Xeroderma Pigmentosum: A Model for Human Premature Aging

Abstract

Aging results from intrinsic changes (chronologic) and damage from external exposures (extrinsic) on the human body. The skin is ideal to visually differentiate their unique features. Inherited diseases of DNA repair, such as xeroderma pigmentosum (XP), provide an excellent model for human aging due to the accelerated accumulation of DNA damage. Poikiloderma, atypical lentigines, and skin cancers, the primary cutaneous features of XP, occur in the general population but at a much older age. Patients with XP also exhibit ocular changes secondary to premature photoaging, including ocular surface tumors and pterygium. Internal manifestations of premature aging, including peripheral neuropathy, progressive sensorineural hearing loss, and neurodegeneration, are reported in 25% of patients with XP. Internal malignancies, such as lung cancer, CNS tumors, and leukemia and/or lymphoma, occur at a younger age in patients with XP, as do thyroid nodules. Premature ovarian failure is overrepresented among females with XP, occurring 20 years earlier than in the general population. Taken together, these clinical findings highlight the importance of DNA repair in maintaining genomic integrity. XP is a unique model of human premature aging, which is revealing new insights into aging mechanisms.

Figure 1.

Clinical features of premature aging in patients with xeroderma pigmentosum. [Patients or their parents or guardians gave permission for publication of their images.] A. Two-year old girl with XP-C (XP358BE) who did not have acute burning on minimal sun exposure but presented with pigmented skin lesions (lentigos) and a squamous cancer of the lip. [From (Bradford et al., 2011)] B. Sensorineural deafness can be improved in some patients with hearing aids (XP12BE). C. Relatively protected buttocks skin (covered by double clothing layers) of 35-year old man shows sparing of the pigmented skin lesions (lentigos) of photodamage (XP19BE). D. Thirty-five-year old XPC patient (XP24BE) had approximately 200 skin cancers including 11 melanomas in situ and one invasive melanoma. This irregularly pigmented skin lesion is one of her melanoma-in -situ lesions. [From (Lai et al., 2013)] E. 31-year old woman (XP572BE) with inflammation and scaling of the lips (cheilitis); atrophy and telangiectasias of the tip of tongue. F. Squamous cell carcinoma tip of the tongue in a 21-year old African man (XP393BE). [From (Mahindra et al., 2008)] G. Reduced age at skin cancer onset in XP. Xeroderma pigmentosum (XP) skin cancer by age at first skin cancer diagnosis and skin cancer type compared to US general population. Upper panel: Proportion of non-melanoma skin cancer (NMSC) patients diagnosed at selected ages. Lower panel: Proportion of melanoma patients diagnosed at selected ages. Individuals with both NMSC and melanoma were used for both analyses. [From (Bradford et al., 2011)] H. Seventeen-year old African boy (XP394BE) with reduced vision from corneal clouding and scarring of the UV exposed tissues of the eye. He has a red, vascular, inflammatory corneal mass (pterygium) on the right side of the image and a white ocular surface tumor. I. Brain of a 36-year old woman with XP-A (XP12BE) at autopsy with severe atrophy weighed equivalent to a 6-month old infant. [From (Lai et al., 2013)]