Xeroderma pigmentosum

What is xeroderma pigmentosum?

Xeroderma pigmentosum (XP) is a very rare skin disorder where a person is highly sensitive to sunlight, has premature skin ageing and is prone to developing skin cancers.

Xeroderma pigmentosum is caused by cellular hypersensitivity to ultraviolet (UV) radiation, as a result of a defect in the DNA repair system. Xeroderma pigmentosum has also been called DeSanctis-Cacchione syndrome.

Dry scaly skin 

Tumour on tongue 

Squamous cell carcinoma on upper lip 

See more images of xeroderma pigmentosum.

What causes xeroderma pigmentosum?

Xeroderma pigmentosum is an autosomally recessive inherited disease, which means that a faulty xeroderma pigmentosum gene comes from each parent. Carriers of the xeroderma pigmentosum trait have one xeroderma pigmentosum gene and one normal gene and do not show signs or symptoms of the disease.

The signs and symptoms of xeroderma pigmentosum are a result of an impaired nucleotide excision repair (NER) system. Two types of NER have been identified:

• Genome (GG)-NER
• Transcription-coupled (TC)-NER.

At least seven different gene abnormalities or complementation groups have been described in different families (XPA to XPG) resulting in varying disease severity.

• XPA and XPC are relatively common
• XPE is fairly rare
• XPG is severe
• XPF is mild and may only demonstrate unusually severe sunburn reactions.

In addition to the genetic abnormality, the immunosuppressive effects of exposure to ultraviolet radiation (UV) contribute to the disease, for example by depleting Langerhans cells from the epidermis.

Who gets xeroderma pigmentosum?

Couples who are each a carrier of the xeroderma pigmentosum trait are at greater risk of producing a child with xeroderma pigmentosum. Parents already with a child with xeroderma pigmentosum have a 1 in 4 chance of having another child with xeroderma pigmentosum.

Xeroderma pigmentosum occurs worldwide and affects men and women of all races. XPA is shown to be more common in Japan than elsewhere.

What are the symptoms of xeroderma pigmentosum?

The disease usually progresses through 3 stages. The first stage occurs around 6 months after birth (skin appears normal at birth).

• Areas exposed to the sun such as the face show reddening of the skin with scaling and freckling. Irregular dark and white spots may also begin to appear.
• These skin changes progress to the neck and lower legs, and in severe cases, to the trunk.
• Over the winter months, these changes may diminish.
• There may be an exaggerated sunburn response on minimal exposure to sunlight.

Continued sun exposure will lead to the second stage, which is characterised by:

• Poikiloderma
• Skin atrophy
• Telangiectasia
• Mottled hyperpigmentation and hypopigmentation.

The third stage is the development of actinic keratoses and skin cancers. These may occur as early as age 4–5 years and a mean of 8 years. They are more prevalent in sun-exposed areas such as the face but can also occur on the tongue and conjunctiva.
They include:

• Basal cell carcinoma
• Squamous cell carcinoma
• Melanoma.

Eye problems occur in nearly 80% of xeroderma pigmentosum patients.

• Eyes become painfully sensitive to the sun (photophobia).
• Eyes easily irritated, bloodshot and clouded. Conjunctivitis may occur.
• Non-cancerous and cancerous growths on the eyes may occur.

Neurological problems occur in about 20% of xeroderma pigmentosum patients.

• These can be mild or severe and include spasticity, poor coordination, developmental delay, deafness, and short stature.
• May develop in late childhood or adolescence. Once they do occur, they tend to worsen over time.

How is xeroderma pigmentosum diagnosed?

Usually, xeroderma pigmentosum is detected in early infancy, around 1–2 years.

A child presenting with severe sunburn after their first exposure to sun may be a clue to the diagnosis of xeroderma pigmentosum. Xeroderma pigmentosum can usually be conclusively diagnosed by measuring the DNA repair factor from skin or blood samples.

What is the treatment for xeroderma pigmentosum?

There is no cure for xeroderma pigmentosum. Gene therapy for xeroderma pigmentosum is still in a hypothetical and investigational stage.

• Family members and known carriers should undergo genetic counselling and avoid consanguineous marriage.
• A fetus at risk of xeroderma pigmentosum can undergo prenatal diagnosis by amniocentesis or chorionic villi sampling and chromosomal breakage studies.

The main goal of treatment is protection from UV from the sun and unshielded fluorescent lamps (sun avoidance).

• Outdoor activities should be restricted to night-time; stay indoors during the day.
• Wear protective clothing (long sleeves and pants, shirts with collars, tightly woven fabrics, wide-brimmed hat).
• Shield eyes with UV–absorbing wraparound sunglasses.
• Apply broad-spectrum sunscreens with SPF of 50 or greater to all exposed areas.

Patients should undergo frequent skin examinations by someone who has been taught to recognise signs of skin cancer. Any suspicious spots or growths should be immediately reported to the doctor.

• Examination by a doctor (preferably a dermatologist) at least every 3 to 6 months.
• Actinic keratoses may be treated by cryotherapy or 5-fluorouracil cream. Any suspicious growths should undergo biopsy. Skin cancers are usually excised.
• Frequent eye examinations by an ophthalmologist.
• Yearly testing (through to age 20) for potential neurological problems.
• Sufferers benefit from personalised psychological support which can significantly improve their engagement with photoprotective behaviours.

Some patients with xeroderma pigmentosum patients may be prescribed isotretinoin. This is a vitamin A derivative that may prevent the formation of new cancers by altering keratinocyte differentiation.

What is the outcome of xeroderma pigmentosum?

Many patients with xeroderma pigmentosum die at an early age from skin cancers. However, if a person is diagnosed early, does not have severe neurological symptoms or has a mild variant, and takes all the precautionary measures to avoid exposure to UV light, they may survive beyond middle age.

Patients with xeroderma pigmentosum and their families will face many challenges in daily living. Constant educating and reminding of the need to protect oneself from sunlight is paramount to the management of xeroderma pigmentosum.