Approach

​Patients present with early-onset ultraviolet radiation (UVR)-induced skin pigmentary changes and UVR-induced damage to the eyes. Those aged <20 years have more than a 1000-fold increased risk of cutaneous malignancies.[24]​ Around 25% of patients with XP experience progressive and irreversible neurologic degeneration.[23]​​

Clinical presentation varies depending on the specific genetic pathologic variant.[20]​ A careful clinical examination can differentiate XP from other conditions (e.g., cerebro-oculo-facio-skeletal syndrome, trichothiodystrophy, Cockayne syndrome). See Differentials.

While the diagnosis can be made clinically, unscheduled DNA synthesis testing and genetic testing, where available, confirms the diagnosis and the subtype.[12]

As there is no cure for XP, early diagnosis, strict and consistent UVR and daylight protection, and regular cutaneous follow-up to evaluate and treat skin cancers increases life expectancy in patients without neurologic disease.​[3][12][25][26]​​​​

Clinical presentation

Consider the diagnosis in a young child (typically <2 years old) with severe and exaggerated sunburn with minimal sun exposure or with early and extensive freckle-like skin lesions (lentigines) in sun-exposed areas.[14][23]​​​ When adults present with XP, they tend to be between 20 and 40 years of age with numerous premalignant or malignant skin cancers.[2]

  • Acute sunburn reaction following minimal UVR exposure is seen in 60% of patients.[3][25]​​​​ This is particularly apparent in patients with subtypes XPA, XPB, XPD, XPF, and XPG.[7]​ Erythema can persist for weeks before resolving.

    [Figure caption and citation for the preceding image starts]: A child with XP (subtype XPD) at 9 months of age with severe blistering erythema of the malar area following minimal sun exposure. Note the sparing of her forehead and eyes that were protected by a hatBradford PT et al. J Med Genet 2011;48:168-76; used with permission [Citation ends].com.bmj.content.model.Caption@7abfe482

  • Around 40% of patients do not have acute burning with minimal sun exposure. These patients will tan normally and have many lentigines on sun exposed areas (including lips) and an increased skin cancer risk.[23] Patients with subtypes XPC, XPE, and XPV, in particular XPC, show significant exposed-site lentigines.[4]​​[7]

  • XPE and XPV subtypes often present in adulthood with early onset of skin cancer.[4]​​[7]​​

If strict and consistent UVR and daylight protection is not initiated, all patients (i.e., with any of the XP subtypes) will develop chronic cutaneous changes. The history may include progressive dry skin, atrophy, and skin wrinkling.[7][23]​​

With time, patients develop numerous premalignant and malignant cutaneous neoplasms, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.[7] These may be noticed as non-healing wounds, growing papules or nodules on the skin, and/or unusual cutaneous pigmentation. For more information see Basal cell carcinoma, Squamous cell carcinoma, and Melanoma. 

Patients <20 years old have a more than 1000-fold increased risk of non-melanoma or melanoma skin cancer.[24]​ The average age at onset of first skin cancer is <10 years old.[14] The median age of onset of their first non-melanoma skin cancer is 9 years old.[25]​ Premalignant and malignant cutaneous neoplasms are highly suggestive of XP if present within the first decade of life.[7]

History

Consider whether risk factors are present. Ask if there is a family history of XP and/or parental consanguinity.

  • XP is an autosomal recessive inherited disorder. Check whether other family members have severe sunburns, early freckling, and/or have developed skin cancer at a young age. Be aware that certain geographical regions have relatively higher incidence of XP (e.g., 45 per million live births in Japan, compared with 1 per million live births in the US).[7]​ Studies have shown that the incidence of XP is increased in countries where consanguinity is common, such as Tunisia, Morocco, Libya and Pakistan.[6][8][9][10][11]​​

Ask about ocular symptoms.

  • These may be acute (e.g., photophobia) or chronic (e.g., dry eyes due to conjunctival xerosis).

  • Eye involvement occurs in around 40% to 90% of patients with XP.[12][23][27]

Ask about neurologic symptoms, including developmental milestones and school progress in a child or day-to-day functioning in an adult.

