancerous and cancerous skin lesions arising at an early age is highly suggestive of XP.
Although there is no consistent abnormality on routine laboratory studies, special laboratories can analyze cultured fibroblasts from a skin biopsy and measure DNA synthesis in the presence of UV radiation. Molecular studies can also identify the specific genetic defect. The histological features of XP are non-specific, often indistinguishable from that of actinic keratosis, non-melanoma skin cancers, or melanoma.
Numerous melanocytic nevi, increased basal melanin pigmentation, elastic changes in the dermis, a chronic upper dermal inflammatory infiltrate and poikiloderma can all be seen in pathological specimens. Patients with neurological involvement may benefit from an electromyography (EMG) and nerve conduction studies (NCS) to better delineate the extent of polyneuropathy.
When patients present with severe photosensitivity and neurological symptoms consistent with a possible diagnosis of XP, metabolic studies should be performed to rule out other conditions that may mimic XP. Serum and urine amino acids, urine porphyrins, serum lactate, serum pyruvate, serum copper, lysosomal enzymes, mucopolysaccharides and long-chain fatty acid analysis will help rule out metabolic causes of CNS dysfunction and photosensitivity.
Besides metabolic diseases such as lysosomal storage diseases, fatty acid oxidation defects, porphyria, and Wilson’s disease, other differential diagnoses to consider when contemplating a diagnosis of XP include trichothiodystrophy (TTD) and Cockayne syndrome (CS) because all three disease entities are characterized by defects in DNA excision repair.
Unlike patients with XP, TTD patients are not at an increased risk of developing skin cancer and do not develop pigmentary abnormalities. TTD patients also have brittle hair characterized by a tiger-tail banding on polarized light microscopy, ichthyosis and short stature. CS is characterized by characteristic facial features (deep set eyes, prominent ears), short stature, pigmentary retinopathy and sun sensitivity without an increased skin cancer risk. Finally, progressive sensorineural deafness is an early feature of both XP and CS, but not TTD, and may help distinguish the three.
Rarely, other disorders of defective DNA repair such as ataxia-telangiectasia (AT), Bloom syndrome (BS), Fanconi anemia (FA) and Rothmund-Thomson syndrome (RTS) may be confused with XP. Patients with AT have cerebellar ataxia, telangiectasias of the conjunctivae and immunological impairment and are not at a significantly increased risk for the development of skin malignancies. BS patients develop telangiectasias of the conjunctivae but do not develop skin malignancies as readily as XP patients.
FA patients demonstrate skeletal anomalies particularly of the thumbs, are less sensitive to the sun, and are not as prone to develop skin malignancies. Distinguishing XP from RTS may be challenging but RTS patients demonstrate less sun sensitivity, lower skin cancer rate than XP, a higher rate of osteosarcomas, gastrointestinal disturbances and radiographic bone abnormalities.
Who is at Risk for Developing this Disease?
The prevalence of XP in the United States and Europe is approximately 1 in 250,000 while in Japan, the prevalence is higher at 1 in 40,000. The prevalence of the specific subtypes of XP also varies from region to region. In the United States, XP-C is the most common, representing approximately one third of all XP patients, followed by XP-D. In Europe XP-A and XP-C are the two most prevalent forms of XP, while in Japan, XP-A is the most common form. There is no racial predilection for the disease with males and females equally affected.
Because XP is a recessive disease, there is typically no family history. Parental consanguinity appears to be a risk factor in some cases of XP.
What is the Cause of the Disease?
XP is an autosomal recessive disease characterized by defective nucleotide excision repair (XP-A to XP-G) or post-replication repair (XP-variant). Each type of XP is characterized by a specific gene mutation. For more details, see Table I.
When normal individuals are exposed to UV light, a major environmental carcinogen, a wide range of defects and distortions occur in cellular DNA. The subsequent DNA damage is normally repaired by a complex system, however, in patients with XP, this repair process is defective. Cyclobutane pyrimidine dimers (CPDs), a form of DNA distortion induced by UV radiation, is unable to be removed from the DNA properly, and this promotes tumorigenesis. As a result, minimal amounts of UV radiation (particularly of the UVB wavelength) can induce numerous types of skin malignancies.
Patients with the XP-variant gene mutation have a defective DNA polymerase, which normally allows DNA synthesis to occur past any CPDs. Similar to other XP patients, these individuals are prone to develop early onset malignancies.
