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Neuroscience 145 (2007) 1388–1396

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ERODERMA PIGMENTOSUM, TRICHOTHIODYSTROPHYND COCKAYNE SYNDROME: A COMPLEX
ENOTYPE–PHENOTYPE RELATIONSHIP
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. H. KRAEMER,a* N. J. PATRONAS,b R. SCHIFFMANN,c

. P. BROOKS,d D. TAMURAa AND J. J. DIGIOVANNAa,e

DNA Repair Section, Basic Research Laboratory, Center for Canceresearch, National Cancer Institute, Building 37 Room 4002 MSC258, Bethesda, MD 20892-4258, USA

Clinical Center, National Institutes of Health, Bethesda, MD, USA

National Institute of Neurological Diseases and Stroke, National In-titutes of Health, Bethesda, MD, USA

National Eye Institute, National Institutes of Health, Bethesda, MD,SA

Division of Dermatopharmacology, Department of Dermatology,rown Medical School, Providence, RI, USA

bstract—Patients with the rare genetic disorders, xero-erma pigmentosum (XP), trichothiodystrophy (TTD) andockayne syndrome (CS) have defects in DNA nucleotidexcision repair (NER). The NER pathway involves at least 28enes. Three NER genes are also part of the basal transcrip-ion factor, TFIIH. Mutations in 11 NER genes have beenssociated with clinical diseases with at least eight overlap-ing phenotypes. The clinical features of these patients haveome similarities but also have marked differences. NER isnvolved in protection against sunlight-induced DNA dam-ge. While XP patients have 1000-fold increase in suscepti-ility to skin cancer, TTD and CS patients have normal skinancer risk. Several of the genes involved in NER also affectomatic growth and development. Some patients have shorttature and immature sexual development. TTD patients haveulfur deficient brittle hair. Progressive sensorineural deaf-ess is an early feature of XP and CS. Many of these clinicaliseases are associated with developmental delay and pro-ressive neurological degeneration. The main neuropathol-gy of XP is a primary neuronal degeneration. In contrast, CSnd TTD patients have reduced myelination of the brain.hese complex neurological abnormalities are not related tounlight exposure but may be caused by developmental de-ects as well as faulty repair of DNA damage to neuronal cellsnduced by oxidative metabolism or other endogenousrocesses. © 2006 IBRO. Published by Elsevier Ltd. All rightseserved.

ey words: cancer, neurodegeneration, DNA repair, geneticisease, neurocutaneous diseases.

eroderma pigmentosum (XP), trichothiodystrophy (TTD)nd Cockayne syndrome (CS) are rare, inherited neurocu-aneous disorders (Table 1) (Bootsma et al., 2002; Cleaver

Corresponding author. Tel: �1-301-496-9033; fax: �1-301-594-409.-mail address: [email protected] (K. H. Kraemer).bbreviations: CS, Cockayne syndrome; NER, nucleotide excision

bepair; TTD, trichothiodystrophy; UV, ultraviolet; XP, xeroderma pig-entosum.

306-4522/07$30.00�0.00 © 2006 IBRO. Published by Elsevier Ltd. All rights reseroi:10.1016/j.neuroscience.2006.12.020

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t al., 1999; Kraemer, 2003a,b; Kraemer et al., 1987;apin et al., 2000; Robbins et al., 1974, 1991, 1993; Vanteeg and Kraemer, 1999). Affected patients have skinypersensitivity to sun exposure in association with abnor-alities in the nervous system. These autosomal reces-

ive diseases are caused by defects in nucleotide excisionepair (NER). The NER pathway serves to repair DNA thats damaged by ultraviolet (UV) radiation in sunlight as wells by other agents that induce bulky DNA distorting le-ions. Thus NER recognizes UV radiation–induced photo-roducts such as cyclobutane pyrimidine dimers, cigarettemoke–induced benzo-a-pyrene DNA adducts and chem-

cal carcinogen induced 4-nitroquinoline oxide DNA ad-ucts. NER also has a role in normal human development

ncluding the nervous system. This article will describeajor clinical features of XP, TTD, CS, and the XP/CS

omplex and provide a summary of the NER pathway.inally, the complex relationship between the clinical fea-

ures and the molecular defects in NER will be outlined.

XP

P patients have marked skin sun sensitivity (Table 1).bout half of the patients give a history of acute burning oninimal sun exposure. Typically the burn will appear aboutne day after the sun exposure. XP patients may developlistering and severe redness that persists for days. Theatients with the more severe burns tend to be those that

ater develop neurological abnormalities. Other XP pa-ients do not experience sunburning but tan normally. How-ver, following sun exposure all XP patients develop in-reased freckle-like pigmentation on exposed skin (Fig.A, B and C). The presence of these pigmentary abnor-alities in children under age 2 years is a clinical marker ofP patients.

