Xeroderma pigmentosum (XP) is a rare, inherited condition that affects the ability to repair DNA damage caused by ultraviolet (UV) light. This genetic defect leads to extreme sensitivity to sunlight and a dramatically increased lifetime risk of developing skin cancers and other complications. The diagnosis of XP is a multi-step process that begins with observing characteristic clinical signs and is confirmed through specialized laboratory and genetic testing. A definitive diagnosis is crucial for initiating the protective measures and management strategies necessary for people with this disorder.
Recognizing the Initial Clinical Signs
The first indications of Xeroderma Pigmentosum typically appear in infancy or early childhood, often prompting the initial consultation with a pediatrician or dermatologist. A defining initial feature is the severe, exaggerated sunburn reaction following minimal sun exposure, sometimes with blistering or persistent redness that lasts for weeks. This acute photosensitivity is a strong clue, often occurring before a child’s second birthday.
Following the initial sun exposure, children often develop a profusion of freckle-like pigmented spots, known as lentigines, on sun-exposed areas of the skin, such as the face. The appearance of extensive, early-onset freckling is highly characteristic of XP, contrasting with the normal development of freckles later in childhood. Over time, the skin may also show signs of atrophy, dryness, and telangiectasias, giving it a prematurely aged appearance.
Ocular manifestations are common, affecting 40% to 90% of individuals. These include photophobia (painful sensitivity to light) and eye irritation. Damage to the cornea and conjunctiva can occur due to UV exposure, leading to issues like dry eyes or the development of growths. In a subset of patients, neurological symptoms such as sensorineural deafness, poor coordination, or cognitive impairment may also be present, which further guides the clinical suspicion.
Functional and Molecular Laboratory Confirmation
Once clinical suspicion is established, specialized laboratory tests confirm the diagnosis and identify the precise molecular defect. The gold standard for confirming the functional impairment is the DNA repair assay, which measures the ability of the patient’s cells to perform Nucleotide Excision Repair (NER). This test typically uses cultured skin fibroblasts, obtained from a small skin biopsy, which are exposed to UV radiation in a laboratory setting.
A commonly performed functional test is the measurement of unscheduled DNA synthesis (UDS). After UV damage, healthy cells immediately begin to repair the DNA, incorporating new nucleotides in a process detected by the UDS assay. Cells from a person with XP, however, show a significantly reduced or absent UDS, confirming the defect in the NER pathway. In the case of the XP-variant form (XPV), the UDS assay may be normal because the NER pathway is intact, but the cells show hypersensitivity to UV-induced killing, which requires a different diagnostic approach.
Molecular analysis, usually involving gene sequencing, identifies the specific mutated gene responsible for the condition. XP is caused by mutations in one of eight genes—XPA through XPG, which are involved in NER, or POLH for the XP-variant. Identifying the specific gene mutation confirms the diagnosis and assigns the patient to one of the complementation groups. This sequencing can be performed on DNA extracted from a blood sample or the cultured fibroblasts.
Genetic Counseling and Long-Term Confirmation
After confirmation through functional and molecular testing, genetic counseling is a necessary part of the diagnostic process. XP is an autosomal recessive disorder, meaning an affected individual inherits one mutated copy of the gene from each parent, who are typically asymptomatic carriers. The counselor explains this inheritance pattern and the 25% chance of recurrence for each future child born to the same parents. Genetic testing can be offered to the parents and close family members to determine their carrier status, which is important for informed family planning decisions.
Once the specific gene mutation is known from the molecular analysis, prenatal testing options, such as amniocentesis, can be discussed for future pregnancies. The identification of the specific complementation group, such as XPA or XPC, is important for personalized long-term management and prognosis.
Different complementation groups are associated with varying severities of skin disease, cancer risk, and neurological involvement. This detailed genetic information helps the medical team create a tailored surveillance plan, including regular skin, eye, and neurological examinations, to optimize the individual’s long-term health outcomes.