: A MULTIDISCIPLINARY APPROACH Mieran Sethi,1 Alan R. Lehmann,1,2 Hiva Fassihi1

1. National Xeroderma Pigmentosum Service, Department of Photodermatology, St John’s Institute of , Guy’s and St Thomas’ NHS Trust, London, UK 2. Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK

Disclosure: No potential conflict of interest. Received: 01.10.2013 Accepted: 06.11.13 Citation: EMJ Dermatol. 2013;1:54-63.

ABSTRACT

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair. Affected individuals are unable to repair ultraviolet radiation (UVR)-induced DNA damage, leading to a variety of clinical manifestations: a dramatic increase in mucocutaneous malignancies, increased lentigines, extreme photosensitivity (in approximately 50% of cases), and neurodegeneration (in approximately 30% of affected individuals). Incidence in Western Europe is recorded as 2.3 per million live births. There are eight different complementation groups, XP-A to XP-G, and XP-variant (XP-V) corresponding to the eight affected genes. Classically, XP patients were identified by clinicians for their tendency to develop severe and exaggerated on minimal sun exposure, however recently it has been shown that XP-C, XP-E and XP-V patients have normal sunburn reactions for skin type compared to the other groups, who suffer not only with severe, exaggerated sunburn, but also have an increased incidence of neurodegeneration.

A diagnosis of XP should be considered in a child with either severe sunburn, increasing lentigines at exposed sites, or development of multiple skin cancers at an early age. Skin biopsy and subsequent testing in cell cultures for defective DNA repair, confirms or excludes the diagnosis. Mean life expectancy is reduced; the two main causes of mortality are skin cancer and neurodegeneration. These clinical features distinguish XP from other disorders of DNA repair, namely Trichothiodystrophy and Cockayne syndrome, although overlapping syndromes do occur. Instigation of meticulous photoprotection for all XP patients has been shown to reduce both the lentigines and number of skin cancers dramatically and would be presumed to increase life expectancy. Compliance with photoprotection is a recognised problem amongst XP patients, particularly in those without easy sunburn. This is further accentuated by lack of social acceptance for people who wear UVR-protective visors. Increased awareness of XP, both within the medical and media spheres will benefit current and future XP patients; this will aid earlier diagnosis and timely photoprotection, with better compliance, and therefore, result in an improved prognosis.

Keywords: Xeroderma pigmentosum, DNA repair, sunburn, skin cancer, neurodegeneration, ultraviolet radiation DNA damage.

INTRODUCTION ), the other, aged 10 years, also had dry, thin skin, without the noted pigmentation, but within Nearly 140 years ago, the term ‘xeroderma’ was 1 year developed a fissured tumour on the nose. first used by Moritz Kaposi1 for patients with dry, Kaposi described xeroderma pigmentosum (XP) wrinkled, parchment-like skin, to characterise a as a condition existing from childhood that never rare disease he had noted in two patients; one improved either spontaneously or as a result of with severely pigmented skin in predominantly any treatment. sun-exposed areas (face, neck, shoulders, and

