Neurologic Manifestations of Xeroderma Pigmentosum 

Updated: Mar 19, 2019
Author: Peter Hedera, MD, PhD; Chief Editor: Amy Kao, MD 

Overview

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 (see image below). Dermatologic changes are the most conspicuous findings and are mandatory for the diagnosis.[1]

Sunlight-induced dermatologic abnormalities in a p Sunlight-induced dermatologic abnormalities in a patient with xeroderma pigmentosum.

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%).[2]

Analysis of 106 patients with xeroderma pigmentosum followed at the National Institutes of Health identified a progressive neurologic degeneration in 25 (24%) patients, and 16 of these patients had complementary group XP-D.[3]

Pathophysiology

Cleaver's seminal work in 1968 elucidated the pathophysiology of xeroderma pigmentosum by demonstrating defective DNA repair. Further studies of this defect led to significant progress in the understanding of nucleotide excision repair (NER) mechanisms under normal and pathologic conditions.[4]

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.[5] 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.[6]

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.

Epidemiology

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

See the list below:

  • 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.[7]

  • 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. The median age at death in xeroderma pigmentosum patients with signs of neurodegeneration was 29 years and in patients without any additional neurologic abnormalities was 38 years.[3]

  • 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.

  • The most common cause of death in xeroderma pigmentosa patients is skin cancer, at 34%, followed by cancer of internal organs, at 17%.

  • Progressive neurodegeneration can be a direct cause of death in approximately one third of patients.

Race

All ethnic groups are affected similarly.

Sex

Both sexes are affected equally.

Age

See the list below:

  • Only 5% of patients manifest the first symptoms after age 14 years.

  • The median age of symptom onset is approximately 2 years.

 

Presentation

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.

  • XP-D complementary group has the highest proportion of patients with a progressive neurodegeneration.

  • 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 images below).

Sunlight-induced dermatologic abnormalities in a p Sunlight-induced dermatologic abnormalities in a patient with xeroderma pigmentosum.
Typical skin manifestation of xeroderma pigmentosu Typical skin manifestation of xeroderma pigmentosum with numerous areas of hypopigmentation and freckles (ie, solar lentigines) with different intensities of pigmentation.

See the list below:

  • 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.[8]

      • 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.[9]

    • 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[10] , 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.[11]

      • 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.[12]

    • 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.[9]

Causes

See Pathophysiology.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Exclude treatable causes of dementia. Order thyroid function tests, vitamin B-12, erythrocyte sedimentation rate (ESR), and fluorescent treponemal antibody (FTA) in patients with intellectual decline.

  • Screening metabolic studies to investigate developmental delay in children with unequivocal diagnosis of xeroderma pigmentosum have low yields. However, in patients with a less certain diagnosis for xeroderma pigmentosum, consider the following:

    • Metabolic screen

      • Serum and urine amino acids

      • Organic amino acids

      • Lysosomal enzymes

      • Cholesterol esterification assays

      • 24-hour urine copper

      • Urine study for mucopolysaccharides and oligosaccharides

      • Venous lactate and pyruvate

      • Long-chain fatty acids

    • Chromosomal analysis

  • Very-long-chain fatty acids, galactosylceramide beta-galactosidase, and arylsulphatase-A levels can differentiate xeroderma pigmentosum from adrenoleukodystrophy, Krabbe disease, and metachromatic leukodystrophy, respectively.

  • Unscheduled DNA synthesis, UV light survival, complementation studies, and direct DNA testing for mutations are not routinely available (see Pathophysiology). These are performed only on a research basis.

Imaging Studies

See the list below:

  • Patients with a new onset of ataxia or spastic weakness should undergo neuroimaging, preferably MRI of the brain and spine, to rule out structural abnormalities, including tumors and arteriovenous malformations.

    • Diffuse atrophy of the cerebral cortex and the cerebellum is seen in patients with xeroderma pigmentosum (see images below).

