Xeroderma pigmentosum

ARTICLE

Xeroderma pigmentosum (XP) was first described in 1874 by Hebra and Kaposi. In 1882 the Hungarian dermatologist Moritz Kohn Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristics [1]. This disease is a rare autosomal recessive genodermatosis [2]. To inherit XP, a child must receive two defective chromosomes, one from each parent. The disease is based on a defect in the DNA repair system [3]. This gene defect manifests already in early childhood by exaggerated light sensitivity and in the occurrence of malignant skin tumours. The incidence in Europe and North America is 1:250 000, and in Japan 1:40 000. Xeroderma pigmentosum occurs equally in both sexes [2].

Clinical pattern of xeroderma pigmentosum

Clinically, xeroderma pigmentosum presents a uniform pattern. Even in very small children, the skin is hypersensitive to light. The disease manifests in serious sunburns (dermatitis solaris) after minimal exposure to sunlight [4]. The dermatitis solaris may persist for weeks as erythema. In the light-exposed skin (face, throat, neck, arms and hands, light-brown to black lentigines and spotty hypopigmentations occur, along with teleangiectasies, calloused thickening and actinic elastoses. The skin becomes colour-flecked — poikilodermatic (Fig. 1). Early clinical signs are erythema, blistering after minimal exposition to sunlight and lentigines. Atrophy, scabbing and scarring follow. The surface of the skin is atrophic and dry, which by the way, accounts for the name "Xeroderma". These manifestations are due to a cellular hypersensitivity to ultraviolet radiation resulting from a defect in DNA-repair.

Numerous precancerous and actinic keratoses and malignant skin tumours develop in childhood and adolescence because of the chronic light damage to the skin areas exposed to sunlight [5]. The skin tumours are mainly squamous-cell carcinomas, basal cell carcinomas and malignant melanomas [6-8]. Keratoakanthomas and sarcomas (fibrosarcomas and angiosarcomas) have also been described [9]. The tumour incidence is 1000 times higher than in the normal population [6]. 2/3 of xeroderma pigmentosum patients die before reaching adulthood because of metastases [6]. Heterozygote-carriers, gene carriers without the external phenotype, show no elevated risk for development of skin tumours.

Neurological manifestation

About 14-40 % of xeroderma pigmentosum patients show neurological disorders. The neurologic problems might overshadow the cutaneous manifestations in some XP patients. These may manifest as motor impairments like reduced reflexes, extrapyramidal symptoms with ataxia and spasticity. Some patients also present with peripheral neuropathy [10, 11]. Mental retardation with impaired speech development has also been described. It is assumed that the DNA damages lead to increased neurodegeneration [12]. The maximal form of neurological involvement has been termed the DeSanctis-Caccione Syndrome [13]. These children are characterized by retarded growth, spasticity and serious intelligence debility. Segmental demyelinisation, microcephaly, inner ear deafness and epilepsy may also be additional neurological debilities of xeroderma pigmentosum patients. The incidence for central nervous system tumours (CNS) is also ten times higher than in the normal population. Astrocytomas, medulloblastomas, glioblastomas and malignant schwannoma are among the CNS tumours [14].

Ocular manifestation

About 40 % of xeroderma pigmentosum patients present with ophthalmological symptoms. Usually the light-exposed lids and the anterior sections of the eye are affected. Conjunctival inflammation, blepharitis, keratoconjunctivitis, ectropion, symblepharon, vascular pterygia, fibrovascular pannus formation and corneal ulcerations are some of the clinical findings which have been described in xeroderma pigmentosum [15]. Benign lid papillomas, corneal dysplasias and ocular neoplasias like basal cell carcinomas and malignant melanomas occur more frequently in these patients than in the normal population [16]. Many of the children require keratoplastic surgery because of progression of eye involvement [17]. The incidence for tumours of the oral mucosa and internal organs is also elevated. A more frequent occurrence of leukaemia is also characteristic of xeroderma pigmentosum patients [18]. The tendency to caries in primary dentition is also conspicuous.