54 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 55 In 1883, Albert Neisser made the link between XP led to identification of seven separate XP and neurodegeneration and in 1932, two Italian ‘complementation groups’ deficient in NER, physicians, De Sanctis and Cacchione,2 reported designated XP-A to XP-G.11-16 a ‘xerodermic idiomacy’ in which three XP patients also had neurological and other physical A separate group of XP patients with normal 17 abnormalities: microcephaly with progressive DNA excision repair in lymphocytes and in 18 mental deficiency, retarded growth and sexual fibroblasts was reported by Burk et al. in 1971, development, hearing loss, choreoathetosis, ataxia, and later these patients were designated ‘XP- and eventual quadriparesis with Achilles-tendon variant’ (XP-V). Their cells showed normal levels shortening. Until recently, the term ‘De Sanctis- of DNA repair after UVR exposure and it was Cacchione syndrome’ was used to describe XP assumed that the defect must lie elsewhere. 19 patients with severe neurodegeneration, but the Indeed, in 1975 Lehmann et al. discovered that term is no longer in use. In 1965, Reed et al.3 XP-V patients have a defect in the DNA post- described XP with choreoathetoid neurological replication repair pathway. complications. Cerebral and olivopontocerebellar There have been several reviews of XP over the atrophy were found at autopsy of two further XP last 40 years,20-24 but with the ever-expanding cases.4,5 A review, at National Institute of Health research into cellular mechanisms of DNA repair (NIH), described all the neurological abnormalities pathways, our understanding of XP as a whole identified in XP patients and commented that continues to develop. the type of neurodegeneration detected can be found in many degenerative and hereditary EPIDEMIOLOGY disorders of the nervous system of non-XP patients, and usually correlates to distinctive XP has been reported to occur in all ethnic groups pathological findings; however, postmortem worldwide and affects men and women in equal cerebral examination of XP patients had failed ratio. Amid Indian and Middle Eastern areas, to reveal any unique morphological or cellular incidence is quoted at 1:10,000-30,000.25-28 In 5,6 abnormality, other than neuronal cell loss. Japan, incidence is reported as 1:20,000– 29,30 Exposure of skin cells to ultraviolet radiation (UVR) 100,000, and in Western Europe it has been 31 causes the formation of cyclobutane pyrimidine estimated at 2.3 per million live births. The dimers (CPDs)7 and pyrimidine (6-4) pyrimidone incidence of XP in Japan appears 10-times higher photoproducts (6-4 PPs)8 by crosslinking of than in Western countries, and approximately adjacent pyrimidines in DNA. These photoproducts 60% of XP patients in Japan belong to the XP-A are removed by the nucleotide excision repair complementation group, twice the proportion 22 (NER) pathway. In 1968, Cleaver9 showed that seen in other countries. 90% of patients are whereas fibroblasts from normal adult skinhomozygous for the XP-A founder mutation, 28 were able to repair damage induced by UVR, carried by 1% of the Japanese population. In 32 cultured fibroblasts from XP patients had a 2010, Soufir et al. reported that 85% of XP marked reduction in, or absence of, repair. Epstein families in the Maghreb region (Algeria, Tunisia et al.10 confirmed thisin vivo in 1970. and Morocco) carried a founder mutation in the XP-C gene. More recently, it has been reported In 1971-2, the spectrum of clinical symptoms in XP that 1 in 5,000 individuals of the black Mahori prompted studies into the genetic heterogeneity population in the Comoro Islands have XP-C. using XP fibroblast cell fusion techniques. This is linked to another founder mutation.33 In Each XP fibroblast was known to be deficient in the latter regions, consanguineous marriages are repairing UVR-induced DNA damage. Fusing two quite common, resulting in higher frequencies of XP fibroblasts from two separate donors enabled homozygous mutations in genes corresponding to a heterokaryon to be formed (a cell containing rare genetic disorders. nuclei from different donors in a common cytoplasm). This heterokaryon was found to AETIOLOGY AND GENETICS exhibit normal DNA repair, implying that separately each cell supplied what the other XP is an autosomal recessive disorder that lacked and therefore the defects in each cell arises from mutations in the genes encoding for were genetically different. This ultimatelyproteins that are integral to NER, a pathway that