The neurological manifestations of XP are also directly attributable to defective DNA repair. Without a complete functioning repair mechanism, neuronal DNA is damaged by reactive oxygen species and other free radicals leading to premature neuronal cell death. Patients with the greatest impairment in DNA repair suffer the greatest amount of neural degeneration (i.e. XP-A and XP-D).
In addition, exposure to UV radiation appears to exert immunosuppressive effects (prominent depletion of Langerhans cells is seen in many XP patients), which contributes to the pathogenesis of XP. The immunosuppressive effects prevent removal of abnormal cells with tumorigenic potential.
Systemic Implications and Complications
The most important systemic complication of XP is the development of skin malignancies, often at a very early age (mean: 8 years), and occurring at a rate of 1,000 times as compared to the normal population. Skin malignancies can range from actinic keratoses, keratoacanthomas to basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Over time, the development of numerous, sometimes thousands, of skin cancers in association with numerous excision procedures can cause severe scarring and disfigurement.
Interestingly, the types of skin malignancies vary with XP subtype. For example, XP-A and XP-C are most frequently associated with squamous cell carcinomas, whereas basal cell carcinomas occur more frequently in patients with type XP-E and XP-variant. XP-D patients are particularly prone to malignant melanomas.
Many patients also have concurrent ophthalmological abnormalities of the eyelid, conjunctiva, cornea and iris secondary to UV radiation exposure. Vision loss and even loss of eyelids are complications seen in patients with advanced eye disease.
Neurological complications are observed in approximately 18% of XP patients, most commonly in the XP-A and XP-D complementation groups. There is great variability in the neurological function of these patients as described previously. However, those with neurological impairment often have progressive and irreversible disease. These patients may become bed-ridden, incontinent and susceptible to infections, aspiration pneumonia and sepsis.
CNS tumors develop in XP patients at a 10-fold higher rate as compared to normal individuals. Astrocytomas, medulloblastomas, glioblastomas and malignant schwannomas have all been described in the literature. The de Sanctis-Cacchione syndrome refers to a severe form of XP in which dermatological signs and neurological symptoms are present in conjunction with hypogonadism and dwarfism.
XP patients are also at an increased risk for internal malignancies. Sarcomas, lung cancer, uterine cancer, breast cancer, pancreatic cancer, gastric cancer, testicular tumors and leukemias have all been reported in these patients.
XP patients have a dramatically decreased life expectancy and are most likely to die from cancer, infections, and other diseases.
Treatment options are summarized in Table II.
|Systemic Complication||Management Strategy|
|Cutaneous malignancies||– Focus on prevention (see photosensitivity)- Dermatological exams every 3 to 6 months- Precancerous lesions: treat with liquid nitrogen, curettage, shave biopsy, or 5% Imiquimod cream once to 3 times daily- Oral isotretinoin as tolerated for prevention: 0.5 to 2.0 mg/kg daily- T4 endonuclease V liposomal lotion (showing promise, but not commercially available)|
|Dental caries and oral lesions||– Routine dental exams on at least an annual basis.- Excision of suspicious oral lesions by oral surgeons|
|Internal malignancies||– Careful history and physical exams annually- Laboratory, imaging or diagnostic studies may be necessary if clinical suspicion for malignancy is high|
|Neurological impairments||– Neurology exams on a 6 month to annual basis|
|Ophthalmological abnormalities||– Focus on prevention (wearing UV protective goggles)- Routine ophthalmological exams|
|Photosensitivity||– Avoidance of sun exposure- Perform normally daytime activities at night- Strict application of sunscreen especially during daytime hours (every 2 hours)- Wear protective clothing, hats, UV protective goggles|
|Photoaging/photodamage||– Avoid smoking or second-hand smoke- Resurfacing procedures with anectodal success (but without extensive evidence): chemical peels, dermabrasion, carbon dioxide laser resurfacing, and even full-thickness grafting|
|Xerosis (xeroderma)||– Avoidance of sun exposure- Application of moisturizers especially after showers/baths|
Optimal Therapeutic Approach for this Disease
Currently there is no cure for XP.
XP patients should be ideally managed by a team of specialists including but not limited to pediatricians, dermatologists, neurologists, oral surgeons and ophthalmologists. See Table II for a summary of the management strategies of the complications of XP.
The first step in management is determining what type of XP a patient has because this can help provide more detailed counseling to the patient regarding the severity of disease.
The cornerstone of management is focused on prevention in the form of avoiding UV light and utilizing both mechanical and chemical means of sunscreen at all times. Patients should perform what are normally day time activities at night to as much of a degree as possible. This has led to the term ’moon babies’ to describe these patients.