      Axial T2-weighted MRI of the brain of a 47-year-ol Axial T2-weighted MRI of the brain of a 47-year-old woman with xeroderma pigmentosum, complementary group D. She developed progressive ataxia and dementia at age 44 years. Note severe atrophy and normal signal from the white matter.
      Coronal T1-weighted MRI image of the brain of a 47 Coronal T1-weighted MRI image of the brain of a 47-year-old woman who developed progressive ataxia and dementia at age 44 and was found to have xeroderma pigmentosum, complementary group D (see image above). Severe diffuse atrophy involves the brain stem and cerebellum.
    • Some patients may have normal neurologic and cognitive examination in spite of significant cortical atrophy.

    • Patients with a mixed phenotype xeroderma pigmentosum (particularly XP-D) and trichothiodystrophy may have white matter abnormalities (increased signal on T2-weighted images) on MRI of the brain, suggesting demyelination.

  • Basal ganglia calcification can be better assessed by the axial computed tomography (CT).

Other Tests

See the list below:

  • Electromyography (EMG) and nerve conduction studies (NCS) are helpful because axonal polyneuropathy is common in xeroderma pigmentosum.

  • Perform electroencephalogram (EEG) in patients who develop seizures. Seizures are typically partial complex with secondary generalization. Focal spike and wave discharges may occur in the interictal period. Diffuse background slowing may be present.

  • Use audiogram and brainstem evoked potentials for screening, since the prevalence of hearing loss is high in xeroderma pigmentosum.

Histologic Findings

The few reports of nerve biopsy in patients with xeroderma pigmentosum demonstrated a marked decrease of myelinated fibers. Sural nerve biopsy is not useful for clinical diagnosis/management.

 

Treatment

Medical Care

See the list below:

  • Skin hypersensitivity and skin cancer should be treated by a dermatologist.[13]

  • Neurologic care is mostly supportive. Seizures can be treated like other complex partial seizures with secondary generalization. Spasticity is usually mild. If it interferes with mobility, baclofen or botulinum toxin (BOTOX┬«) injection may be beneficial.

Consultations

Every patient with xeroderma pigmentosum needs to be monitored regularly by a dermatologist and ophthalmologist. Consultation with a geneticist may help to differentiate xeroderma pigmentosum from other related conditions, such as Cockayne syndrome and progeria.

Activity

Patients must avoid the sun to protect their skin. If sun exposure cannot be entirely avoided, patients should wear long sleeves, use sunscreen with SPF 50, and wear dark glasses. Some families reverse their day/night cycle to eliminate sun exposure entirely.[14]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Anticonvulsants

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Carbamazepine (Tegretol, Carbatrol, Epitol)

Treats complex partial seizures. Appears to act by reducing polysynaptic responses and blocking posttetanic potentiation. Major mechanism of action is to reduce sustained high-frequency repetitive neural firing.

Phenytoin (Dilantin)

May act in motor cortex where may inhibit spread of seizure activity. Activity of brain stem centers responsible for tonic phase of grand mal seizures also may be inhibited.

Dose should be individualized. Administer larger dose before retiring if dose cannot be divided equally. Phosphorylated formulation, fosphenytoin, available for parenteral use and may be given IM or IV.

Valproic acid (Depakote, Depakene, Depacon)

Chemically unrelated to other drugs that treat seizure disorders. Although mechanism of action not established, activity may be related to increased brain levels of GABA, or enhanced GABA action.

Also may potentiate postsynaptic GABA responses, affect potassium channel, or have direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 wk. This reduction may start at initiation of therapy or be delayed by 1-2 wk if concern that seizures may occur with reduction. Monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response achieved at daily doses < 60 mg/kg/d.

 

Follow-up

Prognosis

See the list below:

  • Xeroderma pigmentosum is a progressive condition with a high incidence of cutaneous and inner organ tumors.

  • Progressive neurologic deterioration may occur.

  • The average life expectancy is reduced by 30 years, and neoplasms are usually the cause of death.

Patient Education

See the list below:

  • Patients and caregivers should be educated concerning the nature of the disease, the photosensitivity, the high incidence of cancer, and the necessity to avoid UV exposure.

  • Discuss skin protection (see Activity).