When DNA is exposed to UVR, nucleic acid-based photoproducts (e.g. pyrimidine 6–4 pyrimidone dimers and cyclobutane pyrimidine dimers) result, which are amendable to DNA repair via the nucleotide excision repair (NER) process.6–10 NER is capable of removing these nucleic acid-based photoproducts and replacing damaged DNA with new DNA.11,12 NER is a central pathway safeguarding cells and genomes damaged by UVR.9 Two types of NER are recognized: the transcription-coupled (TC)-NER and the global genome (GG)-NER.6 TC-NER repairs actively transcribed DNA whilst GG-NER repairs DNA not undergoing transcription at that time.13,14 Eight NER proteins (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XPV) and their genes have been identified.2 XPA–XPG are involved in different steps of the NER in the presence of DNA damage whereas XPV is involved in the postreplication repair of damaged DNA.2 Based on the mutation of the specific gene, XP can be divided into seven complementation groups (XPA, XPB, XPC, XPD, XPE, XPF and XPG) and an XP variant (XPV).5,11,15 Generally, patients with XP are unable to clear the UVR-induced photoproducts or employ NER to mend UVR damage to the DNA.6 Those with XPV have normal NER but have mutations in the translational DNA Pol η gene.16 Pol η is involved in DNA synthesis and allows transcription past UVR-damaged DNA that has not been repaired by NER, in a process known as trans-lesion synthesis.5,6,14,16 As such, the ability to replicate DNA after UVR damage is impaired in individuals with XPV.17,18 The cutaneous features of XP, their progression and patients’ propensity to early cancer result from an accumulation of UVR-induced photoproducts and unrepaired DNA damage.2 Oxidative stress and the cumulative oxidative DNA damage in neurons are responsible for neurodegeneration.2

XP is inherited as an autosomal recessive trait with 100% penetrance.4,19 As such, absence of a family history of XP does not preclude the diagnosis.

XP affects all races with a worldwide incidence of 1 in 250,000 live births.20,21 The incidence of XP is estimated to be 1, 2.3, 17.5 and 45 per million live births in the United States, Western Europe, Middle East and Japan, respectively.4,6,11,22,23 The incidence is increased in areas where consanguinity is common.24 The sex ratio is approximately equal.5 Worldwide, the subtypes XPA, XPC and XPV account for approximately 75% of all cases of XP whilst XPV alone accounts for approximately 30% of cases.11 XPC is the most common subtype in the United States, Europe and Africa whilst XPA is the most common subtype in China and Japan.6,11,24–26

Histological findings include increased melanin and melanocytes in the basal cell layer, hyperkeratosis, lymphocytic infiltrate in the upper dermis, atrophic and/or elastotic dermis, thinning of the stratum malpighii with atrophy and/or elongation of the rete, telangiectasia and keratinocyte atypia.5,27,28

XP is characterized by increased photosensitivity, early-onset UVR-induced skin pigmentary changes, UVR-induced damage to the eyes, an increased risk of cutaneous tumour development and, in some cases, progressive neurological degeneration.29,30 Many risk factors can exacerbate the cutaneous manifestations, including chronic exposure to UVR, sunny weather, poor protection from sunlight and fair skin.28 Clinical manifestations vary and are influenced by the precise gene mutation and environmental factors such as cumulative exposure to UVR.14,31,32

The appearance of the skin of patients with XP is usually normal at birth.11,33 However, the skin has an extreme sensitivity to UVR and is soon damaged with minimal exposure to UVR.20 This may manifest as severe or exaggerated sun tanning, burning, or blistering upon minimal sun exposure.11 Erythema may persist for weeks in about 60% of cases.34 XP subtypes XPA, XPB, XPD, XPF and XPG are associated with severe and exaggerated sunburning after minimal sun exposure.4,6,35,36 On the other hand, patients with subtypes XPC, XPE and XPV have less severe sunburning and can even tan after minimal sun exposure; yet, affected patients still develop abnormal skin pigmentation, including freckles and lentigos.4,6,35 Marked freckling-like skin changes typically present before the age of 2 years on sun-exposed areas.4,6,11 Over time, the skin undergoes premature aging, with progressive xerosis, atrophy, wrinkling, telangiectasia, early-onset lentigos which increase in size, number and colour, and poikiloderma (Figures 1–7).4,6,31,37,38 The hypopigmented areas may represent mutated melanocytes that have lost their ability to produce melanin.20 Actinic keratoses are observed at an early age, and actinic cheilitis is not uncommon.11,23,39

