Xeroderma pigmentosum (XP) is an autosomal recessive hereditary disease
It is a congenital sensitization of the skin to ultraviolet radiation, due to a defect in normal nucleotide excision and repair pathways involved in repairing the DNA damaged by ultraviolet radiation
More than 90% of patients with XP may have nonmalignant ocular manifestations including photophobia, blepharospasm, conjunctivitis, corneal neovascularization, dry eye, keratitis and corneal scarring, ectropion due to skin atrophy, blepharitis, conjunctival melanosis, or cataracts
The risk of developing cancer in these patients is extremely high, and malignant and premalignant conditions include conjunctival intraepithelial neoplasia, squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or keratoacanthoma
Neurologic manifestations are seen in approximately 25% of patients
There is no cure for XP, although a complete and consistent UV radiation protection is paramount
Localized ocular surface tumors can be treated by surgical excision with cryotherapy to the remaining conjunctival margins; however, diffuse lesions are more difficult to treat
With early diagnosis, appropriate protection from sunlight, and timely surveillance and management of cutaneous and ocular complications, the prognosis is generally good
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder. The worldwide prevalence is variable, affecting one per million population in the United States, 2.3 per million in Western Europe, and 45 per million in Japan.1,2,3 Higher frequencies have also been reported in North Africa and the Middle East.1,2,4,5,6,7
XP was first described in 1874 by Hebra and Kaposi8 based on four patients having thin, parchment-like dry skin, with wrinkling of the epidermis, checkered pigmentation, dilatations of blood vessels, and skin contraction. They also mentioned a red, fissured tumor that had developed on the skin within 1 year. The disease was further defined in later reports where neurologic abnormalities were described in some patients.9 In 1932, de Sanctis and Cacchione described three brothers from the same family with features of XP and mental deficiency, associated with dwarfism, gonadal hypoplasia, and progressive neurologic degeneration beginning at 2 years of age.10
As early as 1926, the disease was recognized as a congenital sensitization of the skin to ultraviolet (UV) radiation,10,11 and subsequent investigations confirmed the role of UV radiation in its pathogenesis.12 Cleaver13 described defective DNA repair in cultured skin fibroblasts, and other studies showed that XP cells were not able to eliminate UV photoproducts or to repair areas of UV-damaged DNA.14,15,16,17,18
In 1971, a variant of XP was described with normal DNA repair mechanisms and normal UV sensitivity.19,20,21,22,23 Patients with the XP variant (XPV) retain a normal nucleotide excision repair (NER) pathway but have a defect in POLH, which encodes the protein DNA polymerase eta required to replicate DNA containing unrepaired damage.20 While mostly uncommon, XPV may comprise as much as 25% of the patients with XP in Japan.6,24,25 Patients with XPV may have a clinical presentation distinct from those with NER-deficient XP and may display a delayed onset of symptoms and lack of neurologic findings, and show disease with variable severity.6,24,26 Patients with XPV typically do not sunburn or present with severe sunlight sensitivity. They tend to be spared the neurologic findings seen in many NER-deficient patients,6,24,26 and also often have a better prognosis and longer life expectancy.24 There are reports of patients with XPV having their first skin cancer as early as 7 years of age26 to as late as 71 years.6 In one study, up to 40% of patients with XPV developed melanoma, and most had nonmelanoma skin cancers.24,26
There are eight XP complementation groups, corresponding to eight genes involved in the repair of UV-induced damage in DNA. The first seven genetic groups of XP (A through G) are related to defects of genes in the NER system that are required to remove UV damage from the DNA. The eighth genetic group, XP-variant, is related to an abnormality in transcription that is required to replicate DNA containing unrepaired damage. These genetic defects are responsible for the wide variability in clinical features both between and within XP groups.27,28,29,30,31,32,33,34,35 Patients with XP from complementation groups C, E, and V (where TC-NER is preserved) have normal sunburn reactions and do not develop manifest neurodegeneration,36 but they have an earlier age of onset of first skin cancer. However, patients with XP from complementation groups A, B, D, F, and G (where TC-NER is impaired) have severe and exaggerated sunburn reactions on minimal sun exposure and suffer neurodegeneration.36
The diagnosis of XP is made largely on clinical presentation and manifestations. These include acute sunburn reaction from birth, early lentiginosis, or onset of skin cancers at a very young age4 and can be confirmed by cellular tests for defective DNA repair.
Etiology and Pathogenesis
UV light is the most mutagenic component of sunlight.37 Solar UV radiation is grouped into three ranges of wavelength: UVC (200-280 nm), UVB (280-320 nm), and UVA (320-400 nm) light.38 UVB and UVA can pass through the Earth’s ozone layer, and UVA contributes 95% of the total UV energy that reaches the surface.39 Moreover, the wavelengths of UVA can penetrate more deeply into exposed skin, where they can initiate cell damage.39,40,41
UV-induced mutagenesis is characterized by a high frequency of transition mutations at dipyrimidine sequences containing cytosine,42 resulting in dipyrimidine DNA photoproducts. In XP, unrepaired DNA segments lead to errors during replication, incorporating the wrong nucleotides in regions of UV damage. In addition, UVA photons induce photosensitization reactions that form reactive oxygen species that cause DNA damage,43,44,45,46,47 by oxidation, single- and double-stranded breaks, and cross-links between DNA and proteins.48,49,50
UV-damaged DNA bases are repaired by the NER system. This involves two distinct pathways. The global genome repair (GG-NER) pathway recognizes damage in DNA that is not being transcribed and is capable of repairing photodimers in chromatin of different compaction levels and different functional states. The transcription-coupled repair (TC-NER) pathway recognizes when RNA polymerase stops in transcriptionally active genes and enables quick resumption of UV-inhibited transcription by efficient repair of the photodimers.51 Mutations affecting individual components of these subpathways result in clinical syndromes. Defects in the GG-NER components (seen in XPC and XPE types) usually lead to pure XP with no neurologic abnormalities. Defects in TC-NER lead to XP with severe neurologic abnormalities.
The repair of UV-induced DNA damage involves several steps.52 The UV-induced nucleic acid-based photoproducts serve as a substrate for DNA repair that is mediated by the transcription-coupled and global genome NER repair pathways.51 These lead to unwinding of the DNA helix in the region of damage, excision of small fragments of the damaged genome, and repair by DNA synthesis pathways that involve DNA polymerase and ligases.
The clinical manifestations of XP are seen most commonly in sun-exposed areas of the skin and mucous membranes. Some patients show a relatively normal response to sun exposure, but about 60% have an exaggerated response to UV exposure with pronounced burning and blistering even with minimal exposure to sunlight. All affected patients develop freckle-like pigmentary changes in skin areas exposed to the sun and eventually develop poikiloderma, which consists of areas of hyperpigmentation and hypopigmentation, skin atrophy, and telangiectasias (Figure 125.1). This freckling pigmentation usually appears before the age of 2 years.