With continued sun exposure the skin and the eyesecome damaged. The skin of children with XP can de-elop pre-cancerous lesions such as actinic keratoses. XPatients develop skin cancers at a mean age of less than0 years. This is a 50 year reduction in age of onset of skinancer in comparison to the U.S. general population andhus XP represents a form of premature aging. Similarly,he eyes may have chronic UV-induced conjunctivitis anderatitis (Fig. 1C). These may progress to inflammatoryesions such as pingueculae (conjunctival growths limitedo the bulbar conjunctiva) and pterygia (conjunctivalrowths that extend onto the corneal surface). In the gen-ral population, these lesions are rarely seen in children
ut have a fairly strong association with UV exposure in
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K. H. Kraemer et al. / Neuroscience 145 (2007) 1388–1396 1389

ormal individuals such as farmers and sailors. The XPatients have 1000-fold increase in cancer of the skin andyes (Kraemer et al., 1987, 1994). There is evidence thatarly diagnosis and rigorous sun protection will preventore of the serious skin cancers in XP patients and pro-

ong their life expectancy.

XP WITH NEUROLOGICAL DISEASE

bout 30% of XP patients have a progressive neurologicalegeneration in addition to the skin abnormalities (Table). In contrast to CS, patients with XP neurological diseasesually have normal sexual development. The course ofhe neurological degeneration is variable. The earliestlinical signs of the presence of XP neurological diseasere diminished or absent deep tendon reflexes and highrequency hearing loss. Progression of sensorineuraleafness may necessitate use of a hearing aid. Otherhanges may develop including abnormal gait, and dif-culty walking eventually leading to the use of a wheel-hair (Fig. 2A, B, and C) or to quadriparesis. Duringhildhood, development may progress, with intellectualapacity initially increasing, however, this may be fol-owed by deterioration over the course of years to de-ades. Swallowing difficulties may become severe lead-ng to aspiration of food. At this late stage patients areften fed with an implanted gastric tube.

The MRI shows atrophy of the cerebrum and cerebel-um with sparing of the white matter (Table 1). Enlarged

able 1. Comparison of features of XP, TTD and CS

eature XP

kinSkin sun sensitivity YesIncreased skin pigmentation YesSunlight-induced skin cancer Yes

yesPhotophobia YesConjunctival growths YesCancer (anterior eye/lids) YesCongenital cataracts NoPigmentary retinal degeneration No

omaticShort stature NoImmature sexual development Noervous systemSensorineural deafness NoDevelopmental delay NoProgressive neurological degeneration NoPrimary neuronal degeneration NoDysmyelination NoCerebral atrophy NoCerebellar atrophy NoCalcification (basal ganglia) Noisease mechanismNER defect YesReaction to exogenous or endogenous damaging agents Yes, sDevelopmental defect No

entricles may be seen early in childhood. This process u

ay progress leading to greatly enlarged ventricles. Therimary histological finding is neuronal degeneration with-ut inflammation or abnormal depositions.

TTD

TD patients have sulfur deficient brittle hair with charac-eristic alternating dark and light banding appearance“tiger tail”) with use of a light microscope with polarizinglters (Fig. 3A, B, C and D) (Itin et al., 2001; Liang et al.,005, 2006; Price et al., 1980). The clinical features inifferent patients are remarkably varied ranging from onlyair involvement to severe neurological and somatic de-elopmental abnormalities. Many TTD patients were bornrematurely or were small for gestational age. Some pa-ients may have a form of TTD called PIBIDS (for photo-ensitivity, ichthyosis, brittle hair, infertility, decreased in-elligence and short stature). There is also a high fre-uency of congenital cataracts and of multiple infections.hey may have skeletal abnormalities including peripheralsteopenia and central osteosclerosis. TTD patients, whileun sensitive, do not develop the pigmentary abnormalitiesf XP and do not have an increased frequency of skinancer.

