Xeroderma pigmentosum is an autosomal recessive inherited disorder caused by genetic defects in proteins involved in the nucleotide excision repair (NER) pathway. Moritz Kaposi first described it in 1874. It is characterized by extreme ultraviolet sensitivity and skin cancer at a young age; the risk of squamous cell carcinoma and basal cell carcinoma of the skin is 10,000 times that of the general population, and the risk of melanoma is 2,000 times higher. Skin cancer is said to develop at an average age of 8 years.
Incidence: 1 in 1 million in the United States and Western Europe9). In Japan and North Africa, due to consanguinity, it is 1 in 22,000 to 1 in 100,000. Worldwide, it is estimated at 1 in 250,0006).
Xeroderma pigmentosum has 8 complementation groups. The seven groups A through G are caused by nucleotide excision repair deficiency, while group V is due to inactivation of DNA polymerase eta (POLH), which makes replication of damaged DNA error-prone. Groups C and E are the most common, accounting for about 50% and 20% of all cases, respectively8).
Frequency of eye symptoms: In a study by Lim et al., ocular abnormalities were found in 93% (83 of 89) of patients with xeroderma pigmentosum. Eye symptoms have also been reported in 40% to 80% of cases6). The anterior eye surface (conjunctiva, cornea, eyelids, lens) is vulnerable to ultraviolet light, and because of the deficiency in nucleotide excision repair, unrepaired damage accumulates.
Prognosis: median age at death is 32 years, and 60% are said to die before age 204). In patients without neurologic symptoms, the median is reported as 37 years, and 29 years in those with neurologic symptoms.
The front of the eye (conjunctiva, cornea, and eyelids) is easily exposed to ultraviolet light, and because nucleotide excision repair is deficient, ultraviolet-induced DNA damage is not repaired, leading to accumulation of inflammation, scarring, and neoplastic changes. In a study by Lim et al., eye symptoms were reported in 93% of patients with xeroderma pigmentosum.
A study of 209 patients with xeroderma pigmentosum (418 eyes) reported the following chief complaints.
The frequency of ophthalmic abnormalities in 87 patients with xeroderma pigmentosum studied by Brooks et al. is shown below.
| Ocular abnormalities | Frequency (87 patients) |
|---|---|
| Conjunctivitis | 51% |
| Corneal neovascularization | 44% |
| Dry eye | 38% |
| Corneal scarring | 26% |
| Ectropion | 25% |
| Blepharitis | 23% |
| Conjunctival melanosis | 20% |
| Cataract | 14% |
| Lagophthalmos | 10% |
Early surface findings
Conjunctival hyperemia: Chronic inflammation caused by ultraviolet exposure. Seen from the early stage.
Pterygium: Conjunctival tissue extending onto the cornea from the limbus.
Conjunctival pigmentation: Ultraviolet-induced melanin deposition. A characteristic finding.
Corneal opacity (mild): In the early stage, punctate opacities or superficial opacities appear.
Late-stage severe findings
Corneal dryness and scarring: As dry eye progresses, corneal stromal scarring develops.
Ectropion (ectropion): Seen in 25% of the Brooks et al. study. It increases the risk of exposure keratopathy.
Limbal stem cell deficiency (limbal stem cell deficiency, LSCD): A rare but severe complication. It presents with 360-degree loss of Vogt palisades, corneal stromal edema, patchy scarring, and superficial neovascularization2).
Cataract: Seen in 14% of the Brooks et al. study.
Ocular tumors:
In a study of 209 patients, ocular surface tumors were seen in 44% (185/418 eyes), and eyelid tumors in 4% (18/418 eyes).
Neuro-ophthalmic findings (89 patients in Lim et al.):
In the Xeroderma pigmentosum group G/Cockayne syndrome overlap, severe ocular findings such as bilateral inferior corneal scarring plus pannus, corneal ulcers, trichiasis, scattered retinal pigmentary changes, narrowed retinal vessels, juvenile cataracts, and optic atrophy have been reported5).
Case of limbal stem cell deficiency: In a 12-year-old boy with bilateral limbal stem cell deficiency, there were 4 years of recurrent pain, redness, and decreased vision, and best-corrected visual acuity was 20/1200 in the right eye and 20/200 in the left eye2).
On the ocular surface, conjunctival squamous cell carcinoma is the most common. In the eyelids, basal cell carcinoma is the most common, as consistently reported in multiple studies. Ocular surface tumors were found in 44% (185/418 eyes) in a study of 209 patients.
Xeroderma pigmentosum is caused by a genetic defect in the nucleotide excision repair pathway that repairs UV-induced DNA damage. UV exposure forms pyrimidine dimers, and if the nucleotide excision repair defect persists, mutations accumulate and skin and eye tumors develop.
Types C and E
Genetic background: Defect in global genome nucleotide excision repair (GG-NER). Mutations preferentially accumulate in the non-transcribed strand4).
Tumor mutational burden: Type E 350 mutations/Mb, Type C 162 mutations/Mb (sporadic cancers 130 mutations/Mb)4).
Eye manifestations: Eye damage is seen most often in Type C among all subtypes.
Clinical features: Skin cancers often occur. Sunburn reactions can be normal.
Types A and D
Genetic background: Both global genome nucleotide excision repair and transcription-coupled nucleotide excision repair (TC-NER) are defective4). Mutations are evenly distributed across the genome.
Neurological symptoms: Types A, B, D, F, and G are more likely to have neurological symptoms4).
Clinical features: Hearing loss, speech articulation problems, visual field defects, and acquired microcephaly may occur.