Other preventative measures include smoking cessation, avoiding second hand smoke and avoidance of caffeine, especially in patients who have the XP-variant. (Despite prior reports suggesting that caffeine may potentially increase the risk of non-melanoma skin cancer, recent evidence suggests that it may actually have a beneficial effect. Until further studies are available, caffeine consumption need not be altered for these patients).
Patients should undergo careful full body dermatological exams at regular 3 to 6 month intervals.
For cutaneous malignancies, early detection and treatment is ideal. Precancerous lesions need to be treated with either 5-fluorouracil, imiquimod 5% cream, liquid nitrogen, shave biopsy or curettage. There are reported cases of the benefit of 5% imiquimod cream applied once daily, twice daily or three times weekly in treating small basal cell carcinomas and slowing new tumor formation. Because of the frequent need for treatment/excisions, XP patients with malignant lesions are best treated with tissue sparing surgery (Mohs) to allow removal of tumors with narrow margins.
There has been some reported success with the use of oral isotretinoin (13 cis-retinoic acid) for the prevention of skin cancers in XP patients. In one study, five patients with XP had a total of 121 tumors in a 2-year interval before treatment and developed only 25 tumors during the subsequent 2 years on oral 2.0 mg/kg daily of isotretinoin therapy.
Once the medication was discontinued, the patients developed tumors at a frequency of 8.5-fold over the frequency during isotretinoin treatment. However, long-term oral isotretinoin therapy is poorly tolerated, as many patients develop mucocutaneous, skeletal and metabolic abnormalities, particularly in triglyceride levels and liver enzymes.
For patients with extensive photodamage, several resurfacing procedures including chemical peels, dermabrasion, carbon dioxide laser resurfacing and even full-thickness grafting have been performed to help prevent the development of skin tumors, although few studies have evaluated the long term effects of these procedural options.
A topically applied T4 endonuclease V liposomal lotion has been demonstrated to reduce the rate of new actinic kerotosis and basal cell carcinoma formation in XP patients with minimal side effects, although it is not commericially available yet. T4 endonuclease V helps repair DNA damage induced by UV-radiation by removing pyrimidine dimers.
With regards to the ophthalmological complications of the disease, the most important step in management is prevention in the form of adequate protection from UV-radiation. Patients should be annually screened by ophthalmologists and sooner if ocular abnormalities develop.
Additionally, patients with associated neurological symptoms should be carefully monitored by a neurologist at 6 month intervals.
Remember that XP patients are also at an increased risk for internal malignancies as well. Although no specific screening recommendations exist for this special population, annual check ups with the primary care physician should include a thorough history (including history of fevers, weight loss and night sweats) and physical exam (especially consisting of palpation for masses, lymph nodes and thyroid nodules). Further laboratory, imaging or diagnostic studies may be necessary if clinical suspicion for malignancy is high.
Finally, much of the current research and future direction for managing XP revolves around gene therapy, an avenue that may ultimately lead to a cure for this debilitating disease.
Patients should understand the genetic nature of the disease and that no cure currently exists for the condition. Inform patients who are considering to conceive that antenatal diagnosis in the form of amniocentesis or chorionic villus sampling is available.
Teach patients the important complications of the disease: dermatological, neurological and ophthalmological. Because patients may not appear to be very sick early in life, they may easily be lost to follow-up. It is imperative to teach parents the importance of routine visits with not only their primary care physician/pediatrician, but also the dermatologist, ophthalmologist and neurologist to ensure that the patient has the best chance of living a long and healthy life.
Counsel patients to stop smoking and to avoid second hand smoke (counsel family members to stop smoking) which can worsen the defect in DNA repair.
Teach patients to strictly avoid sun exposure/UV radiation. Remind patients and parents that UV radiation-induced damage is cumulative. In addition to applying sunscreen to all exposed skin areas at all times, patients should also wear protective clothing that covers all body areas, hats and UV protective goggles to minimize UV-induced damage.
Encourage patients to perform as many normally daytime activities at night.
Advise patients to have their homes and cars fitted with special window films that block UV light.
For school-aged children, it is important to educate school personnel (teachers and students) on the implications of having a child with XP in the classroom. Everyone must be assured that this is not a contagious disease. Protecting the patient from the effects of UV light is accomplished by keeping the child away from windows, pulling the window shades down at all times when the child is in the classroom, and reminding or helping the child to apply sunscreen on all sun-exposed areas of the body every 2 hours.
