Xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a rare autosomal recessive condition that leads to extreme sun sensitivity, an increased risk of certain cancers and, in approximately 25% of cases, neurological degeneration. Extreme sun sensitivity causes sunburn, blistering, freckle-like pigmentation, photophobia and an increased risk of malignancy in sun-exposed areas, including the eyes.

• Cutaneous features:
• • exaggerated sun sensitivity and severe sunburn reaction;
• • atypical pigmentary changes: dense freckling, poikiloderma (telangiectasia, mottled hyperpigmentation and hypopigmentation); and
• • actinic keratoses and greatly increased risk of malignant skin changes, including basal cell carcinoma, squamous cell carcinoma and melanoma (patients often develop skin cancer within the first decade of life).
• Sunlight-induced ocular features:
• • photophobia;
• • corneal clouding and severe keratosis; and
• • benign and malignant ocular growths.
• Neurological features (occurring in 20%–25% of patients with XP):
• • ataxia;
• • progressive cognitive impairment;
• • sensorineural hearing loss;
• • acquired microcephaly; and
• • progressive neurodegeneration.
• Other features:
• • premature menopause;
• • increased solid organ cancer risk; and
• • thyroid nodules and cancer.

There are multiple subtypes of XP, classified according to the genes affected.

• Many of the genes implicated in XP are involved in the nucleotide excision repair (NER) pathway. This is a cellular process in which damaged DNA is detected, removed and repaired. The XP genes DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA and XPC are all involved in NER.
• Another XP gene, POLH, also plays a role in protecting cells from UV damage via a different mechanism.

Note that while biallelic variants in ERCC1 have been reported as a rare cause of XP, they are more typically associated with other disorders of DNA repair, such as Cockayne syndrome or cerebro-oculo-facio-skeletal syndrome.

There is significant clinical overlap between the different genetic subtypes, so multigene panels are the best way of making a molecular diagnosis. However, some genotype/phenotype correlations have been described, especially in relation to the neurological features (see table 1).

Table 1: Clinical features of XP subtypes

Adapted from Moriwaki S, Kanda F, Hayashi M and others (see ‘Resources’ section below).

Diagnosis of XP normally follows clinical suspicion of the disease, with symptoms such as increased photosensitivity and characteristic cutaneous, ophthalmological and neurological signs.

Molecular diagnosis can be made by the identification of pathogenic variants through genomic testing.

XP may be identified before any symptoms appear – for example, through the Generation Study. Confirmation of the diagnosis will require referral to the national XP service based at Guy’s and St Thomas’ Hospital in London. Please refer to the local pathway for your region.

Diagnosis of condition-specific manifestations of XP will also be required. For example, biopsy and non-invasive procedures such as dermoscopy can be used to determine whether XP-associated skin lesions are benign or malignant.

XP is an autosomal recessive condition. The parents of most affected individuals are carriers for the condition, which means that each child they have together has a 1-in-4 (25%) chance of being affected and a 1-in-2 (50%) chance of being an asymptomatic carrier of one of the familial variants.

Reproductive options are available to couples at risk of having a child with XP. The Human Fertilisation and Embryology Authority has approved the use of preimplantation genetic testing for couples if both individuals are carriers of a likely pathogenic or pathogenic variant in a gene associated with XP. Other options may include prenatal testing with termination of affected embryos, adoption, gamete donation or natural conception and pregnancy with testing of children later in life. It is best practice that discussions regarding preimplantation genetic testing and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

When a patient is diagnosed, consideration should be given to their siblings, who are at an increased theoretical risk of being affected. If a genetic diagnosis has been ascertained, relatives can be tested for the variant(s). Early diagnosis and appropriate management reduces long-term morbidity and mortality.

Prevalence

The prevalence of XP is in the order of 1 per 1,000,000 in Europe, but occurs with increased frequency in certain populations, including Japan (1 in 22,000) and certain parts of North Africa (as high as 1 in 10,000) – particularly in those populations where consanguineous relationships are common.

Carrier frequency of variants in genes associated with XP varies by gene and by ethnic population. Overall, the worldwide carrier frequency of XPA variants is approximately 1 in 532; of XPC 1 in 695; and of ERCC5 1 in 589. The frequency of variants in the other genes is lower.

• Management of children with XP is complex and should be delivered via speciality doctors and a multidisciplinary team.
• The mainstay of management includes strict sun protection, screening and treatment of skin cancers, and supporting symptoms of neurodegeneration.
• Numerous novel therapies are in the pre-clinical phase, including topical DNA repair enzymes, aminoglycosides, gene therapy and genome editing.

For clinicians

• GeneReviews: Xeroderma Pigmentosum
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Lehmann J, Schubert S and Emmert S. ‘Xeroderma pigmentosum: Diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches‘. Journal der Deutschen Dermatologischen Gesellschaft 2014: volume 12, issue 10, pages 867–872. DOI: 10.1111/ddg.12419
• Moriwaki S, Kanda F, Hayashi M and others. ‘Xeroderma pigmentosum clinical practice guidelines‘. The Journal of Dermatology 2017: volume 44, issue 10, pages 1,087–1,096. DOI: 10.1111/1346-8138.13907

For patients

• British Society of Dermatologists: Xeroderma pigmentosum
• XP Support Group