eMedicine Specialties > Neurology > Pediatric Neurology

Xeroderma Pigmentosum

Author: Peter Hedera, MD, Assistant Professor, Department of Neurology, Vanderbilt University
Contributor Information and Disclosures

Updated: Jan 8, 2009

Introduction

Background

Xeroderma pigmentosum (XP) is a group of rare autosomal-recessive inherited disorders characterized by extreme skin sensitivity to ultraviolet (UV) light, abnormal skin pigmentation, and high frequency of skin cancers, especially on sun-exposed skin. Dermatologic changes are the most conspicuous findings and are mandatory for the diagnosis.

Neurologic involvement is often part of a phenotypic spectrum. Albert Neisser first described neurologic abnormalities associated with xeroderma pigmentosum in 1883. Neurologic involvement in xeroderma pigmentosum was emphasized in 1932 by De Sanctis and Cacchione, who described 3 brothers with xeroderma pigmentosum who had mental retardation, dwarfism, and gonadal hypoplasia. Subsequently, some authors referred to xeroderma pigmentosum associated with CNS abnormalities as De Sanctis-Cacchione syndrome.

In 1987, Kraemer et al reviewed clinical characteristics of 830 patients with xeroderma pigmentosum who were described in 297 articles. These researchers found neurologic abnormalities in 152 (18%) of these patients, a rate similar to those in other reports. Among patients with nervous system involvement, the most common abnormality was mental retardation (80% of subjects with neurologic involvement). Among these patients, the median intelligence quotient (IQ) score was 45, and the range was 15-81. The second most common neurologic abnormality was spasticity or ataxia (30% of subjects with neurologic involvement), followed by microcephaly (24%).¹

Pathophysiology

UV radiation induces cross-linking (dimerization) between thymine nucleotides. After exposure to UV light, normal cultured cells identify and excise the UV-induced thymine dimers and insert undamaged nucleotides after DNA synthesis and ligation. This repair process, known as unscheduled DNA synthesis, is deficient in xeroderma pigmentosum. Cell complementation analysis of cultured cells from patients with xeroderma pigmentosum demonstrated that xeroderma pigmentosum was genetically heterogeneous for the ability to repair UV-induced thymine dimers.

Fibroblasts from different patients with xeroderma pigmentosum were fused, and DNA repair after UV exposure was assayed. Correction of DNA repair deficiency in the fused cells indicates that each cell line has a unique abnormality of DNA repair. This finding led to identification of 7 specific complementation groups (A through G).

The genes that are responsible for defective NER in each xeroderma pigmentosum complementary group are highly conserved; homologous genes have been discovered in several species ranging from yeast to mammals.

Two overlapping pathways for NER have been proposed: the rapid transcription-coupled repair directed at the transcribed strand and slower global genome repair, which also includes the nontranscribed strand. Most xeroderma pigmentosum complementary groups are defective in both pathways. The complementary group C (XP-C) is a notable exception in which only global genome repair is defective.

The xeroderma pigmentosum variant complementation group (XP-V) has normal unscheduled DNA synthesis after UV exposure. However, the ability to repair DNA is reduced after adding caffeine to cultured cells. This defect is caused by mutations in the (pol)eta polymerase, which initiates translesion synthesis of UV-damaged DNA in an error-free manner.

Xeroderma pigmentosum is a multisystem disorder; sun-exposed skin and eyes (ie, eyelids, conjunctivae) are the most affected tissues. Cutaneous photosensitivity and early development of skin cancer is caused by defective DNA repair.

CNS involvement is due to premature neuronal death.

Necrosis in tissues that are not exposed to UV light suggests that these cells in patients with xeroderma pigmentosum are unable to repair DNA damage from other mutagens (eg, reactive oxygen species, other free radicals). Neurodegeneration probably results from accumulating mutations due to cells' inability to repair DNA damage. Increased oxidative damage in neurons due to abnormal function of free radical scavengers, such as superoxide dismutase, has been suggested.

The presence of neurologic abnormalities correlates with the degree of NER repair defect; patients with the greatest impairment of DNA repair are more prone to develop neurodegeneration.

Pathologic studies showed diffuse neuronal loss without other histologic hallmarks. Selective degeneration of dopaminergic neurons has been reported in some patients who were affected neurologically. Diffuse axonal loss was seen in the peripheral nerves in patients with clinical evidence of polyneuropathy.