  • Abnormalities vary in presentation and severity and the age of onset ranges from infancy to adulthood. Worldwide, approximately 25% of patients with XP will develop features of progressive and irreversible neurodegeneration.[24]​ A wide range of neurologic manifestations are associated with XP; the most severe include: 

    • Acquired microcephaly[7][23]

    • Progressive sensorineural deafness[7][23][28][29]

    • Progressive cognitive impairment[7][23][28]

    • Ataxia.[7][23]

  • Other neurodegenerative manifestations include decreased visual acuity, developmental delay, speech delay, and hyporeflexia.[7]

While any XP subtype may be affected, neurodegeneration appears to be most common in subtypes XPA and XPD followed by XPB, XPG, and XPF; and least common in XPC, XPE, and XPV.[7] Adult-onset neurodegeneration has been reported in patients with mutations in the XPF (ERCC4) gene.[30]

Physical exam

Inspect the skin, looking for acute and/or chronic cutaneous changes. Check for acute changes after minimal sun exposure over sun-exposed areas of skin, such as:

  • Erythema

  • Blistering.

Look for chronic changes of poikiloderma, including:

  • Early excessive freckle-like lesions (lentigines), especially before age 2 years. These are clinically atypical pigmented lesions that are variable in intensity of brown in color, with irregular shapes, sizes, and borders. This finding is common in XP and rare in the general population.[14]

  • Progressive xerosis

  • Atrophy

  • Skin wrinkling

  • Telangiectasia

  • Signs of cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, such as:

    • Non-healing wounds

    • Papules or nodules on the skin

    • Unusual cutaneous pigmentation.

    For more information see Basal cell carcinoma, Squamous cell carcinoma, and Melanoma.

[Figure caption and citation for the preceding image starts]: A child with XP (subtype XPC) at age 2 years. Her parents reported that she did not sunburn easily, but she developed multiple hyperpigmented macules on her face. A rapidly growing squamous cell carcinoma or keratoacanthoma grew on her upper lip and a pre-cancerous lesion appeared on her foreheadBradford PT et al. J Med Genet 2011;48:168-76; used with permission [Citation ends].com.bmj.content.model.Caption@2765f220

XP may be diagnosed later in patients with darker Fitzpatrick skin phototypes, as the manifestations of poikiloderma may be less prominent or less noticeable.[31]

[Figure caption and citation for the preceding image starts]: Poikilodermatous changes of the upper extremity in an 18 year old woman presenting with XP. The changes had been present since early childhood with progressive increase in size and number. A diagnosis of freckles had initially been madePlante J et al. JAAD Case Rep 2021;13:141-43; used with permission [Citation ends].com.bmj.content.model.Caption@7b9485a2

Examine the eyes. The eyelids and anterior portions of the globe and retina may show evidence of sun damage, such as:[7][27]

  • Pigmentation and atrophy of the eyelids

  • Ectropion or entropion

  • Prominent conjunctival injection

  • Signs of keratitis (painful red, watery eyes)

  • Clouding of the cornea

  • Cataracts

  • Signs of ocular neoplasms of the lids, conjunctiva, or cornea.

[Figure caption and citation for the preceding image starts]: A 23 year old man from northern Africa with XP (subtype XPC) presenting with numerous hyperpigmented macules on his face. Nodular basal cell cancer is present on his left nasal root. Pigmented basal cell cancer is present on his left cheek. His eyes show corneal scarring from unprotected sun exposureBradford PT et al. J Med Genet 2011;48:168-76; used with permission [Citation ends].com.bmj.content.model.Caption@27dece2f

Perform a complete neurologic examination and a neuropsychological assessment to assess for learning disabilities.

  • Check for signs of neurodegeneration, such as sensorineural deafness, acquired microcephaly, and ataxia.

  • Be aware that loss of the deep tendon reflexes can be an early sign of neurodegeneration.

Initial investigations

Establish the diagnosis of XP on the basis of clinical findings and family history.

Confirm a definite diagnosis and subtype with unscheduled DNA synthesis from skin biopsy and genetic testing, where available.

  • Unscheduled DNA synthesis from skin biopsy measures unscheduled DNA synthesis in cultured skin fibroblasts after UV irradiation.[2]

  • Genetic testing identifies biallelic pathogenic variants in one of the causative genes (i.e., XPA, XPB [ERCC3], XPC, XPD [ERCC2], XPE [DDB2], XPF [ERCC4], XPG [ERCC5], or XPV [POLH] genes).[2][12]​​​​​​​​ Molecular genetic testing may include:​[23]

    • Multigene panel

    • More comprehensive genomic testing.

Traditionally, serial single-gene testing was used and can still be done, but multigene testing is preferred as preselected genes can be tested on one platform.[23]​ If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example, the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[32]

Consider discussing prenatal diagnosis if there is a family history of XP and the familial pathogenic variants are known. This can be made through DNA testing on cells or fluid obtained from the pregnant mother during chorionic villus sampling or amniocentesis.[33]

Use of this content is subject to our disclaimer