The anterior parts of the eye (conjunctiva, lens, cornea and eyelids) are particularly susceptible to damaging effects of UVR in patients with XP.6,40 The posterior parts of the eye are protected by the lens which acts as a barrier to UVR.13 Approximately 90% of patients with XP have ocular involvement.14,39 Common ophthalmological manifestations include photophobia, conjunctival xerosis, blepharospasm, prominent conjunctival injection, conjunctival neovascularization (Figure 8) and conjunctival melanosis; findings are usually obvious in the first decade of life.6,14,22,41 Other ophthalmological manifestations include irregularities in eyelid border, increased pigmentation of the eyelids with loss of eyelashes, trichiasis, blepharitis, ectropion, entropion, lagophthalmos, symblepharon, lacrimal point stenosis, blepharitis, keratitis, punctate keratopathy, band keratopathy, keratoconjunctivitis, corneal opacification (Figure 8), corneal ulceration and corneal scarring, pinguecula, pterygium, fibrovascular pannus of the cornea, iritis, ciliary body hamartoma, cataracts, macular oedema, chorioretinal adhesion, retinal degeneration with pigment migration and optic nerve atrophy.11,14,27,34,41–43 Neuro-ophthalmic abnormalities in the form of minimal pupillary constriction to light, strabismus and abnormal extraocular movements have been reported in 25%, 8% and 7% of patients with XP, respectively.14 Interesting, patients with subtypes XPC, XPE and XPV who have preserved TC-NER have significantly more ophthalmological abnormalities than those with subtypes XPA, XPB, XPD, XPF and XPG who have impaired TC-NER, presumably due to lack of aggressive and early initiation of sun-protective measures in patients with preserved TC-NER.4,14

The accumulation of 6–4 pyrimidine–pyrimidine dimers and cyclobutene–pyrimidine dimers from UVR exposure is crucial in cutaneous carcinogenesis.12,44,45 Patients with XP develop numerous precancerous actinic keratoses early in life.46,47 Affected patients are at risk for skin and mucous membrane cancers in sun-exposed areas.47,48 The most prevalent skin cancers are squamous cell carcinoma followed by basal cell carcinoma and malignant melanoma.49–53 Patients with XP have a 10,000-fold and 2000-fold increased risk over their lives of developing non-melanoma skin cancers (notably squamous cell carcinoma and basal cell carcinoma) and malignant melanoma, respectively.34,54 The mean age for the first appearance of non-melanoma skin cancer and melanoma is 9 and 22 years, respectively, in patients with XP.6,11,55 In contrast, the mean age of onset of UVR-induced non-melanoma skin cancer and melanoma is about 67 and 55 years, respectively, in the general population.31,35,56 Multiple cutaneous malignancies are commonly found on sun-exposed areas in patients with XP.28,57,58 Affected patients with no or minimal protection against UVR may develop hundreds of skin cancers on sun-exposed areas.35 The incidence of intraoral cancers (notably squamous cell carcinoma of the tip of the tongue) is 3000–10,000 higher than in the general population.4,59 Squamous cell carcinoma of the lower lip is also common.60 XP is associated with various ocular surface malignancies, notably squamous cell carcinoma, basal cell carcinoma and melanoma.14,61 The risk of ocular malignancies is increased about 2000-fold.37 Ocular malignancies usually occur in the areas that are exposed to UVR such as the eyelids, conjunctiva and cornea.21 Other skin cancers that occur with increased frequency in patients with XP include keratoacanthoma, epithelioma, sebaceous cell carcinoma, fibrosarcoma and angiosarcoma.27,62,63 Surprisingly, patients without severe sunburn response tend to develop skin cancer earlier than those who have a severe sunburn response, presumably due to less strict sun-protective measures in the former.35,36,64

Progressive neurodegeneration occurs in approximately 25% of patients with XP.6,34,36,65,66 The most common subtypes associated with neurodegeneration are XPA and XPD, followed by XPB, XPG and XPF.2 Neurodegeneration is rarely seen in patients with XPC and XPE.4 Patients with XPV tend to be spared the neurodegeneration seen in other subtypes.67 Neurological manifestations include acquired microcephaly, progressive cognitive impairment, deterioration of neurological status, progressive sensorineural hearing loss, speech delay, dysarthria, ataxia, diminished or absent deep tendon stretch reflexes, loss of ability to walk, spasticity, dyskinesia, chorea, dysphagia, neurogenic bladder, dysuria, supranuclear ophthalmoplegia and seizures.68–75 These manifestations are progressive and irreversible and may be attributed to loss of neurons in the cerebrum and cerebellum, primary axonal degeneration in the peripheral nerves and, occasionally, secondary demyelination.76,77 Oxidative stress may play an important role in damaging the DNA of affected neurons.78

