Patient Presentation A 20-year-old Caucasian female presented to the dermatologic surgery clinic with complaints of a slow-growing, erythematous papule on her right upper cheek. She first noted this lesion 3 months ago. She had a history of sun sensitivity since childhood, and has had three prior facial skin surgeries. There is no family history of cancer. On examination, the patient had fair and sun-damaged skin, numerous solar lentigines, and an ill-defined 6-mm x 5-mm erythematous to pearly papule with overlying telangiectatic borders on the right upper cheek. The patient had two linear scars on her right cheek from previous surgeries. The rest of the examination was within normal limits. What is Your Diagnosis? Diagnosis:Basal Cell Carcinoma in a Patient with Xeroderma PigmentosumXeroderma pigmentosum (XP) is a rare, autosomal recessive inherited disease caused by abnormal DNA repair of ultraviolet (UV) induced damage that occurs in the United States at a frequency of approximately 1 in 250,000.1,2 XP is found worldwide in all races,2,3 more commonly in Japan (frequency there being about 1 in 40,000),2 and affects men and women equally.2 XP is characterized by early sun sensitivity with numerous cutaneous changes, ocular abnormalities, and occasional neurological abnormalities.4 Patients usually develop cutaneous malignancies including basal cell carcinomas, squamous cell carcinomas, and melanomas as part of their clinical disease.4HISTORYMoritz Kaposi introduced the terms “xeroderma” in 18705 and “pigmentosum” in 18826 to describe the skin changes detected in patients with this disease. Dr. Albert Neisser7 is attributed with describing the first case of XP with neurological signs. In 1932, the term “DeSanctis-Cacchione syndrome” was introduced by DeSanctis and Cacchione for patients with severe neurological deficiencies.8Research by James Cleaver in 1968 demonstrated that cells from XP patients were unable to complete nucleotide excision repair, a part of DNA repair.9 In 1972, studies by De Weerd-Kastelein10 et al. demonstrated through cell fusion the genetic heterogeneity of XP, which classified patients into three complementation groups.11 Today, patients with XP are classified into eight composite groups (XPA-XPG, XPV).4 PATHOGENESISPatients with XP have a deficiency in DNA repair. Typically, UV light-induced skin damage is repaired by either nucleotide excision repair (NER) or post-replication repair (PRR).12 Mutations in XP genes generate a defect in one of these processes, leading to the synthesis of error-filled DNA that produces atypical cells.13 These cells have abnormal proliferation resulting in the early development of malignancies.13 Patients with XP can be divided into eight complementation groups based on the affected gene.12 Individuals with defects in NER are part of complementation groups XPA-XPG, while those with a defect in PRR make up complementation group XPV.4,12 Two bands of UV light, UVA and UVB, contribute the most to the development of DNA aberrancies, cyclobutane pyrimidine dimers and 6-pyrimidine-4-pyrimidone photoproducts.14 These errors are normally repaired by NER, but in approximately 80% to 90% of XP patients, the genes that regulate NER are mutated.15 Without NER, individuals become more prone to developing malignancies where damaged DNA is not removed.14,16,17The remaining 10% to 20% of patients with XP have normal NER, but abnormal PRR.15 These patients have a mutation on their XPV gene that produces a defective DNA polymerase.18 This error causes the failure of DNA polymerase to recognize and remove DNA lesions, allowing DNA synthesis to occur past these lesions, and producing damaged DNA.18CLINICAL FEATURESThe severity of XP depends largely on the amount of UV exposure and the quantity of residual DNA repair.19 All XP patients develop early skin changes, most have ocular abnormalities, and approximately 30% suffer from neurological anomalies.4 Any patient under the age of 20 is at a greater than 1000-fold risk for developing cutaneous squamous cell carcinoma, basal cell carcinoma or melanoma as compared to the unaffected individual.4,13,20 The median age of onset for non-melanoma skin cancer in XP patients is 8 years old.4 Additionally, XP patients are at a 10- to 20-fold increase in risk for developing an internal neoplasm.4Skin. Patients with XP have healthy skin at birth, but by a median age of 1 to 2 years develop cutaneous symptoms.4,21 One of the first features identified is multiple freckle-like hyperpigmented macules that appear on any UV exposed surface.4 These macules, or solar lentigines, retain their color for many years and are often accompanied by diffuse erythema, bullae, edema, and eventually xerosis and scaling.1,4,21 With continued UV exposure the skin becomes atrophic, develops telangiectasia and multiple patches of hyper- and hypopigmentation.1,2,4 As actinic changes accumulate, XP patients develop multiple actinic keratoses.2 By age 3 to 4 years, a patient may have his or her first malignant skin tumor.2 Numerous basal cell carcinomas and squamous cell carcinomas are more typically seen than melanomas.2Ocular lesions. The majority of XP patients have ocular abnormalities limited to UV-exposed structures of the eye (lids, cornea, conjunctiva, cornea and iris).1,3,22 The most common symptoms are photophobia and conjunctivitis.2,21 In more advanced cases patients may develop entropion or ectropion, loss of lids, corneal opacities, or loss of vision.1,4,13 Severe damage may lead to cancer of the eye including intraepithelial epitheliomas and squamous cell carcinomas.1,13Neurological features. Approximately 30% of individuals with XP have associated neurological complications that range from mild to severe.4 A few of the more common neurological findings include progressive mental retardation, sensorineural