Type V
Genetic background: Inactivation of DNA polymerase eta (POLH gene, 6p21.1). Nucleotide excision repair itself still works, but damaged DNA replication is error-prone9).
Tumor mutational burden: 248 mutations/Mb4).
Clinical features: There is no abnormal acute reaction to sunlight. This makes it harder to keep protective measures in place, leading to pigmentation and early skin cancer. Eye findings: photophobia, dry keratoconjunctivitis, conjunctival redness, ectropion, keratitis9).
Environmental factors and risk factors:
Neurological symptoms: Neurological complications occur in 17–25% of all people with xeroderma pigmentosum5). These include hearing loss, dysarthria, visual field defects, reduced deep tendon reflexes, acquired microcephaly, and optic neuropathy. If there is a genetic variant, there is no way to prevent onset.
Type C is known to have the most frequent eye damage. Types C, E, and V have a higher risk of skin cancer, while nervous system symptoms tend to be less common. Types A and D are more likely to have neurologic complications, and optic neuropathy or visual field defects may also occur.
The combination of photophobia, sun damage, and skin cancer at a young age strongly suggests xeroderma pigmentosum. Important skin clues include freckles before age 2 on sun-exposed areas and the absence of lesions on non-exposed areas. About half show a tanning phenotype rather than sunburn. Photophobia is usually present.
| Test method | Details |
|---|---|
| Unscheduled DNA synthesis test | Measures DNA repair synthesis in patient cells after ultraviolet exposure. In patients with xeroderma pigmentosum, it falls to 10–20% of normal7) |
| Whole-exome sequencing | Rapid identification of xeroderma pigmentosum gene mutations. Also useful for clarifying genotype-phenotype correlations7, 8) |
| MTT assay | Functional assay to measure patient cell viability after ultraviolet irradiation |
| Host cell reactivation assay | Functional assay to test the repair capacity of an ultraviolet-irradiated plasmid |
The following are used to diagnose ocular surface squamous tumors.
Stage classification of ocular surface squamous tumors (epithelial tumors that arise on the ocular surface and commonly occur at the limbus):
No curative treatment is currently available; lifelong UV protection and regular checkups are the mainstay of treatment.
Local treatment for ocular surface tumors:
Systemic drug therapy:
In a study of 36 patients with xeroderma pigmentosum, overall visual prognosis improved, but graft failure occurred in 15 of 54 eyes (35.7%). The main causes were rejection with neovascularization and progressive scarring, so long-term management after transplantation is especially important in xeroderma pigmentosum.
Nucleotide excision repair is the main DNA repair mechanism that removes ultraviolet-induced cyclobutane pyrimidine dimers and (6-4) photoproducts. It is broadly divided into two subpathways.
TFIIH complex: a multifunctional complex involved in both nucleotide excision repair and transcription. XPB (ERCC3) and XPD (ERCC2) function as subunits. Defects in this complex cause xeroderma pigmentosum/Cockayne syndrome overlap (43 cases over 52 years), impairing both DNA repair and transcription5).
In type V, nucleotide excision repair itself functions, but DNA polymerase eta (POLH) is inactivated. Polymerase eta is the enzyme that carries out translesion synthesis using thymine dimers as a template, and its deficiency lowers replication fidelity and leads to mutation accumulation.
Tumor mutational burden is important as a predictor of sensitivity to immune checkpoint inhibitor therapy. In xeroderma pigmentosum, the following tumor mutational burdens have been reported4).
The main mutation type is C>T transitions (at dipyrimidine sites), and each xeroderma pigmentosum subgroup has a specific mutational signature4).
The front of the eye (conjunctiva, cornea, sclera, eyelids, and lens) is easily exposed to ultraviolet light, while the posterior segment is protected by the structures in front. In a nucleotide excision repair deficiency, ultraviolet-induced mutations on the ocular surface are not repaired and accumulate, leading to malignant transformation. In the cornea, chronic ultraviolet exposure can cause neovascularization, scarring, and damage to limbal stem cells, and limbal stem cell deficiency may occur2).
Xeroderma pigmentosum skin cancer has a high tumor mutational burden, and response to immune checkpoint inhibitors is expected. As of 2025, 10 patients with xeroderma pigmentosum worldwide had received immune checkpoint inhibitor therapy, and tumor shrinkage was confirmed in all cases4).
Gambichler et al. (2025) administered cemiplimab 3 mg/kg (intravenous every 2 weeks) to a 7-year-old boy (type C) with giant facial cutaneous squamous cell carcinoma and cervical lymph node metastasis4). One week after the first dose, dramatic tumor shrinkage was obtained; complete response was achieved after 3 cycles, and cervical lymph node metastasis also completely resolved after 17 cycles (8 months). Improvement in corneal opacity and ectropion was also confirmed during treatment.
Report of three pediatric xeroderma pigmentosum cases4):
The frequency and types of adverse events with immune checkpoint inhibitor treatment are considered similar to those in the general population4).
For recurrent basal cell carcinoma after surgery, the Hedgehog signaling inhibitor (vismodegib) is being considered as a treatment option for unresectable or metastatic basal cell carcinoma8).
A liposomal formulation of T4 endonuclease V, a bacteria-derived DNA repair enzyme, has been shown to help suppress the development of actinic keratosis and basal cell carcinoma.
There is a report of pembrolizumab treating metastatic cutaneous squamous cell carcinoma of the left lower eyelid and the right conjunctiva and cornea in a child with xeroderma pigmentosum type C (with added topical 5-fluorouracil)4). In cases given cemiplimab, improvement in corneal opacity and ectropion has also been confirmed. However, these are reports at the research stage and have not been established as standard treatment.