TTD patients may have developmental defects in theervous system including microcephaly. While TTD pa-ients may have intellectual impairment, they usually areery social and have an outgoing, engaging, friendly per-onality. Typically, standard intelligence tests appear to

XP with neurolgicaldisease

TTD CS XP/CScomplex

Severe Yes/No Yes YesYes No No YesYes No No Yes

Yes Yes/No Yes YesYes No No YesYes No No Not reportedNo Yes Yes NoNo No Yes Yes

No/Yes Yes Yes YesNo No/Yes Yes Yes

Yes No Yes YesYes Yes Yes YesYes Unknown Yes YesYes No No NoNo Yes Yes YesYes No/Yes Yes YesYes No Yes YesNo No/Yes Yes Yes

Yes Yes Yes YesYes, severe No Yes YesYes Yes, severe Yes, severe Yes, severe

evere

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K. H. Kraemer et al. / Neuroscience 145 (2007) 1388–13961390

atients may have ataxia. The MRI shows predominantlyypomyelination of the white matter of the cerebrum. At-ophy of the brain is not a major feature. Some patientsay have calcification of the basal ganglia. At present the

linical course of TTD patients is not known.

CS

S patients are often normal at birth but experienceostnatal failure of brain growth (Nance and Berry,992; Rapin et al., 2000). They have a characteristicacies with deep set eyes, prominent ears and a wizened

ig. 1. Skin and eye involvement in XP. (A) Patient XP6BE, 17 yearncreased freckle-like pigmentation, areas of decreased pigment and aids. She had multiple surgeries for removal of skin cancers including bister of XP6BE. Her skin shows marked poikilodermatous changeeurological disease. They inherited a defect in the XPD (ERCC2) DNAalf of patient XP1BE at age 46 years. She had multiple large pigmenthen excised. (D) Right eye of patient XP1BE at age 29 years. Thpproaching the limbus and loss of lashes on the lower lid. She is weaquamous cell carcinoma that required enucleation. This patient inheobbins et al. (1974, 1993).

acial appearance. CS patients have extremely short f

tature and immature sexual development. They are sunensitive but do not have the pigmentary changes or

ncreased skin cancer frequencies seen in XP (Table 1).nlike XP, where diminished deep tendon reflexes maye an early sign of neurologic involvement, deep tendoneflexes may be increased in CS. CS patients have arogressive sensorineural deafness beginning with high

requency hearing loss. The eye shows progressive vi-ual loss with pigmentary retinal degeneration (“salt andepper retinopathy”) and involvement of the lens andornea (Dollfus et al., 2003). CS patients develop pro-

ale with marked poikilodermatous changes of her face with areas ofhe lips show cheilitis and there is absence of eyelashes on both lowercarcinoma and melanoma. (B) Back of patient XP5BE, age 26 years,sharp cutoff at her sun-protected buttocks. These sisters had XPne. Detailed information is reported in Robbins et al. (1974). (C) Rights. Lesion 15 was a large melanoma that measured 0.55 mm in depthuding of the cornea, prominent vascular growth on the conjunctivantact lens. She subsequently had a corneal transplant and an ocularfect in the XPC DNA repair gene. Detailed information is reported in

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ig. 3. Clinical appearance of TTD. (A, B) Three year old female with short, brittle hair which is sparse and broken off at different lengths. She rarely

ig. 2. Progressive cachexia in XP patient XP12BE. At age 4 years she had prominent pigmentary changes on the sun-exposed portions of her bodyface, arms) with sparing of her chest. By age 17 years she had had many basal cell and squamous cell carcinomas excised. Her main neurologicalbnormalities were loss of deep tendon reflexes and bilateral sensorineural hearing loss. By age 37 years she had become cachectic, was unable towallow her food and required assistance to walk. Details of her neurological status up to age 22 years are described in Robbins et al. (1991). This

as haircuts except to trim uneven areas. (C) Tiger-tail appearance of hair with polarizing microscopy. (D) Irregular, undulating hair shaft with lighticroscopy. From Liang et al. (2005).

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heir clinical course typifies premature aging and usu-lly results in early death.

Like TTD patients, CS patients are very sociable withn outgoing affect. They develop progressive ataxia and

oss of ability to walk and care for themselves. The brainRI shows decreased or absent myelin. Cerebral atrophyay be present. CT scan may reveal prominent calcifica-

ion of the basal ganglia and other areas in the brain (Fig.A and B). The primary histological finding in CS is aemyelinating neuropathy rather than the neuronal degen-ration seen in XP.

XP/CS COMPLEX

atients with the XP/CS complex have skin and eye diseasef XP and the somatic and neurological abnormalities of CSTable 1) (Lindenbaum et al., 2001; Rapin et al., 2000). Thusheir skin is hypersensitive to sunlight and they develop thereckling and other pigmentary changes of XP. They have thehort stature and immature sexual development as well ashe retinal degeneration as in CS. The disease course is onef progressive neurological degeneration (Fig. 5A–G). Lesshan two dozen patients with the XP/CS complex have beeneported in the literature.