Histologic findings

The histologic findings of the first stage of the disease include hyperkeratosis and increased melanin pigment (this corresponds to the clinical freckling) in the basal cell layer (not necessarily accompanied by an increase in the number of melanocytes). Some rete ridges may be elongated while the others may be atrophic. These findings may be accomanied by a chronic inflammatory infiltrate in the upper dermis. In the second stage, atrophy ensues and the hyperkeratosis and hyperpigmentation are more marked. Teleangiectasia may be prominent. These findings correspond to poikiloderma. In addition, the epidermis may exhibit architectural disorder and atypia, and the dermis may be elastotic. Therefore, the histologic picture might be indistinguishable from that of actinic keratosis. The histologic appearance of the various neoplasmas, which complicate XP, are seen in the third stage of XP.

Classification

Genetically, xeroderma pigmentosum is a very heterogeneous disease, which is reflected in the following classification. Differentiation is made between 7 complementation groups (XP-A to XP-G) and the xeroderma pigmentosum variant (XP-V) [19]. The complementation group is the term denoting various mutations which do not form a wild type after crossing. In principle, the complementation group applies when in vitro cells of two different patients with the same defect are fused and the DNA damage is maintained. If the two patients have different damage, the cells correct each other reciprocally and the DNA damage is repaired. Fibroblasts of xeroderma-suspected patients are fused with fibroblasts of xeroderma pigmentosum patients of a known complementation group for specific cytogenic ascription [20]. The capacity to carry out excision repair is determined after UV-irradiation by uptake of radiolabeled thymidine into the DNA, an assay defined as "unscheduled DNA-Synthesis (UDS)" and indicates the residual activity of the excision repair, which is reduced in xeroderma pigmentosum [3]. XP-A shows the least repair activity and the most frequent neurological symptoms, and XP-C shows the highest repair activity. Polymorphisms of the XP-D gene defects are expressed in varying repair capacity [21]. Xeroderma pigmentosum fibroblasts grow normally without radiation, after radiation they show hypermutability with chromosome fractures and increased sister-chromatide exchange (SCE = sign of hypermutability) [22]. Radiation of XP-fibroblasts is performed with 1 mJ/cm² UVC and UVB and shows elevation of the SCE of 15-17. Spontaneous unradiated SCE is in the normal range in these cells.

The incidence of the complementation groups varies geographically. In general, the most frequent complementation group is A, followed by XP-V and XP-C. All three account for about 90 % of cases. In Germany, complementation groups C, D and E are most prevalent, whereas complementation group A is most prevalent in Japan [23]. Patients with complementation groups A and D have the most frequent neurological disorders. XP-Groups A and C are more frequently associated with squamous cell carcinomas. Basal cell carcinomas occur more frequently in patients with XP-Group E and the XP-variants, while malignant melanomas occur more frequently in patients with XP-Group D. Antenatal diagnosis is possible by amniocentesis or chorionic villi sampling.

Defects of the nucleotide excision repair system

The gene defects of xeroderma pigmentosum are distributed among various chromosomes (Table I). The individual gene segments code repair proteins, which are involved in various sub-steps of the nucleotide excision repair system (NER). Generally, differentiation is made between Global Genome Repair (GGR) and Transcription-Coupled Repair (TCR) [24]. The last decade has seen the cloning of the key elements or NER and the process has been reconstituted in vitro. While global genome repair serves to prevent mutagenesis and carcinogenesis, the transcription-coupled repair attempts to prevent apoptosis following genotoxic damage [25]. The repair protein of the XP-variant is a component of the postreplication repair system.