The diagnosis should be suspected in patients with increased photosensitivity and characteristic cutaneous, ophthalmological and neurological findings (vide supra). A family history of XP or the finding of cutaneous malignancy within the first decade of life further supports the diagnosis. A definite diagnosis can be made by the identification of biallelic pathogenic variants in one of the causative genes.34,79 Molecular testing may include the use of serial single-gene testing, multigene panel and more comprehensive genomic testing.34 In families with a known history of XP, prenatal diagnosis can be made through DNA testing on chorionic villus-derived cells or on amniotic fluid cells from the pregnant mother in the course of an amniocentesis.80

Dermoscopy is a useful non-invasive diagnostic tool to discriminate between benign and malignant lesions in XP.81,82 The presence of an asymmetrical blotch or irregular globules and dots are common dermoscopic features of malignant lesions.82 Malignant melanoma can be differentiated from benign melanocytic nevi by the presence of variegated colours, asymmetry, prominent pigment network, blue-grey areas, blotches, atypical dots/globules, perifollicular pigmentation and follicular obliteration.81,82

The differential diagnosis includes Cockayne syndrome, XP/Cockayne syndrome complex, trichothiodystrophy, XP/trichothiodystrophy complex, Cockayne syndrome/trichothiodystrophy complex, cerebro-oculo-facio-skeletal (COFS) syndrome, UV-sensitive syndrome, Bloom syndrome (also known as Bloom–Torre–Machacek syndrome or congenital telangiectatic erythema), Rothmund–Thomson syndrome, Hartnup disease, Carney complex, De Sanctis–Cacchione syndrome, erythropoietic protoporphyria, cutaneous lupus erythematosus and LEOPARD syndrome (also known as Noonan syndrome with multiple lentigines).83–96 The distinctive features of many of these conditions help to differentiate them from XP.

Dry parchment-like prematurely aged skin, poikiloderma (constellation of hyperpigmentation, hypopigmentation, atrophy, telangiectasia and keratotic skin lesions) and cutaneous premalignant and malignant lesions in visible areas have been reported by patients as disfiguring and embarrassing.97,98 Affected children are more likely to experience loneliness, sadness, discrimination, shame, ridicule, harassment, teasing, bullying, rejection and abuse.99 The psychological impact can be profound especially those individuals with malignancy and has an adverse effect on the quality of life.45

Patients with XP under 20 years of age have a 50-fold increased risk of developing tumours in the central nervous system, including glioblastoma, medulloblastoma, spinal cord astrocytoma, schwannoma and neurilemoma.6,13,100–102 These malignancies are not UVR-related.13 Haematological malignancies, such as acute lymphoblastic leukaemia, acute myeloid leukaemia, lymphoma and myelodysplastic syndrome, occur with increased frequency in patients with XP.103–106 Patients with XP have a 12-fold increased risk for internal malignancy, such as nasopharyngeal carcinoma, squamous cell carcinoma of the oesophagus, carcinoma of the thyroid, adenocarcinoma of the lung, carcinoma of the breast, carcinoma of the pancreas, leiomyosarcoma of the kidney, cancer of the ovary and cancer of the prostate, suggesting that UVR might not be the only culprit causing malignancy in patients with XP.107–116 Patients with XP are at higher risk of developing smoking-induced cancers.13

Women with XP are at risk for premature menopause.117 In one study of 45 women aged 18 years or older with XP, 14 (31%) had premature menopause (before 40 years of age); the median age of menopause was 49.5 years.117

Patients with subtype XPC are at risk of developing pyogenic granuloma and multinodular thyroid.118

Approximately 60% of patients with XP die before the age of 20 years.12 The median age of death is 32 years.13 Metastatic skin cancer is the leading cause of death, followed by neurodegeneration and internal cancer.34,63,119,120 In one study, the mean age of death in patients with XP with and without neurodegeneration was 29 and 37 years, respectively.65 In general, the prognosis depends on how early sun avoidance and protection are initiated, how appropriate treatment is provided to slow down the progress of disease and its complications, how early malignancy is detected and treated, how severe the disease is, and the mutation of the specific gene. In this regard, patients with XPV typically fare better than patients with other subtypes.11

At present, there is no cure for XP. Therefore, prevention of complications is crucial for this disfiguring and potentially lethal disease. Strict and consistent sun avoidance and protection and early detection and treatment of premalignant and malignant skin lesions are the mainstays of management. These and other treatment options are summarized in Box 1. Regular paediatric, dermatological, ophthalmological and neurological follow-up is essential.