Xeroderma pigmentosum: beyond skin cancer

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XERODERMA PIGMENTOSUM: BEYOND SKIN CANCER Vanessa Lichon BS MS4,a Amor Khachemoune MD CWS b a. Fourth year medical student, University of Illinois, Chicago, IL b. New York University Medical Center, New York, NY

Abstract Xeroderma pigmentosum (XP) is a rare, autosomal-recessive inherited disease that is found worldwide at a frequency of approximately 1:250,000. XP is caused by a deficiency in either nucleotide excision repair (NER) or postreplication repair (PRP), and is characterized by severe actinic changes leading to early onset of skin cancers, various ocular manifestations, and occasional neurological abnormalities. Diagnosis is usually made clinically and can be confirmed by unscheduled DNA synthesis. Early preventative care is the most important treatment modality. We present a review of the history, clinical manifestations, pathogenesis, diagnosis, and treatment of XP.

Introduction

Clinical Presentation

Xeroderma Pigmentosum (XP) is a rare, autosomal-recessive inherited disease that is found worldwide at a frequency of approximately 1:250,000 and more commonly in Japan with an occurrence of approximately 1:40,000.1-3 XP affects men and women equally3,4 and all races including Caucasians, African Americans, Asians, and Native Americans.3,5,6 XP is caused by abnormal DNA repair and is characterized by extreme photosensitivity, photophobia, early onset of freckling, early onset of skin cancer with a 1,000-fold increase in malignant neoplasms, and occasional neurological abnormalities.1,2,5,7

Individuals with XP present with a variety of signs depending on the severity of their disease. All will have skin hypersensitivity to ultraviolet (UV) light, the majority will have ocular abnormalities, and approximately 30% will have neurological abnormalities.5 The most devastating part of this disease is the increased incidence of early onset cutaneous neoplasms.5

Historical Perspective In 1870, Moritz Kaposi8 first used the term “xeroderma” to characterize the dry, dyspigmented skin that is the first permanent cutaneous change observed in patients with this disease; 12 years later he added “pigmentosum.”9 The first XP case with neurological signs was described by Dr. Albert Neisser10 and in 1932, DeSanctis and Cacchione11 helped coin the term “DeSanctis-Cacchione syndrome” to apply to cases of XP with severe neurological deficiency. In 1968, James Cleaver12 conducted a study which demonstrated that fibroblasts from patients with XP were unable to perform nucleotide excision repair of DNA. This discovery was later confirmed by Richard Setlow13 and his research team, as well as John Epstein14 and his coworkers.

Complementation Groups In 1972, De Weerd-Kastelein15 and associates established the genetic heterogeneity of XP through cell fusion experiments, which led to the classification of XP into 3 complementation groups.15,16 This designation was expanded to 5 groups (XPA-XPE) by Kraemer et al17,18 in 1975 and a few years later a sixth (XPF)19 and seventh (XPG)20 complementation group were added. The XP variant (XPV) was named by Burk21 and associates in 1971, but was first described as “pigmented xerodermoid” by Jung22 in 1970. Research by Cleaver23 and associates in 1980 demonstrated that the defects in pigmented xerodermoid and XPV were identical, and use of the term pigmented xerodermoid was discontinued.24

Skin At birth, an individual’s skin is healthy, but is soon damaged with minimal sun exposure.2 By the age of 6 months, individuals demonstrate acute sun sensitivity characterized by diffuse erythema, edema, and bullae, then xerosis and scaling follow.2,5,6,25 Multiple freckle-like hyperpigmented macules present by the median age of one to 2 years and are frequently described as “freckles” or ephelides but are actually solar lentigines that retain their color for many years.2,5,25 Actinic changes accumulate leading to poikiloderma characterized by skin atrophy, telangiectasias, and patches of hyperpigmentation and hypopigmentation.2,5,6 Areas of achromia may repFigure 1. XP patient with severe actinic cheilitis, solar lentigines, extensive actinic changes on nose, upper cheeks, and upper eyelids with a scar from previous surgery for a basal cell carcinoma on the left side of the tip of the nose.

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Table 1. Clinical manifestations of xeroderma pigmentosum.

System

Clinical Features

Cutaneous

Limited to sun-exposed areas Erythema and bullae6,25 Freckles, or solar lentigines6,25 Xerosis, scaling6 Hyperpigmentation, hypopigmentation6,25 Telangiectasia5,6,25 Atrophy5,6,25 Increased risk of skin tumors including: actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, pigmented lesions5,6,25 Keratoacanthoma, angioma, fibroma, sarcoma25

Ocular

Lids Inflammation, erythema and pigmentation6,25 Atrophy → entropion, ectropion, loss of cilia and loss of lower lid5,6,25 Neoplasms including papilloma, epithelioma of free border of lid, and basal and squamous cell carcinomas of lids5,6,25 Conjunctiva Inflammation with photophobia, lacrimation and edema6,25 Dryness, pigmentation and telangiectasia6,25 Neoplasms including intraepithelial epitheilomas and squamous cell carcinomas5,6,25 Cornea Inflammation, edema, vascularization6,25 Dryness, opacification, ulceration and scarring6,25 Neoplasms6,25 Iris Inflammation, atrophy and neoplasms6,25

Neurological

Microcephaly6,25 Cerebral dysfunction including low intelligence, progressive mental retardation, abnormal electroencephalogram6,25 Ventricular dilation and cortical atrophy25 Basal ganglia involvement leading to choreoathetosis6,25 Cerebellar involvement leading to ataxia, dysarthria, and abnormal eye movements6,25 Pyramidal tract involvement leading to extensor plantar response and spasticity6,25 Sensorineural deafness6,25 Peripheral neuropathy25 DeSanctis-Cacchione syndrome: microcephaly, growth retardation, immature sexual development, progressive mental deterioration, low intelligence, hyporeflexia, choreoathetosis, ataxia, spasticity, Achilles tendon shortening leading to eventual quadraparesis5

Other

Increased risk for internal malignancies including sarcomas, medulloblastomas, lung, central nervous system, uterine, breast, pancreatic, gastric, renal, testicular tumors, and leukemias5

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resent mutated melanocytes that have lost their ability to produce melanin.25 At an early age, individuals develop numerous actinic keratoses, basal, and squamous cell carcinomas.5,6 As children, these individuals experience accelerated photoaging, and often their skin is described as looking like the skin of farmers or sailors who have had many years of chronic sun exposure.5

a median age onset of nonmelanoma skin cancer at 8 years.5,7,26 This presentation is almost 60 years before the general population, and occurs commonly in this disease.5 Individuals with XP are also at a 10- to 20-fold increased risk for other internal malignancies including sarcomas, medulloblastomas, lung, central nervous system, uterine, breast, pancreatic, gastric, renal, and testicular tumors, as well as leukemias.5,27

Cancer Individuals with XP who are under 20 years old have a greater than 1,000-fold increase in risk for developing basal cell carcinoma, squamous cell carcinoma, or melanoma, with

Ocular Abnormalities Individuals with XP may also develop ocular abnormalities in any UV-exposed structure (Table 1) including the eyelid,

Table 2. Classification of genes involved in xeroderma pigmentosum (XP).

Skin Cancer5

Neurological Abnormalities5

DNA Repair, Approximate % of Normal5

9q22.3

Yes

Mild or severe