NER PATHWAY

atients with XP, TTD, CS and the XP/CS complex haveefects in the NER pathway (Fig. 6) (Van Steeg and Krae-er, 1999). This pathway serves to remove DNA damage

aused by exposure to ultraviolet radiation and some otherxogenous and endogenous agents that cause bulky le-

ig. 4. Calcification of brain in CS. (A) Axial brain CT scan of a 3 yearomographic sections at higher levels (not shown) revealed mild enlar

o leukodystrophy and thick skull. She had CS with skin sun sensitivitcan of a 16 year old girl showing extensive bilateral and symmetric cucleus. Prominent calcifications are also identified in both cerebellaatter junction of the frontal and the parietal lobes which were app

here was evident leukodystrophy in the white matter of the cerebrahort statue and progressive neurological degeneration. Modified f

ions or oxidative damage. There are at least 28 proteins v

n the NER pathway. They serve to recognize DNA lesions,nwind the surrounding DNA, excise the lesion and then fill

n the resulting gap. Three of the proteins are also part ofhe 10 protein complex of the basal transcription factor,FIIH. Thus the NER pathway is closely linked to

ranscription.Repair of actively transcribing genes (transcription

oupled repair) proceeds more rapidly than DNA repair ofamage located in the remainder of the genome. DNAamage in these actively transcribing genes is signaled bySA and CSB proteins along with other proteins. The XPCnd XPE (DDB2) proteins are involved in recognition ofNA damage in the remainder of the genome (globalenome repair). The XPB, XPD and TTDA proteins areart of the basal transcription factor TFIIH. The XPB andPD helicases unwind the DNA. The XPF and XPG pro-

eins are endonucleases that make asymmetric singletrand breaks on either side of the damage about 30ucleotides apart.

RELATIONSHIP OF CLINICAL DISEASE TONER MUTATIONS

here is a complex relationship between the clinical dis-ases and the molecular defects in NER (Fig. 7) (Kraemer,004). Patients with one of several clinical disease mayave inherited a defect in one of several different NERenes. Since the NER pathway functions in sequence, aefect in one portion of the pathway impairs the function ofhe subsequent steps. Thus patients with XP can haveefects in XPA, XPB (ERCC3), XPC, XPD (ERCC2), XPEDDB2), XPF (ERCC4) or XPG (ERCC5) genes. Con-

owing bilateral and symmetric speckled calcifications of the putamen.f the lateral ventricles, decreased attenuation in the white matter duetature and progressive neurological degeneration. (B) Axial brain CTns in the putamen, the globus pallidus and the head of the caudate

heres. Less prominent calcifications were present at the gray–whitein higher tomographic sections. Furthermore in the higher sectionsheres and increased skull thickness. She had skin sun sensitivity,mer (2003b).

old girl shgement oy, short salcificatior hemispreciated

ersely, different defects in one gene may lead to different

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linical diseases. Thus different mutations in the XPDERCC2) gene may lead to one of six different clinicalisorders: XP, XP neurological disease, TTD, the XP/CSomplex, XP/TTD complex or a severe form of CS known

ig. 5. Patient XP20BE with XP/CS complex. (A) Patient at age 4 mohe sharp change in redness on his lower legs where his socks blockedharacteristic skin lesions of XP: freckling and hypopigmented macuypical appearance of CS with deep set eyes, prominent ears, and profnd wrinkling of the dorsum of the hand showing signs of prematureorsiflexion of the hand. Note small size in comparison to the mother wyanosis and permanently upgoing toes. From Lindenbaum et al. (20

s COFS (cerebral, ocular, facial, skeletal syndrome). o

THEORETICAL MECHANISMS OF DISEASE

he skin and eye disease in XP and the 1000-fold in-reased frequency of neoplasms in these sun-exposed

he developed severe sunburn in March, the first sign of illness. Notenlight. (B) Normal fullness of the face at age 1 year. (C) Age 1.5 years.n and lips. A benign pedunculated lesion is circled. (D) Age 6 years.hexia with posturing of the hand. (E) Age 6 years. Pigmentary changes(F) Age 6 years. Signs of advanced CS with profound weakness ofing him. (G) Profound wasting and contractures of the legs with distal