54 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 55 repairs many types of DNA damage including repair of both strands of actively and non- those produced by UVR (CPDs/6-4PPs).34-37 actively transcribed genes. TC-NER identifies Patients have mutations in one of seven different and rapidly repairs damage, specifically on the XP genes (XP-A to XP-G) resulting in impaired transcribed strand of actively transcribing DNA. NER. XP-V patients have normal NER, but RNA polymerase II stalls at the site of the mutations in DNA polymerase η (POLH) cause a photoproducts; recognition of this and recruitment defect in the ability to replicate DNA containing of subsequent NER proteins is mediated by the unrepaired damage. CSA and CSB proteins. Defects in either of these proteins result in Cockayne syndrome rather NER consists of two sub-pathways that differ than XP. at the initial recognition step; global nucleotide excision repair (GG-NER) and transcription- The two NER sub-pathways then converge coupled nucleotide excision repair (TC-NER), to form the common stem where TFIIH (a (Figure 1). GG-NER is a relatively slow, scanning complex containing 10 polypeptides including the of the entire genome; XP-E (with its partner helicases, XP-B and XP-D) is recruited to open protein DDB1) binds to the photoproduct,38 up DNA around the site of the photoproduct. and recruits XP-C, which recognises and binds XP-A binds to verify that all the proteins are in to the distortion affecting the strand opposite the correct position. The heterodimeric nucleases the photoproduct.39 GG-NER is responsible for ERCC1/XP-F and XP-G cleave the damaged

DNA damaged by UV radiation

GLOBAL GENOME REPAIR TRANSCRIPTION-COUPLED (GG-NER) REPAIR (TC-NER)

Damaged DNA stalled by RNA polymerase, Photoproducts recognised by XPC and XPE recognition by CSB then CSA

Photoproducts TFIIH Complex recruited RNA polymerase XPA binds for damage verification

Cockayne Syndrome Protein A (CSA)

Cockayne Syndrome Protein A (CSB) DNA unwinds 5’ XPC 3’ Incision by XPF + ERCC1 and XPG XPE

XPA

TFIIH (XPB+XPD+8 other components) DNA with photoproduct is excised

XPF+ERCC1

XPG DNA repaired: Unscheduled DNA Synthesis

Figure 1. A model for NER of UVR-induced DNA damage.

56 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 57 DNA strand 5’ and 3’ to repair the damage eyes) and therefore also by age of the patient respectively. An approximately 30-nucleotide at diagnosis and timing of photoprotection fragment containing the damaged nucleotides initiation. XP includes a clinically heterogeneous is then excised and the resulting gap filled group of patients with some genotype-phenotype in using the undamaged strand as template. correlations, both between and within different The DNA polymerisation that fills in the gap is complementation groups. known as unscheduled DNA synthesis (UDS). Mutations in XP-A, XP-B, XP-D, XP-F, and XP-G The main recognised clinical manifestations are: genes result in the impairment of both GG-NER photosensitivity, leading to severe and exaggerated and TC-NER. However, mutations in XP-C and sunburn reactions, increased lentigines, and XP-E genes affect only GG-NER, and therefore pigmentary change, an overwhelming increase there is some preservation of NER via the in skin cancer frequency, ocular abnormalities, TC-NER pathway. and neurodegeneration.

