Thompson & Thompson Genetics in Medicine, 8th Edition

Case 48. Xeroderma Pigmentosum (Defect of Nucleotide Excision Repair)

Autosomal Recessive


• Variable expressivity

• Genetic heterogeneity

• Genetic complementation

• Caretaker tumor-suppressor genes

Major Phenotypic Features

• Age at onset: Childhood

• Ultraviolet light sensitivity

• Skin cancer

• Neurological dysfunction

History and Physical Findings

W.S., a 3-year-old girl, was referred to the dermatology clinic for evaluation of severe sun sensitivity and freckling. On physical examination, she was photophobic and had conjunctivitis and prominent freckled hyperpigmentation in sun-exposed areas; her development and physical examination were otherwise normal. W.S. was the child of nonconsanguineous Japanese parents; no one else in the family was similarly affected. The dermatologist explained that W.S. had classic features of xeroderma pigmentosum, that is, “parchment-like, pigmented skin.” To confirm the diagnosis, W.S. had a skin biopsy to evaluate DNA repair and ultraviolet (UV) radiation sensitivity in her skin fibroblasts. The results of this testing confirmed the diagnosis of xeroderma pigmentosum. Despite appropriate preventive measures, W.S. developed metastatic melanoma at 15 years of age and died 2 years later. Her parents had two other children; neither was affected with xeroderma pigmentosum.


Disease Etiology and Incidence

Xeroderma pigmentosum (XP) is a genetically heterogeneous, panethnic, autosomal recessive disorder of DNA repair that causes marked sensitivity to UV irradiation (see Table). In the United States and Europe, the prevalence is approximately 1 in 1 million, but in Japan, the prevalence is 1 in 100,000.


Repair of DNA damaged by UV irradiation occurs by three mechanisms: excision repair, postreplication repair, and photoreactivation. Excision repair mends DNA damage by nucleotide excision repair or base excision repair. Postreplication repair is a damage tolerance mechanism that allows replication of DNA across a damaged template. Photoreactivation reverts damaged DNA to the normal chemical state without removing or exchanging any genetic material.

Nucleotide excision repair is a complex but versatile process involving at least 30 proteins. The basic principle is the removal of a small single-stranded DNA segment containing a lesion by incision to either side of the damaged segment and subsequent gap-filling repair synthesis with use of the intact complementary strand as a template. Within transcribed genes, DNA damage blocks RNA polymerase II progression. The stalled RNA polymerase II initiates nucleotide excision repair (transcription-coupled repair). In the rest of the genome and on nontranscribed strands of genes, a nucleotide excision repair complex identifies DNA damage by detection of helical distortions within the DNA (global genome repair).

On occasion, nucleotide excision repair will not have repaired a lesion before DNA replication. Because such lesions inhibit the progression of DNA replication, postreplication repair bypasses the lesion, allowing DNA synthesis to continue. DNA polymerase η mediates translesional DNA synthesis; it efficiently and accurately catalyzes synthesis past dithymidine lesions.

XP is caused by mutations affecting the global genome repair subpathway of nucleotide excision repair or by mutations affecting postreplication repair. In contrast, Cockayne syndrome, a related disorder, is caused by mutations affecting the transcription-coupled repair subpathway of nucleotide excision repair. XP and Cockayne syndrome have been separated into 10 biochemical complementation groups; each group reflects a mutation of a different component of nucleotide excision repair or postreplication repair (see Table).

The reduced or absent capacity for global genome repair or postreplication repair represents a loss of caretaker functions required for maintenance of genome integrity and results in the accumulation of oncogenic mutations (see Chapter 15). Cutaneous neoplasms from patients with XP have a higher level of oncogene and tumor suppressor gene mutations than tumors from the normal population, and those mutations appear to be highly UV specific.

Phenotype and Natural History

Patients with XP develop symptoms at a median age of 1 to 2 years, although onset after 14 years is seen in approximately 5% of patients. Initial symptoms commonly include easy sunburning, acute photosensitivity, freckling, and photophobia. Continued cutaneous damage causes premature skin aging (thinning, wrinkling, solar lentigines, telangiectasias), premalignant actinic keratoses, and benign and malignant neoplasms (Fig. C-48). Nearly 45% of patients develop basal cell or squamous cell carcinomas, or both, and approximately 5% develop melanomas. Approximately 90% of the carcinomas occur at the sites of greatest UV exposure—the face, neck, head, and tip of the tongue. Before the introduction of preventive measures, the median age for development of cutaneous neoplasms was 8 years, 50 years younger than in the general population, and the frequency of such neoplasms was more than 1000-fold greater than that of the general population.