The detrimental effect of UV-radiation on cells is due to selective absorption of the UV-rays by chromophors. DNA is the most important chromophor for short wavelengths. Its bases determine its absorption behaviour at 200-260 nm (maximum at 260 nm). UVB (280-320 nm) is also able to directly stimulate and thus directly damage DNA-molecules. Below 200 nm, absorption is primarily by the desoxyribosephosphate of the DNA. Pyrimidine dimers between two neighbouring thymine bases — also termed cyclobutane-pyrimidine-dimers (CPD) — are the most frequent UV-related lesions of DNA [26]. However, damage also includes dimers between cytosine- and thymine bases, also called pyrimidine-(6,4) pyrimidone photoproducts (6-4 photoproducts) [27]. Damage of this type is eradicated by the intact nucleotide excision repair system (NER). Whereas the NER repairs cyclobutane-pyrimidine dimers more rapidly via TCR, 6-4 photoproducts are more quickly eradicated by GGR [25]. The individual steps in the complex repair procedure of the nucleotide excision repair systems are recognition, incision, removal of the DNA damage, filling with intact nucleotides and closure of the newly-incorporated gene segment [24]. Helikases, endo- and exonucleases, DNA-polymerases and ligases are involved. At least 30 proteins are part of the multienzyme complex: 6 nucleus-NER-factors are coordinated in performance of the repair work. The following proteins are essential to NER-activity: Ribonuclease Protection Assay (RPA), XPC-hHR23B, Transcription factor IIH (TFIIH), XPG, Excision-Repair Cross Complementing rodent repair deficiency-XPF (ERCC1-XPF) and XPA [28]. The basal transcription factor TFIIH consists of 9 subunits whereby the repair proteins XP-B and -D are two components of transcription factor TFIIH. First the resultant dimer is recognized. This involves the recognition proteins of XP-A, XP-C and XP-E (Table II). A helicase locally despirals the DNA-double-strand. This task is performed by the repair proteinases XP-B- and XP-D. Endonucleases like repair proteins XP-G and XP-F incise the affected DNA-single strand near the thymine dimer and an exonuclease completely removes the segment of the mutated strand. The DNA-polymerase inserts complementary nucleotides step-wise into the new single strand, and finally its free end is connected by a ligase to the other incision surface. The xeroderma pigmentosum variant gene codes a polymerase. Since NER and transcription are coupled, this repair proceeds most rapidly via a transcribed strand of genes ("transcription-coupled repair"). UV-induced DNA-damage is not removed from the genome in xeroderma pigmentosum because of the gene defects in this repair protein. These damages are fixed as mutations and thus replicated.

Carcinogenesis in Xeroderma pigmentosum

The transformation of normal cells to malignant cancer cells, designated carcinogenesis, may be influenced by both genetic and environmental factors. The complicated process usually takes years. Although the rate of carcinogenesis cannot be predicted, it is known that the mean age of carcinogenesis in xeroderma pigmentosum is 8 years and for the general population 60 years. Squamous cell carcinomas, basal cell carcinomas and lentigo-malignant melanomas are the most frequent tumours in xeroderma pigmentosum. There is no doubt that basaliomas and squamous cell carcinomas are caused by the ultraviolet rays in sunlight [29]. This is based on the observation that these tumours occur in areas of the skin which are exposed to the sun. In lentigo-malignant melanoma, unlike in other malignant melanomas, the total UV-dose plays a role, as in the case of epithelial tumours. The incidence for all types of malignant melanoma is increased up to 1000-fold and the distribution is identical to that observed in the regular population, therefore it had been increasingly suggested that UVB may play a crucial role in causing malignant melanoma in xeroderma-pigmentosum [5].

It could be demonstrated in XP-A transgenic mice that an increased proportion of sunburned cells is associated with an increased inflammatory infiltration of lymphocytes in radiated skin [30]. XP-A transgenic mice have a complete defect of both the TCR-NER and the GGR-NER. These transgenic mice, like the human phenotype, have a 1000-times higher risk of developing UV-induced skin cancer cells. Transgenic mice also show a higher mutation rate in the tumour suppressor genes p53 compared to the ras-oncogens, which supports the hypothesis that UV-induced mutation of the so-called "checkpoint-molecules" play an essential role in the carcinogenesis of xeroderma-pigmentosum patients [31]. The UV-related hypermutability can be proven by an elevated sister-chromatide exchange rate in xeroderma pigmentosum fibroblasts after UV-radiation [22].

