Brief Summary of Disease
Sandra Webb found it concerning that at just 7 weeks old her son Alex Webb developed a severe burn from minor sun exposure through a car window. This began a series of sunburns, pigmented spots, and patches of dry flaky skin that Alex would endure throughout his entire early childhood, some developing as quickly within being outdoors for 15 minutes. It was not until he was 3 years old that a dermatologist diagnosed him with xeroderma pigmentosum (XP), a rare autosomal disease that affects 1 in every 250,000 individuals of all races and both genders.1 The prevalence rates of XP are 6 times more common in Japanese people than any other ethnic group. The disease primarily affects the skin due to a genetic inability to repair DNA damage caused by the sun’s ultraviolet light.1,2 The doctor told his mother that unless Alex was kept indoors and out of sunlight at all times, he would not make it past 30 years old.
Etiology & Pathology
DNA in our skin cells is prone to damage by ultraviolet light from the sun, which is why healthcare professionals often stress the importance of sunblock and minimizing extreme sun exposure. One of the ways that ultraviolet light can affect DNA is by mutating it or causing a change in the DNA sequence that is not supposed to be there. Our bodies possess repair mechanisms that are able to detect these mutations and fix them so they don’t negatively affect the cell. The products of seven genes (XPA to XPG) are involved in the repair of UV damage in the DNA through nucleotide excision repair. However, individuals with XP are born without this functioning repair mechanism, which means any mutations that occur in the DNA are not fixed and go on to damage the cell and its functions.3,4
The presence of severe sunburns that result in dry flaky skin is a hallmark symptom of XP. Additionally, freckles can develop all over the skin and eyes become bloodshot and cloudy from being extremely sensitive to the sun. 1 in 5 patients are also affected by neurological abnormalities and a progressive loss of neurons, which could result in growth delays, microcephaly, and deafness.6 Irregular spots and moles that form often become tumorous, making skin cancer the most common cause of death for XP patients.7 It is recommended that individuals with XP go through screenings every three months by a dermatologist and have annual ophthalmological and neurological assessments to manage their symptoms.
Specific DNA testing, genetic family history exams, and skin biopsies that study an individual’s skin cells in a laboratory are the ways XP can be diagnosed. Due to its rare nature, XP is often misdiagnosed as just a sun allergy, which is an immune system reaction to sunlight and results in itchy red rashes, hives, or blisters on the skin.6 Patients with sun allergies differ from those with XP, as they are not lacking DNA repair mechanisms. A sun allergy will trigger an immune response to sun exposure that can be managed with antihistamines, unlike XP which has no available drug treatment to date.1,6
Since his diagnosis, Alex’s daily prescribed routine consists of applying sunscreen on his entire body every two hours, taking vitamin D supplements, wearing long-sleeved shirts and pants for the entire year, and a face mask and gloves if ever outdoors. There is currently no known cure for XP, however avoiding the sun and regular follow-ups to assess for skin cancers can increase life expectancy.
XP is a rare disease that begins to affect the individual early on in life, as sunlight is extremely hard to avoid and many parents initially raise their children unknowing of their condition. This causes the onset of symptoms to appear immediately from minimal sun exposure, which is why even newborns up to a few weeks old are able to develop severe sunburns.
The cumulative effects of XP on the skin has been linked to understanding human aging and cancer. Risks of melanoma skin cancer increase as people age, with the average age of diagnosis being 63. However, individuals with XP can be diagnosed with melanoma skin cancer as young as 8.1,7 Clinical studies have found skin cancer in those with XP occurs at rates over 1000 times greater than average, which emphasizes the importance of DNA repair for cancer prevention in the general population.7 Naturally with age, many DNA repair mechanisms become less efficient in the body, which increases risks of irreversible damage. XP showcases an accelerated aging process of what can result over an average lifetime of accumulated UV damage from sun exposure and the body’s decreased ability to cope with repair. As a result, research has largely shifted to focus on the assessment of patients affected by XP, as greater understanding of this rare disease could provide insight on skin cancer prevention and detection.
Xeroderma Pigmentosum Society
The Xeroderma Pigmenotsum Society is based in Crayville, New York. The XP Society offers international support, advocacy, and protection to the XP family, patient, and caregiver while promoting research in the founder for a cure.
XP Family Support Group
The XP Family Support Group is based in Sacramento, California, and exists to improve the quality of life persons of those with XP and other diagnosed UV light conditions. The group raises funds for creating awareness and educate the public about XP, give grants for ultraviolet protective equipment and products, and helps families attend annual xeroderma pigmentosum conventions at various locations.
1. Webb S. Xeroderma pigmentosum. BMJ. 2008;336:444-446. doi:10.1136/bmj.39485.698356.AD.
2. Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis. 2011;6:70. doi:10.1186/1750-1172-6-70.
3. Berneburg M & Lehmann AR. Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. Adv Genet. 2001;43:71-102.
4. Cleaver JE. Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmenotsum. J Dermatol Sci. 2000;23(1):1-11.
5. DNA proofreading and repair. Khan Academy Biology website. https://www.khanacademy.org/science/biology/dna-as-the-genetic-material/dna-replication/a/dna-proofreading-and-repair. Updated Jan 9, 2015. Accessed Mar 6, 2018.
6. DiGiovanna JJ & Kraemer KH. Shining a light on xeroderma pigmenotsum. J Invest Dermatol. 2012;132(302):785-796. doi:10.1038/jid.2011.426.
7. Kano Y & Fujiwara Y. Defective thymine dimer excision from xeroderma pigmentosum chromatin and its characteristic catalysis by cell-free extracts. Carcinogenesis. 1983; 4(11):1419-24.
Cite This Article:
Khalid S., Chan G., Palczewski K., Lewis K., Ho J. Xeroderma pigmentosum. Illustrated by R. Michaels-Walker. Rare Disease Review. January 2019. DOI:10.13140/RG.2.2.19617.04963.