FIGURE C-48 Cutaneous and ocular findings of xeroderma pigmentosum. Note the freckled hyperpigmentation, the papillomatous and verrucous lesions on the skin, and the conjunctivitis. See Sources & Acknowledgments.

In addition to cutaneous signs, 60% to 90% of patients experience ocular abnormalities, including photophobia, conjunctivitis, blepharitis, ectropion, and neoplasia. Again, the distribution of ocular damage and neoplasms corresponds to the sites of greatest UV exposure.

Approximately 18% of patients experience progressive neuronal degeneration. Features include sensorineural deafness, mental retardation, spasticity, hyporeflexia or areflexia, segmental demyelination, ataxia, choreoathetosis, and supranuclear ophthalmoplegia. The severity of neurological symptoms is usually proportionate to the severity of the nucleotide excision repair deficit. The neurodegeneration may result from an inability to repair DNA damaged by endogenously generated oxygen free radicals.

Complementation Groups in Xeroderma Pigmentosum and Related Disorders


CS, Cockayne syndrome; TTD, trichothiodystrophy; XP, xeroderma pigmentosum; XP-CS, combined XP and Cockayne syndrome phenotype.

Nucleotide excision repair also corrects DNA damage from many chemical carcinogens, such as cigarette smoke, charred food, and cisplatin. Consequently, patients have a 10- to 20-fold increase in the incidence of internal neoplasms, such as brain tumors, leukemia, lung tumors, and gastric carcinomas.

Patients with XP have a shortened life span; without preventive protection, their life span is approximately 30 years shorter than that of individuals without XP. Metastatic melanoma and squamous cell skin carcinoma are the most common causes of death.

Two related disorders, Cockayne syndrome and trichothiodystrophy, are also caused by defects in other components of the cellular mechanism for repair of UV-induced DNA damage. Both are characterized by poor postnatal growth, diminished subcutaneous tissue, joint contractures, thin papery skin with photosensitivity, mental retardation, and neurological deterioration. Children with Cockayne syndrome also have retinal degeneration and deafness; children with trichothiodystrophy have ichthyosis and brittle hair and nails. In both syndromes, affected patients rarely live past the second decade. Interestingly, neither syndrome shows an increase in the frequency of skin cancers. However, defects in some repair genes (ERCC2, ERCC3, and ERCC5) produce phenotypes that combine characteristics of XP and either Cockayne syndrome or both Cockayne syndrome and trichothiodystrophy (see Table).


Confirmation of the diagnosis of XP relies on functional tests of DNA repair and UV sensitivity; such tests are usually performed on cultured skin fibroblasts. Diagnostic confirmation by identification of mutations in an XP-associated gene is clinically available for some of the genes associated with the condition. However, failure to identify a causative mutation in one of these genes does not rule out XP as a clinical diagnosis.

The management of patients with XP includes avoidance of exposure to sunlight, protective clothing, physical and chemical sunscreens, and careful surveillance for and excision of cutaneous malignant neoplasms. No curative treatments are currently available.

Inheritance Risk

Because XP is an autosomal recessive disease, many patients do not have a family history of the disease. For parents who already have a child affected with XP, the risk for future children to have XP is 25%. Prenatal diagnosis is possible by functional testing of DNA repair and UV sensitivity in cultured amniocytes or chorionic villi or by molecular testing if the mutations have been identified.

Questions for Small Group Discussion

1. Define complementation groups and explain their use for defining the biochemical basis of disease.

2. Compare and contrast XP and Cockayne syndrome. Why is Cockayne syndrome not associated with an increased risk for neoplasia?

3. Patients with XP have a defect of cutaneous cellular immunity. How could the sensitivity of patients with XP to UV irradiation explain this immunodeficiency? How could this immunodeficiency contribute to cancer susceptibility?

4. Werner syndrome, Bloom syndrome, XP, ataxia-telangiectasia, and Fanconi anemia are inherited diseases of genomic instability. What are the molecular mechanisms underlying each of these disorders? What types of genomic instability are associated with each disorder?


DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J Invest Dermatol. 2012;132:785–796.

Kraemer KH, DiGiovanna JJ. Xeroderma pigmentosum. [Available from]

Menck CF, Munford V. DNA repair diseases: what do they tell us about cancer and aging? Genet Mol Biol. 2014;37:220–233.