Ultraviolet radiation plays a further role in the skin. On the one hand, UV-radiation causes DNA-damage and mutations. These head the chain of causes of UV-induced skin carcinogenesis in xeroderma pigmentosum. On the other, ultraviolet radiation has an immunosuppressive effect, so that the immune monitoring in the skin with defence against premalignant and malignant cells is disrupted. Although autologous melanoma cells or squamous cell carcinoma cells express tumour-associated antigens which are recognized by T-cells, tumour progression still occurs in many cases. Immunosuppressed kidney-transplant patients tend to an increased rate of skin carcinoma in UV-exposed skin. UV-radiation causes immunosuppression and thus impairment of the immune monitoring, so that malignant transformed keratinocytes or melanocytes are no longer recognized immunologically and eliminated. The immune system is capable of generating a cell-mediated immunoresponse to tumour cells, which leads to elimination of the tumour tissue. Immunosuppression by UV can be local (unspecific) and systemic (Immunosuppression by T-suppressor cells). UVB-radiation can lead to induction of T-suppressor cells, so that UVB is made primarily responsible for UV-induced immunosuppression [32]. In transgenic and knockout-mice with XP-A-genes, it could be proven that the dendritic cells, which play an essential role in tumour recognition and NK-cells, which are important in fighting the tumour, are reduced compared to the so-called wild type mice without gene defect. It is assumed that a defective immune system supports the promotion of premalignant cells to malignant cells in xeroderma pigmentosum. Ahrens et al. for instance could show that XP-D- and TTD-patients have a different photoimmunological phenotype that correlates with their risk to develop skin cancer [33]. The extent to which this knowledge from animal experiments can be applied to the in vivo situation in human skin has not yet been clarified.

Differential diagnoses

Xeroderma pigmentosum must be distinguished from other so-called DNA-Repair Deficiency Syndromes in the differential diagnosis. These include the Cockayne Syndrome (CS) and trichothiodystrophy (TTD). Like xeroderma pigmentosum, both diseases are characterized by autosomal recessive inheritance and exaggerated sensitivity to light. Among the clinical symptoms of CS-patients are characteristic neurological symptoms (ataxia, mental retardation, inner-ear deafness), distinct facies (large, deepset eyes, prominent nose), progressive weight loss (cachexia), myopathy, microcephalus, dwarfism, calcifications of the basal ganglia and retinal pigment degeneration [34]. Other ocular symptoms are optic nerve atrophy, cataracts. Cockayne Syndrome is divided into 2 complementation groups and the corresponding genes are known (CSA and CSB). Recently the first cases of combined XP/TTD- and TTD/CS- cases have been reported [35, 36]. In Cockayne Syndrome there is a defect in transcription-coupled repair (TCR) but the global genome repair (GGR) is usually functional.

Whereas neurological disorders prevail in the Cockayne Syndrome, trichothiodystrophy is characterized mostly by short, brittle hair, ichthyoses and dwarfism. The main symptoms of trichothiodystrophy like the short, brittle hair, are due to sulphur deficient hairs (deficit of cystein-rich proteins in the hair keratines) [37]. Under the polarization microscope, the hairs show a characteristic "tiger-tail pattern". Additional symptoms of trichothiodystrophy are limited intelligence and reduced fertility. Certain defects in the XP-genes XPB and XPD result in TTD. Apparently, however, there is at least one other gene, TTD-A, which causes this disease, but it has not yet been identified. Trichothiodystrophy is divided into 3 complementation groups (TTD-A Group, XP-B-Group and XP-D-Group). Trichothiodystrophy (TTD)-patients with a mutated XPD-gene are deficient in the TCR and GGR of cyclobutane-pyrimidine-dimers, whereby the repair of pyrimidine-(6,4) pyrimidone photoproducts is functional.

Interestingly, these 3 genes are part of the transcription factor TFIIH. It is interesting that mutations in the XPD-genes, which are very close together, cause either only the clinical pattern of trichothiodystrophy, Cockayne Syndrome or xeroderma pigmentosum.

Although the gene defects of both diseases affect the repair proteins of xeroderma pigmentosum groups B and D, the Cockayne Syndrome and Trichothiodystrophy do not have a higher risk of skin cancer than the normal population [38, 39]. This observation has led to the assumption that the elevated carcinogenesis in xeroderma pigmentosum is not due solely to a deficient DNA repair system. The extent to which various mutations of the defect repair genes or other additional, as yet unidentified initiation or promotion factors may play a role in the carcinogenesis of xeroderma pigmentosum is not yet clear.