NER is fully functional in XP-V patients. The Sunburn defect is in the process of translesion synthesis, Sunburn is a normal response to UVR exposure. which is carried out by a specialised DNA The confluent and well-demarcated, erythematous, polymerase, polη, that is able to replicate DNA oedematous, and tender reaction is caused 19,40 past unrepaired photoproducts. by vasodilation and inflammation. Apoptotic 45 The inability of XP patients to repair UVR- keratinocytes are present in histological analysis. The sunburn response is probably triggered by induced DNA damage explains the skin changes UVR-induced DNA damage. Patients with XP in these patients (lentigines and skin cancers). suffer with severe and prolonged sunburn. Their The neurodegeneration seen in only 30% of increased susceptibility to severe sunburn may patients is harder to explain. It is likely to be relate to the persistence of UVR photoproducts related to the DNA repair defect and an efficient in the DNA.46 DNA repair mechanism is required to maintain 19 the functional integrity of neuronal cells. Acute severe sunburn on minimal sun exposure 41 Brooks et al. showed that DNA from neuronal was once considered a cardinal presenting feature cells that are exposed to endogenous oxygen of XP. However, with increasing research and radicals, produce oxidative DNA lesions called analysis of larger groups of XP patients, it has been cyclopurines (cPu) (cyclo-2-deoxyadenosine and shown that only 50% of XP patients will suffer (5 S)-8,5’-cyclo-2’-deoxyguanosine). cPus requires from severe and prolonged sunburn reactions.21,47,48 42 removal from DNA, specifically via NER. In XP-A The remaining 50% have sunburn reactions that cells (without functioning NER), the presence are normal for their skin type and present with of a single cPu lesion on a transcribed DNA lentigines at sun-exposed sites, (together with strand of a reporter gene strongly reduced an early onset of skin cancer). Our recent study, gene expression. It was demonstrated that within a cohort of patients in the UK National neuronal death resulted from accumulation of XP service, has shown that patients in these unrepaired cPus. Later cPus were re- complementation groups XP-A, XP-D, XP-F, and named as 8,5-cyclopurine-2-deoxynucleosides or XP-G have been shown to suffer from severe ‘cyPudNs’.42 The biological properties of cyPudNs sunburn reactions; whereas, those in groups XP- are very similar to other substrates of NER C, XP-E and XP-V have normal sunburn reactions, such as UVR-induced thymidine dimers. cyPudNs consistent with similar findings of Kraemer and have been shown to block gene expression in XP colleagues at the NIH.47,48 XP-A, XP-B, XP-D, cells, a biological effect that is compatible with XP-F, and XP-G proteins are all required for the causing neurodegeneration.43,44 common stem of NER whereas XP-C and XP-E proteins are only required for GG-NER. In XP-C CLINICAL MANIFESTATIONS AND and XP-E, TC-NER is preserved. XP-V patients ASSOCIATIONS with mutations affecting DNA polymeraseη , also have normal functioning TC-NER (and GG-NER). Cutaneous clinical features of XP patients are It is therefore hypothesised that normal sunburn largely determined by the cumulative amount of reactions in approximately half of the XP patients UVR exposure at sun-exposed sites (skin and relate to preservation of TC-NER.49

56 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 57 Skin Cancers of the ocular surface, and (3) the ocular manifestations of neurodegeneration. Even XP patients have a >10,000-fold increased risk patients with few ophthalmic signs commonly of developing non-melanoma and a 2,000- describe photophobia, which is the earliest fold increased risk of melanoma skin cancer in presenting ophthalmic symptom of XP.21 patients under 20 years of age. The median age at diagnosis of first non-melanoma skin cancer Damage to the eyelids and periocular skin can (NMSC) is between 8 and 9 years,21,50 significantly result in the development of cicatricial skin younger than the median age at diagnosis of changes as well as skin cancers, which require first melanoma, at age 22 years. This is an inverse excision.59 The ocular surface (conjunctiva and pattern to what is observed in the general cornea) can develop UVR-related damage population, where younger patients are more likely including dry eye, conjunctival injection, and to present with melanoma and older patients with inflammation (without infection), as well as non-melanoma skin cancers.51 UVR exposure to development of premature pingueculae and the oral cavity in XP patients can result in pterygia. Prolonged corneal exposure can mucocutaneous malignancy, most commonly result in corneal scarring and visual impairment. seen as squamous cell carcinoma of the tip of Ocular surface cancers, mainly squamous cell the tongue.52 carcinomas, have also been reported in patients with significant UVR exposure and poor Studies on UVR-induced mutagenesis in cultured ocular photoprotection.60 cells have indicated a ‘UVR-signature mutation’, namely C to T transitions and CC to TT tandem Patients with XP-related neurodegeneration may mutations. The latter, in particular, are rarely found also develop neuro-ophthalmological features, after exposure to any mutagenic agent other including sluggish pupils, nystagmus, and than UVR. Analysis of the p53 gene in skin tumours strabismus. (S. Morley, UK National XP Clinic from XP patients has revealed these classical ophthalmologist, personal communication). UVR-induced ‘signature’ mutations in the DNA,53 indicating that the high level of p53 mutations Neurodegeneration found in the tumours is directly caused by unrepaired UVR-induced DNA photoproducts.54 Neurological manifestations of XP typically There is a significantly higher level of the UVR follow skin symptoms in the natural history of signature mutations in XP skin tumours compared the disease and do not arise before 2 years of to those found in non-XP, sporadic skin cancers.55 age.61 Parents notice mild cognitive impairment first, usually when the child is starting The XP patients in complementation groups that school; EEG studies confirm a spectrum of have severe sunburn reactions (XP-A, XP-B, XP-D, encephalopathy from mild-to-severe. Cerebellar XP-F, XP-G) have lower rates of skin cancer than signs manifest usually between age 4 and 16 those patients with sunburn reactions that are years, usually dysarthria and difficulties with normal for skin type (XP-C, XP-E, XP-V). This may balance. Ataxia and areflexia follow suit; EMG be due to severe sunburn reactions prompting studies show evidence of axonal sensory and earlier diagnosis of XP and earlier age of motor neuropathy although this is not usually 47 initiating more rigorous photoprotection. seen before the second decade of life. Some patients will also exhibit choreoathetoid In addition to skin cancer, the XP-C patient group involuntary movements in the upper limbs.3 Most seems to be at greater risk of developing other XP patients with neurological abnormalities will forms of malignancy, particularly neurological develop sensorineural deafness, and the degree cancers.56,57 This patient group has also been of hearing loss has been shown to predict future reported to occasionally develop pyogenic 48 granulomas and multinodular thyroid carcinomas.58 neurological involvement. Involvement of the corticospinal tract can result in tetraplegia, Ocular becoming wheelchair-bound and eventually bed-bound, a few years before death.61 There are three ways in which the eyes can be affected in XP; (1) UVR exposure resulting in Approximately 30% of XP patients will develop DNA damage of the eyelids and periocular skin; neurodegeneration; patients with mutations (2) UVR exposure resulting in DNA damage causing lack of XP-A, XP-D, XP-F, and XP-G