Frequency

United States

XP-C and XP-D are the most common complementary forms, representing 30% and 20% of all xeroderma pigmentosum cases, respectively. XP-A is rare.

International

The worldwide frequency of xeroderma pigmentosum is estimated at 1 case in 250,000 population. Frequencies of complementary groups vary significantly in different populations. XP-A accounts for as many as 40% of all cases in Japan. Other complementary groups, with the exception of XP-V (in which all patients have only dermatologic manifestations), are rare. For example, only 3 cases of the XP-B type have been reported.

Mortality/Morbidity

• Skin cancer represents the major morbidity in xeroderma pigmentosum.
  • The median age of the first cutaneous cancer in xeroderma pigmentosum (most commonly basal cell or squamous cell carcinoma) is 8 years. In striking contrast, the mean age for squamous cell carcinoma in the general population is 58 years.
  • The incidence of malignant melanoma in patients with xeroderma pigmentosum who are younger than 20 years is 2000-fold higher than in an age-matched US population.
  • Skin tumors are typically multiple, and patients with as many as 100 tumors have been reported. This may result in disfigurement in severely affected subjects.
• Keratitis, together with squamous cell tumors of the conjunctiva and corneoconjunctival junction, is a major source of ophthalmologic morbidity.
• Other malignancies also occur at increased frequency in patients with xeroderma pigmentosum. The frequency of inner organ neoplasms, including malignant brain tumors, is estimated to be increased 20-fold compared to subjects without xeroderma pigmentosum.
• Mental retardation (or dementia in subjects with adult-onset neurologic deterioration), hearing loss, spasticity, ataxia, and polyneuropathy are the most common morbidity factors in the subset of patients who have with neurologic impairment.
  • As many as 50% of patients with XP-D manifest neurologic deterioration. Neurologic involvement is rare in patients with XP-C, the most common complementary group in the United States.
  • Seizures are common and epilepsy may be present in almost 25% of all patients.
  • Neurologic symptoms are progressive and may result in severe disability.
• Many patients become bedridden and incontinent. Some have significant cachexia in the terminal stages despite adequate caloric intake.
• Urinary tract infection, sepsis, and aspiration pneumonia are potential complications.
• Patients with early onset of neurologic symptoms tend to have more profoundly defective DNA repair, making them more susceptible to skin and inner organ tumors.
• Kraemer et al constructed the Kaplan-Meier survival curve for patients with xeroderma pigmentosum. The following were estimated:
  • 90% probability of surviving to age 13 years
  • 80% probability of surviving to 28 years
  • 70% probability surviving to 40 years
  • Overall, life expectancy of patients with xeroderma pigmentosum reduced by 30 years
• Various comorbid cancers usually cause death.

Race

All ethnic groups are affected similarly.

Sex

Both sexes are affected equally.

Age

• Only 5% of patients manifest the first symptoms after age 14 years.
• The median age of symptom onset is approximately 2 years.

Clinical

History

Xeroderma pigmentosum is a clinical diagnosis that is based on a history of sun hypersensitivity and skin neoplasms. Dermatologic symptoms precede neurologic manifestations, and diagnosis is typically straightforward. Before assuming that neurologic symptoms are indeed due to xeroderma pigmentosum, exclude any differential diagnoses.

• Skin cancer is detected in approximately 50% of patients by age 14 years.
  • Patients with neurologic symptoms can be classified on the basis of age of neurologic symptom onset: juvenile (before age 20 years) and adult (after 20 y).
  • The former group can be divided further into juvenile early onset (symptom onset before age 4 y), juvenile intermediate onset (symptom onset between 4 and 12 y) and juvenile late onset (symptom onset between 13 and 20 y).
• Neurologic involvement varies with each complementary group.
• The presence of progressive neurologic involvement and the age of symptom onset correlate with the degree of defect of DNA repair.
  • Fibroblasts from neurologically affected patients are the most sensitive to UV light and levels of unscheduled DNA synthesis are among the lowest.
  • Earlier onset of neurologic symptoms correlates with more profound degree of DNA repair defect.
  • Patients with later onset of neurologic deterioration tend to have an intermediate DNA repair defect.
  • The average age of onset of dermatologic symptoms among neurologically affected patients is 6 months (in contrast to 2 years in patients without neurologic involvement).