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NA. This results in increased cell killing and increasedrequency of mutations in many of the genes in the surviv-ng cells. Accumulation of mutations that activate onco-enes or inhibit tumor suppressor genes in dividing cells

ig. 6. NER pathway. Transcription-coupled repair (TCR) removesemoves damage from the remainder of the genome. In GGR damahotoproducts (6-4 PP) are recognized by proteins including the XProgress of RNA polymerase II in a process involving the CSA and CShe XPB (ERCC3) and XPD (ERCC2) helicases unwind the region sureplication protein A (RPA). The XPF and XPG (ERCC5) endonucleasehe resulting gap is filled in by de novo DNA synthesis. This system i

ails to function normally. Mutations in the genes in rectangles have bnd Kraemer (1999).

ventually leads to cancer. r

In the XP patients who develop progressive neurolog-cal degeneration the brain is not exposed to ultravioletadiation. The progressive nature of the degeneration sug-ests that there might be ongoing damage that is not

from actively transcribing genes while global genome repair (GGR)as ultraviolet induced cyclobutane pyrimidine dimers (CPD) or 6-4

) and XPC gene products. In TCR, the lesion appears to block theroducts. Following initial damage recognition the pathways converge.the lesion along with the XPA and XPG (ERCC5) gene products, andincisions to remove the lesion in a fragment of about 30 nucleotides.

ated so that if one part of the pathway is mutated the entire pathwayciated with clinical disease. This diagram is modified from Van Steeg

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amage could result in impaired cellular function and even-ually in cell death. An effect of the damage might be tolter the process of transcription so that mutations mighte introduced into newly synthesized RNA. This could

mpair functioning of essential proteins. The NER pathways present in all cells in the body including those in theervous system. Recent studies from several laboratoriesave reported the discovery of some bulky DNA lesionsroduced by oxidative damage that are substrates for theER pathway. Unrepaired lesions such as cyclo-deoxya-enine or cyclo-deoxyguanine might accumulate in theNA of neurons of patients with defective NER and lead to

he progressive neurological degeneration (Brooks et al.,000). There are many unanswered questions relating tohis theory including why only some of the XP patientsevelop neurological degeneration and why certain partsf the brain are typically affected more than others.

Patients with TTD have neurological defects that ap-ear to be mainly related to impaired development andaturation of the nervous system. They have decreased tobsent myelin in the cerebrum. While not proven defini-

ively, it seems that the myelin in these patients neverormed properly (dysmyelination) rather than sustaining aoss of normally formed myelin (demyelination). This sug-ests the presence of a developmental defect as is alsoeen in the congenital cataracts in the eye, the problemsuring in utero growth, and the short stature. In additionTD patients do not have an increased frequency of skinancer. TTD patients have defects in XPD, XPB or TTDAenes. These genes are part of the basal transcriptionactor, TFIIH as well as in NER. It has been proposed thathe specific defects in these genes in TTD patients have areater effect on the transcription activities of these geneshan on their repair activities (Dubaele et al., 2003). Atriking example is the finding that mutations in the XPDomponent of TFIIH result in beta-thalassemia in TTD

ig. 7. DNA repair diseases; relationship of clinical disorders (redectangles) to molecular defects (gray ovals) in DNA repair diseases.ight clinical diseases are represented. One disease may be causedy mutations in several different genes. Conversely, different muta-

ions in one gene may result in several different clinical diseases.odified from Kraemer (2004). For interpretation of the references to

olor in this figure legend, the reader is referred to the Web version ofhis article.

atients without mutations in hemoglobin genes (Vipraka-

it et al., 2001). At present we have no evidence of pro-ressive neurological degeneration in TTD patients.

CS patients have both developmental defects and pro-ressive neurological degeneration. Like TTD patientshere is primary involvement of the myelin in the brain. TheSA and CSB proteins have a role in transcription-coupled

epair and may also be involved in transcription of undam-ged genes. CSA and CSB proteins are involved in regu-

ation of recruitment of chromatin remodeling and repairactors to stalled RNA polymerase II after UV damageFousteri et al., 2006). The transcriptional response afterxidative damage is defective in cells from patients withutations in the CSB gene (Kyng et al., 2003). Thus therogressive neurological degeneration in CS may involveaulty repair of oxidative damage or of bulky DNA damages in XP patients. However major questions remain suchs the differences in the type of involvement—for exampleetinal degeneration is present in CS but not in XP—andhe differences in cancer susceptibility.

cknowledgments—This research was supported by the Intramu-al Research Program of the NIH and the Center for Canceresearch of the National Cancer Institute, the Clinical Center, theational Institute of Neurological Diseases and Stroke, and theational Eye Institute.

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(Accepted 6 December 2006)(Available online 1 February 2007)

xeroderma pigmentosum, trichothiodystrophy and cockayne...

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