58 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 59 proteins have an increased susceptibility.23,47,48,50 Other psychological issues include potential This is most likely due to the requirement for for developing anxiety and depression from these proteins to deal with oxidative damage ongoing surgical procedures, many focused on such as cyPudNs, which accumulate in DNA in the face, with potential for facial disfigurement neuronal cells.44 or developing fatal skin cancers. Many patients are also anxious about the possibility of XP-C and XP-E patients classically do not neurodegeneration, with loss of memory and develop clinically detectable neurodegeneration; early onset dementias as well as physical however there have been reports of late- disabilities (J. Baulcomb, UK National XP clinic onset asymptomatic neurological disease in XP-C educational psychologist, personal communication). patients.62 In one report, post-mortem analysis of an XP-C patient provided evidence of neurodegeration with neuronal loss in dorsal root DIAGNOSIS ganglia.63 A conceivable explanation for this was Initially the diagnosis is predominantly clinical: proposed by Nouspikel, who suggested a role for a young child may be brought to the paediatric XP-C in domain-associated repair (DAR) (repair department with bright, confluent erythema of both the transcribed and non-transcribed strand of active genes). As the non-transcribed over all sun-exposed sites, or with lentigines at strand of DNA serves as a template for repair, an unusually early age in sun-exposed areas. In failure to repair the non-transcribed strand the former case, the clinician assessing the will eventually impact repair of the transcribed child may suspect a skin allergy, drug reaction or strand. XP-C is required for DAR so therefore lack even in some cases sunburn caused by parental of XP-C may result in lack of DAR and therefore neglect. After all differentials are excluded, the gradual onset of neurodegeneration.44 clinician would then request cellular tests to assess for defective DNA repair. This requires a Psychological 4 mm punch biopsy of the skin taken from an unexposed site (e.g. buttock area). This Although not a presenting feature of XP, the specimen is used to culture fibroblasts followed social isolation and clothing restrictions of the by UVR exposure and subsequent measurement disease can inevitably predispose these patients of unscheduled DNA synthesis (UDS), (Figure 1). to depression. In patients with XP, adherence to UDS refers to the newly synthesised DNA, which a very restrictive photoprotection regime is formed when the damaged DNA is excised. (including wearing a UVR-protective visor), which UDS can be measured as incorporation of is highly visible to other people, causes poor nucleotides into DNA of the irradiated cells by health-related quality of life in terms of mental autoradiography,64 liquid scintillation counting,65 health (low mood, anxiety) and social isolation. 66 There is a potential for bullying for school-age or fluorescence assay. Typically a reduced level children, and concerns for job-security in adults of UDS confirms diagnosis of XP. Mutational at work should they disclose XP. A 20-year analysis to assign complementation group and observational study of XP patients in Finland define pathogenic mutation(s) in the affected reported the symptom of increased fear and gene(s) is then performed. Using next- tendency to weep amongst 8/11 adults.61 generation sequencing techniques, a platform of DNA repair genes can be used for rapid Compliance is an issue; for children at school there identification of both complementation group is an impact on behaviour with tantrums and and mutation analysis. outbursts, due to the frustration of having to photoprotect, restrictions on outdoor activities, Diagnosis of XP-V is different as XP-V cells have and being treated differently. This may create normal levels of UDS. However, UVR-exposed a barrier to successful learning at school, XP-V cells show an exquisite sensitivity to potentially limiting academic progress and caffeine, which impairs their survival.67,68 Therefore, impacting on social relationships (observations if XP-V is suspected, cultured fibroblasts are from the UK National XP clinic). In teenage years incubated in caffeine for a few days and their the necessity for photoprotection links more viability compared to that of normal cells. If UDS widely to patients’ understanding and acceptance is normal and post-UV sensitivity to caffeine is of XP. detected, a diagnosis of XP-V is confirmed.69