There should be an established plan and arrangement for XP patients when the school needs to be evacuated (either in an emergency or during a fire drill).
With regard to skin care, encourage patients to keep their skin well moisturized as they are particularly prone to xerosis. Teach patients to apply a moisturizer immediately after taking a shower or bath.
Because patients must avoid UV light at all times, XP patients are particularly prone to vitamin D deficiency. Therefore, advise patients to take a vitamin D supplement on a routine basis.
Teach patients how to recognize the early signs of skin cancer by monitoring for the development of new lesions or changes in size and color of existing ones (explain the ABCD’s of melanoma – asymmetry, border irregularity, color changes/unevenness, diameter increases) and to seek treatment as soon as possible when any of these changes are observed.
Encourage patients to obtain annual dental exams by dentists/oral surgeons, who can evaluate for oral lesions and dental caries (both of which are seen at a significantly increased rate).
Patients with neurological abnormalities should be followed closely by neurology.
Advise patients to obtain ophthalmological exams on at least an annual basis and sooner if they develop vision changes or other ophthalmological complaints.
Encourage patients to visit the XP Society website for more information at www.xps.org. The XP Family Support Group (www.xpfamilysupport.org) is another excellent foundation that provides support for XP patients and their families.
Unusual Clinical Scenarios to Consider in Patient Management
XP is primarily a clinical diagnosis that should be suspected in any young child who has increased sensitivity to sunlight, who easily develops severe sunburns with minimal exposure to UV light.
The de Sanctis-Caccione syndrome is a special from of XP characterized by severe neurological involvement with patients demonstrating mental retardation, growth retardation, spasticity, ataxia, immature sexual development, Achilles tendon shortening, and eventual quadraparesis.
What is the Evidence?
Daya-Grosgean, L. “Xeroderma pigmentosum and skin cancer”. Adv Exp Med Biol. vol. 637. 2008. pp. 19-27. (A detailed discussion of the molecular basis of XP is presented with sections on tumor suppressor genes, oncogenes and the impaired immune system.)
Giordano, CN, Yew, YW, Spivak, G, Lim, HW. “Understanding photodermatoses associated with defective DNA repair: Syndromes with cancer predisposition”. J Am Acad Dermatol.. vol. 75. 2016 Nov. pp. 855-870. (An excellent review of XP and other disorders associated with defective DNA repair.)
Hengge, U, Emmert, S. “Clinical features of xeroderma pigmentosum”. Adv Exp Med Biop. vol. 637. 2008. pp. 10-18. (This article provides an excellent overview of the clinical features of XP.)
Kraemer, KH, DiGiovanna, JJ, Moshell, AN, Tarone, RE, Peck, GL. “Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin”. N Eng J Med. vol. 318. 1998. pp. 1633-1637. (This study found that oral retinoid therapy benefits XP patients by significantly decreasing the rate of skin cancer formation. Doses of 2.0 mg/kg daily were found to be beneficial, although this high dose was limited by systemic side effects.)
Kraemer, KH, Lee, MM, Scotto, J. “Xeroderma pigmentosum. Cutaneous, ocular and neurological abnormalities in 830 published cases”. Arch Dermatol. vol. 123. 1987. pp. 241-250. (This comprehensive analysis of over 800 published cases of XP reviews the most common cutaneous, ocular and neurological features of the disease.)
Lambert, WC, Gagna, CE, Centurion, SA, Li, H, Lebwohl, M, Heymann, WR, Berth-Jones, J. “Xeroderma pigmentosum”. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 2006. pp. 694-698. (An excellent overview of XP is presented, which includes a summary of several major studies addressing therapeutic approaches to the disease.)
Lichon, V, Khachemoune, A. “Xeroderma pigmentosum: beyond skin cancer”. J Drugs Dermatol. vol. 6. 2007. pp. 281-288. (This article provides a comprehensive overview of the clinical features, pathogenesis and treatment of XP.)
Yarosh, D, Klein, J, O’Connor, A, Hawk, J, Rafal, E, Wolf, P. ” Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study”. Lancet. vol. 357. 2001. pp. 926-929. (In this study, 30 XP patients were randomly assigned to receive either a topical T4 endonuclease V liposome lotion or a placebo liposome lotion. After 1 year, the rate of new actinic keratoses and basal cell carcinomas was significantly less in the treatment group as compared to the placebo group.)
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.