Physical

• Patients with xeroderma pigmentosum typically experience sunlight-induced skin abnormalities, such as widespread areas of hypopigmentation and freckles (ie, solar lentigines) with different intensities of pigmentation (see Media files 1-2).
• XP-A
  • This group has the most profound defect with absent or minimal DNA repair activity.
  • Patients with XP-A present with delayed motor and language development. Neurologic involvement is obvious before the age of 7 years. It corresponds to the early juvenile type and resembles the clinical features originally reported by De Sanctis and Cacchione.
  • Mimaki analyzed 32 Japanese patients with XP-A and neurologic abnormalities and found that mental retardation (21 of 32), microcephaly (17 of 32), and short stature (13 of 32) were the most common neurologic manifestations.²
    • Each patient had a progressive neurologic disturbance and exhibited nystagmus, dysarthria, and ataxia at or before age 7 years.
    • Neuroimaging demonstrated atrophy of the cortex and brain stem in most patients, although the white matter was normal.
    • Epilepsy is common in this subgroup of xeroderma pigmentosum patients and may be seen in 15% of patients.
  • Long-term follow-up of Finnish patients with XP-A demonstrated that neurologic symptoms appear in early childhood and dermatologic and ocular skin abnormalities may be relatively subtle.³   
  • A subset of patients with XP-A develop axonal polyneuropathy.
  • In subjects with a less severe DNA repair defect, symptom onset is more common in late juvenile age. These patients exhibited dementia (rather than mental retardation). Additional signs included choreoathetosis, ataxia, and oculomotor abnormalities.
• XP-B
  • Few patients have been reported in this group. Patients with XP-B and neurologic abnormalities show signs of Cockayne syndrome, a rare autosomal-recessive inherited disorder that is characterized by the following:
    • Short stature and failure to thrive (ie, cachectic dwarfism)
    • Signs of premature aging
    • Progressive retinal atrophy
    • Cataracts
    • Hearing loss
    • Skin hypersensitivity
    • Mental retardation
    • Ataxia
    • Sensory polyneuropathy
  • In contrast to xeroderma pigmentosum, skin cancer is rare in Cockayne syndrome.
• XP-C
  • XP-C is the most common group in the United States, constituting almost one third of all patients with xeroderma pigmentosum.
  • Unscheduled DNA synthesis is between 15% and 30% of normal.
  • Patients with XP-C may have signs of significant cortical atrophy on neuroimaging studies without any neurologic or cognitive problems. 
  • Neurologic symptoms are rare in XP-C, and few of these patients have been reported with features that are consistent with De Sanctis-Cacchione syndrome.
    • Late-onset, progressive neurologic impairment (eg, hearing loss, polyneuropathy, subtle ataxia) was reported in one patient with XP-C.
    • This is an important observation, because it suggests that neurodegeneration is caused by defective DNA repair. This finding may provide insight into other neurodegenerative disorders.
• XP-D
  • This is the second most common type of xeroderma pigmentosum in the United States, but it accounts for the majority of US patients with neurologic symptoms. Neurologic signs are present in approximately 50% of all patients with XP-D. Clinical presentation in this complementary group is heterogeneous, and various degrees of cutaneous and neurologic problems are reported.
  • The age of onset is typically between 7 and 12 years; however, the onset may occur earlier or even in adulthood.
  • Some patients manifest features of Cockayne syndrome (described with XP-B) or trichothiodystrophy, which is characterized by brittle and poorly growing hair.
  • Mental retardation (or dementia in patients with late-onset disease), progressive deafness, ataxia, choreoathetosis, and axonal polyneuropathy may be associated with either XP-D or trichothiodystrophy.
  • Brain magnetic resonance imaging (MRI) in patients with XP-D shows diffuse atrophy and basal ganglia calcification without demyelination. This differs from neurologically affected patients with trichothiodystrophy, who have prominent white matter abnormalities on T2-weighted MRI.
• XP-F and XP-G
  • Neurologic abnormalities have been reported in some of these patients. For example, two patients with XP-F had relatively mild cutaneous problems and developed progressive dementia, ataxia, and choreoathetosis in the fourth decade of life.
  • Neuroimaging showed severe cortical atrophy without additional abnormalities.
  • Patients with mutations in the ERCC1/XP-F gene may also manifest cerebro-oculofacioskeletal syndrome with microcephaly and arthrogryposis.⁴  
  • XP-G can be associated with a severe psychosomatic retardation, micro-ophthalmia, cataracts, and infantile spasm.
  • Finnish patients with XP-G suffered from sensorineural hearing loss, laryngeal dystonia, and peripheral polyneuropathy.³  

Causes

See Pathophysiology.

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