58 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 59 Of the eight genes implicated in XP, mutations in mental health teams. Towards the end of their life, the XP-C gene count for a substantial proportion XP patients with severe neurodegeneration will in most but not all populations.47,48,50,70 require maximal assistance with all activities of Immunohistochemistry staining with an antibody daily living, and careful planning with all members for XP-C protein has recently been shown to be a of a multidisciplinary team is required. new rapid and cost-effective method for both diagnosis and potentially as a screening tool As soon as the diagnosis of XP is confirmed, in suspected XP-C patients. UVR-protected, the most crucial aspect of their care is the tumour-free skin of XP-C patients will show instigation of meticulous photoprotection. This negative expression of the XP-C protein compared includes the application of sunscreen to all to normal controls.71 In principle, use of antibodies exposed areas of skin (20 minutes before UVR to other XP proteins can be used to also look exposure), thickly woven clothing, gloves, and a at deficiencies in other XP complementation UVR-protective visor. Some patients choose not groups. However, although this procedure is a to wear a visor and instead wear broad-brimmed rapid method of identifying reductions or absence hats, hoodies and UVR-protective wrap-round of protein, as is the case for most XP-C and XP-V glasses. All windows in the home, car, and school patients, immunohistochemistry cannot be used as should be covered with UVR-protective film, a diagnostic tool in many other complementation which is commercially available. Hospital theatre groups because pathogenic missense mutations lights, halogen lights, metal halide lamps, and result in production of a defective XP protein some fluorescent lights need to be avoided or present in normal quantity. covered. In addition, educational support from specialist XP nurses in the community has been All the diagnostic procedures require specialised shown to dramatically improve both adherence to laboratories and technical skills and are therefore and social acceptance of photoprotection often not available in poorer countries, in which (our unpublished audit data from the UK National there may be high incidences of XP. XP clinic).

