Last Updated on October 29, 2023
Xeroderma pigmentosum is a genetic disorder of extreme sensitivity to ultraviolet light and is characterized by photosensitivity, pigmentary changes, premature skin aging, and malignant tumor development.
It is transmitted as an autosomal recessive character caused by defective repair of the damage to DNA induced by sunlight.
The frequency is about 1 case per 250,000 population
Groups XPA and XPC are the most common types [see below]
The disease is usually detected at age 1-2 years. And there is no gender or racial predilection.
About two-thirds of the patients die by age of 20 years
The most common causes of death are skin cancer.
Pathophysiology of Xeroderma Pigmentosum
The basic defect in xeroderma pigmentosum is in nucleotide excision repair (NER), leading to deficient repair of DNA damaged by UV radiation.
This procedure is concerned with removal and the replacement of damaged DNA with a new one.
There are two types of nucleotide excision repairs
- Global genome (GG-NER)
- Transcription-coupled (TC-NER)
Seven xeroderma pigmentosum repair genes are identified. These are named XPA, XPB, XPC, XPD, XPE, XPF and XPG.
Their key roles are below
- Detection of DNA damage [Damage sensing phase] – XPA and XPC
- Formation of open complex – XPG, XPB, XPD
- Coding of endonucelases – XPG and XPF
- Repair by gap filling by new DNA by polymerases
- New DNA by polymerases.
Defects in these genes lead to defect in repair.
Most common affected is XPA.
The occurrence of skin cancer is attributed to continues the presence of repair proteins at sites of DNA damage.
In addition, UV-B radiation causes immunosuppression which could be contributory. The decrease in Langerhans cells, poor immune response, decreased T-cells and impaired production of interferon in lymphocytes may occur.
Natural Course of Xeroderma Pigmentosum
Xeroderma pigmentosum typically passes through three stages.
At birth, the skin is healthy.
The first stage appears after about 6 months.
Following are the features of this stage
- Diffuse erythema
- Scaling
- Freckles
The findings are seen in the light-exposed areas and may begin on the face and then progress to the rest of the body.
Changes initially may be less pronounced in winters/decreased sun exposure but become permanent over the period.
The second stage is characterized by poikiloderma [areas of hypopigmentation, hyperpigmentation, telangiectasias and atrophy]
The third stage is suggested by the appearance of numerous malignancies which could be
- Basal cell carcinoma
- Squamous cell carcinoma
- Melanoma
- Fibrosarcoma
These malignancies are more prevalent in exposed areas.
Eye Problems causes by sun-exposure are seen in 80%
- Photophobia
- Conjunctivitis
- Keratitis
- Atrophy of the skin of the lids
- Eyelid solar lentigines
- Ectropion
- Symblepharon [partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball] with ulceration
- Infections and scarring might develop in these patients
- Pterygium
- Malignancies
- Epitheliomas
- Squamous cell carcinoma
- Basal cell carcinoma
- Sebaceous cell carcinoma
- Fibrosarcoma can also involve the eyes of patients with xeroderma pigmentosum.
About one-fourth of affected individuals of xeroderma pigmentosum also have neurologic manifestations
- Acquired microcephaly
- Diminished or absent deep tendon stretch reflexes
- Progressive sensorineural hearing loss
- Progressive cognitive impairment
- Hyporeflexia or areflexia
- Segmental demyelination [loss of myelin sheath]
- Mental retardation.
Clinical Presentation of Xeroderma Pigmentosum
Photosensitivity should be suspected and evaluated in any patient with intermittent or persistent abnormalities in light-exposed areas.
A history of severe persistent sunburn can be found in many patients.
As the disease is autosomal recessive, usually, no family history is present as parents could be heterozygous.
The earliest manifestations may consist of photophobia [fear of light] and mild erythema on the checks which usually starts in infancy.
With advancing age, the patient develops hyperpigmented macular lesions somewhat resembling freckles, which first appear on the areas exposed to sunlight, but later these spread to the unexposed sites as well.
At any time, however, these are always most numerous on the exposed parts.
After a few years, a few small depigmented macules appearing in between the hyperpigmented macules can also be seen and the skin starts showing signs of atrophy as well as hypertrophy in several localized areas.
In the later stages, the patient develops multiple malignant tumors which may consist of squamous cell epitheliomas, basal cell epitheliomas, malignant melanomas or even fibrosarcomas and this change usually leads to a fatal termination.
The rate of progression of the disease is quite variable; some patients live an almost normal lifespan, while others may terminate fatally even in childhood due to early malignancies.
Some patients have associated neurologic defects such as mental deficiency, areflexia, impaired speech and hearing, convulsions and microcephaly.
Ocular changes apart from photophobia may include ectropion, entropion, conjunctivitis, keratitis and ocular neoplasms.
Differential Diagnoses
- Acanthosis Nigricans
- Bloom Syndrome
- Ephelides (Freckles)
- Hartnup Disease
- Porphyria Overview
- Werner Syndrome
Diagnostic Work Up
The tests are available only in specialized labs and include
- Cellular hypersensitivity to UV radiation and chromosomal breakage studies
- Different doses of ultraviolet rays are given to the fibroblasts of the patient
- Chromosome breakage is evaluated and compared with the patient’s parents and controls
- Can aid in prenatal diagnosis in at-risk fetuses
- Complementation studies
- Assessment of DNA repair
- Gene sequencing
Treatment of Xeroderma Pigmentosum
Patients should be protected from sunlight.
- Sunscreens
- Apply on exposed parts
- Both physical or chemical type can be used
- SPF [sun protection factor should be more than 15
- Protective clothing
- Oral retinoids
- Reduce the incidence of skin cancer
- Chemical therapy with 5-fluorouracil
- Repair of damaged DNA after exposure
- Topical application of DNA repair enzymes
- Delivery into the skin by engineered liposomes
- Gene therapy
- It is still in an experimental stage
- Surgery
- Tumors should be surgically removed
Patients should receive follow-up care every 3 months.
Genetic counseling and antenatal diagnosis should be considered by amniocentesis or chorionic villi sampling.
Prognosis
Multiple cutaneous neoplasms develop at a young age. 8 years is the mean age in persons with xeroderma pigmentosum. Death is usually caused by metastatic malignant melanoma or squamous cell carcinoma.
Less than 40% of patients survive beyond the age of 20 years. Death often occurs due to the metastatic spread of malignancies. Metastatic malignant melanoma and squamous cell carcinoma are the most common causes.
Those with milder disease usually live till middle age.
References
- DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J Invest Dermatol. 2012 Mar. 132(3 Pt 2):785-96
- Schaffer JV, Orlow SJ. Radiation Therapy for High-Risk Squamous Cell Carcinomas in Patients with Xeroderma Pigmentosum: Report of Two Cases and Review of the Literature. Dermatology. 2011 Oct 21.
- Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 1987 Feb. 123(2):241-50.
- Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988 Jun 23. 318(25):1633-7.
