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.