GENETIC COUNSELLING AND XP patients complying with good photoprotection are inevitably vitamin D deficient. Long-term PRENATAL DIAGNOSIS supplementation of vitamin D in tablet, spray or in severe cases intramuscular form, should be As XP is an autosomal recessive disorder with 100% administered and regular serum vitamin D levels penetrance, it is only possible to offer prenatal checked at outpatient follow-up to ensure optimum diagnostic testing for XP in a family where parents levels are maintained. already have an affected child.72 Counselling and psychological support is of paramount Avoidance of cigarette smoke and environmental importance in families at reproductive risk. These carcinogens are recommended. Carcinogens families can have prenatal diagnosis by mutational in cigarette smoke also cause DNA damage analysis or DNA repair testing on chorionic requiring NER, so XP patients are at higher risk 73-76 villus sampling at 10-12 weeks gestation. In of developing further lung cancer-promoting principle pre-implantation genetic diagnosis can mutations.77 It may be suggested that excess also be carried out, if the pathogenic mutations levels of caffeine are not recommended in XP-V are known and the carrier status of both patients because of cellular sensitivity to UVR in parents confirmed, although to our knowledge this the presence of caffeine, although there is no has not yet been done for XP. definitive evidence to support this guidance.

MANAGEMENT The UK National XP Service was launched in April 2010 at St. John’s Institute of Dermatology, Guy’s Patients with XP require a multidisciplinary and St. Thomas’ NHS Trust, London, serving the team approach to their care with involvement current UK XP population (approximately 70 from dermatologists, specialist nurses, clinical patients) and can also offer services to XP psychologists, neurologists, and ophthalmologists. patients worldwide. Patients are invited to attend Particularly in childhood, if there is recognised a one-stop clinic with assessments from the entire early cognitive impairment, XP children require multidisciplinary team. This allows regular skin support from special schools and community checks to assess and remove precancerous and

60 DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL DERMATOLOGY • December 2013 EMJ EUROPEAN MEDICAL JOURNAL 61 cancerous lesions, photographic monitoring death. We anticipate improved survival in those of indeterminate lesions, as well as reviews without neurodegeneration who maintain lifelong from clinical psychology, clinical genetics, vigorous photoprotection. neuropsychology, neurology, and ophthalmology. Diagnostic services for XP patients, of which we CONCLUSIONS are aware, are also available in the USA,78 France,79 Germany,80 Italy,81 the Netherlands,82 and Japan.83 The diagnosis of XP has a profound consequence on patients, particularly as their lifestyle measures FUTURE PROSPECTS require rigorous photoprotection. That said, there is a dramatic reduction in the number of XP is a monogenic disorder and therefore skin cancers and improvement in life expectancy although the future invites the possibility of observed with photoprotective-compliant XP protein or gene therapy, as yet there is no cure. patients. Unfortunately the manifestation of Exciting work using retroviral-mediated XP-C neurodegeneration signifies a poor prognosis. gene transfer into deficient stem cell keratinocytes A multidisciplinary team approach is crucial for all (from XP-C patients) has given hope that XP patients. corrective therapy is not far away. However, this therapy has yet to be carried out in humans and With the advances in medicine and genetics over still carries with it the risk of retroviral-mediated the last half-century, the spectrum of XP as a mutagenesis and oncogenic activation.84 disease has become increasingly acknowledged. From the first two patients described by Moritz Median age of death reported by the NIH is 32 Kaposi,1 to several thousand patients diagnosed years with two main causes identified as skin worldwide, the field of XP requires further research, cancer in 34% and neurodegeneration in 31% of particularly to identify mechanistic links behind XP patients.50 Better understanding, identification sunburn reactions and neurodegeneration. Most of milder phenotypes, with earlier diagnosis importantly, it is to be hoped that the recent rapid and improved photoprotection in recent years advances in genetics may ultimately result in a cure has resulted in an increase in median age of for this severe disorder.

Acknowledgements

The authors are indebted to Susie Morley, Consultant Ophthalmologist and Oculoplastic Surgeon, Guy’s & St Thomas’ NHS Foundation Trust; Jennifer Baulcomb, Educational Psychologist, Evelina Children’s Hospital; Sally Turner, XP Clinical Nurse Specialist, Guy’s & St Thomas’ NHS Foundation Trust for helpful comments and advice.

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