deafness, seizures, spasticity and isolated hyporeflexia.4,12 Individuals with severe neurological deficiencies have DeSanctis-Cacchione syndrome, which includes microcephaly, progressive mental deterioration, eventual quadraparesis due to achilles tendon shortening, dwarfism, immature sexual development, choreoathetosis, ataxia and spasticity.1,3,4 Neurological abnormalities are only found in complementation groups XPA, XPB, XPD and XPG.4DIAGNOSIS AND DIFFERENTIAL DIAGNOSESDiagnosis of XP is usually made clinically by identifying the classic features of XP: early onset of skin changes including acute sun sensitivity reaction with minimal UV exposure, hyper- and hypopigmented macules and patches, xerotic scaly skin and severe actinic changes.23,24 At an early age numerous premalignant and malignant skin lesions are identified and help establish the diagnosis.24 Laboratory confirmation can be achieved by unscheduled DNA synthesis.19,23 Generally, other photosensitive disorders can be excluded based on clinical presentation.24 Other diseases to rule out include sun-sensitive porphyrias, nevoid basal cell carcinoma syndrome, Rothmund-Thomson syndrome, Fanconi anemia, Bloom syndrome, Cockayne syndrome, Hartnup-syndrome, progeria, and acrogeria.2,24MANAGEMENTThe mainstay of treatment for XP is avoidance of sunlight combined with surgical removal of premalignant or malignant lesions.24 Preventative therapy must begin immediately following diagnosis of XP and involves meticulous self-care when outdoors.2 Individuals should wear two layers of clothing, use broad-brimmed hats, wear UV-protective sunglasses or goggles, and apply broad-spectrum (encompassing UVB and UVA) sunscreens with a minimum sun protective factor rating of 15 to all sun-exposed areas.2,4 If possible, patients should stay indoors during daylight hours and avoid windows and direct exposure to fluorescent lightbulbs.2,4Patients of complementation group XPV should avoid other triggers of defective DNA repair like caffeine, smoke, and toxic fumes.24 Peri-operative precautions for XP patients requiring surgery include shielding from damaging lights, avoiding drugs that damage DNA such as halothane, and evaluating for neurological abnormalities.25 It is strongly recommended that patients with XP be regularly followed by an interdisciplinary team of specialists including a dermatologist, an ophthalmologist, and if necessary, an oral surgeon (for cancer in exposed areas like tip of the tongue) and a neurologist.24 Individuals must be educated about their care and the importance of being proactive. They should be counseled on how to consistently monitor themselves for the development of new skin or non-skin lesions and to observe existing lesions or growths for changes in size or color.4,21 A dermatologist should examine all cutaneous lesions or growths, and any precancerous spots should be treated with topical 5-fluorouracil (Carac, Efudex, Fluoroplex), liquid nitrogen, or shaving with or without curettage.26 Any suspicious lesion requires a biopsy and, if malignant, should be removed by electrodessication and curettage, surgical excision or Mohs micrographic surgery depending on the type of cutaneous malignancy.4 Wider excisions are necessary if melanoma is diagnosed.24In some instances, the application of imiquimod 5% cream (Aldara) has been demonstrated to clear small superficial basal cell carcinomas.27 Studies by Kraemer et al. demonstrated that high- dose oral retinoids could prevent the development of new skin cancers, but this treatment is not recommended in the pediatric population and is limited in adults due to toxic systemic side effects (especially liver function tests) and rapid tumor growth after discontinuation of the medication.4,28,29A few reports have suggested resurfacing procedures for prophylaxis against the development of skin tumors.24,30 Further long-term research is necessary to determine the utility of procedures such as full-thickness grafting, dermabrasion, and chemical peels for XP patients.24On the HorizonResearch by Yarosh et al. focuses on re-enabling cells to perform DNA repair by delivering an enzyme capable of restoring NER.31,32 In 1975, Tanaka33 et al. determined that T4 endonuclease V (T4NV), a bacteriophage DNA repair enzyme, could recognize DNA lesions such as cyclobutane pyrimidine dimers, cleave at their sites, and allow the production of error-free DNA.31 Recently, Yarosh and associates were able to deliver this enzyme to cells via liposomes in a topically applied cream with minimal systemic side effects.24,32 In a trial of XP patients that used T4NV lotion for 1 year, individuals demonstrated a 68% reduction in the rate of new actinic keratoses and 30% reduction of new basal cell carcinomas.32 Unlike oral retinoids, 6 months after discontinuation of treatment, rates of cutaneous malignancies did not increase.32 Although these results seem promising, further research regarding the regulation of T4NV lotion is necessary before this therapy becomes available to the public.24Gene therapy is the latest hope for treating individuals with XP. Recent studies by Magnaldo and Sarasin target individuals with XPC because they lack neurodegenerative abnormalities and total more than half of XP patients in North Africa and Europe.34 By using recombinant retroviruses, gene therapy attempts to restore DNA repair in XPC patients.19 This treatment modality requires further development before it can be clinically tested.24,34 MORE RESEARCH NEEDEDThe future treatment of XP patients places hope in finding ways to restore cellular DNA repair. Further research is needed to evaluate the clinical applicability and long-term outcomes of protein and gene therapy. For now, the optimal management of XP is early diagnosis, immediate preventative care against UV light exposure, and proper treatment of manifesting skin lesions.