Treating xeroderma pigmentosum

Early diagnosis is in the basis of treatment of xeroderma pigmentosum. A strict light-protective lifestyle with shift in the day-night rhythm, and application of broad-spectrum UV protective preparations are essential in prevention. The use of sunscreens in conjunction with other sun avoidance methods such as protective clothing, hats and eyewear can minimize ultraviolet-induced damage in XP patients. Constant education of the patient is one of the most important objectives in the managment of XP. An attempt to attain a canceroprotective effect with systemic administration of retinoids, such as acitretin or isotretinoin has been made [40, 41]. Their long-term administration is, however, limited by side effects. Retinoids may prevent some of the neoplasmas in XP. Decrease cohesiveness of the abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. Retinoids modulate keratinocyte differentiation and have been shown to reduce the risk of skin cancer formation. Early recognition and radical excision of skin tumours are important measures in the treatment of xeroderma pigementosum patients. Regular, close dermatological, neurological and ophthalmological control examinations are necessary. These are essential components of a prevention program. Patients should be followed every 3 months. Follow-up should be geared to education of the patient and the parents in effective sun protection and early recognition of skin cancer. High-speed dermabrasion has been described for xeroderma pigmentosum patients [42, 43]. Abrasion is performed to the papillary dermis and the therapeutic success evaluated after 6 months. The procedure achieves a certain rejuvenation of the skin. Several years of tumour-free observation document this. Histologically, there are none of the typical signs of xeroderma pigmentosum in the treated areas. Phenotypically disease areas of keratinocytes are replaced by regeneration from deep, relatively light-protected adnexepithelias.

Comparable long-term success has been attained by complete excision of affected skin and subsequent covering with free transplantates from light-protected skin regions. However, protection from light must be maintained after every procedure. Chemical therapy with 5-fluorouracil (chemotherapy agent) may be useful for actinic keratosis and precancerous skin. UVA and UVB-related erythema and pigmentation are very dependent on oxygen and are accompanied by a decrease in antioxidative protective factors. Topically or systemically-applied antioxidants influence UV-related formation of erythema. Their effect remains, however, questionable. Furthermore, topical application of photolyase-containing liposomes to UVB-irradiated skin and subsequent exposure to photoreactivating light decreased the number of UVB radiation-induced dimers by 40-45 %. The authors suggested that topical application of photolyase is effective in dimer reversal and thereby leads to immunoprotection and therefore could be helpful for patients with xeroderma pigmentosum [44]. Currently, successful use of a topically-applied DNA-repair enzyme is reported. The medication is applied once daily locally to the skin and uses liposomes to transfer DNA repair enzyme to the skin. This is a recombinant liposomal encapsulated T4 endonuclease V, which repairs UV-induced cyclobutane-pyrimidine-dimers [45]. These repair enzymes correct the DNA damage to skin cells caused by sunlight. The therapy reportedly reduced the skin cancer rate of xeroderma pigmentosum patients by 30 % and the rate of precancerous lesions by as much as 68 %.

In future, a causal therapy based on gene therapy may be possible [46, 47]. The insinuation of an intact repair gene, which specifically codes the repair protein, could open new possibilities in the treatment of xeroderma pigmentosum. Skin cells could then synthesize the functional enzyme in xeroderma pigmentosum.

Article accepted on 23/9/2002

REFERENCES

1
Kaposi M. Xeroderma pigmentosum. Medizinische Jahrbücher Wien 1882; 619-33.

2
Mallory S. Xeroderma Pigmentosum In: Disorders with malignant potential: Genodermatoses. Joel L Spitz, ed. Williams & Wilkins, 1995; 152-5.

3
Epstein JH, Fukuyama K, Reed WB, Epstein WL. Defect in DNA synthesis in skin of patients with xeroderma pigmentosum demonstrated in vivo. Science 1970; 168: 1477-8.

4
Hölzle E. Xeroderma Pigmentosum. In: Dermatology and Venereology. Braun-Falco O, Plewig G, Wolff HH, ed. Springer Verlag, 1997. p. 515-7.

5
Kraemer KH, Lee MM, Scotto J. Early onset of skin and oral cavity neoplasms in xeroderma pigmentosum. Lancet 1982; 1: 56-7.

6
English JSC, Swerdlow AJ. The risk of malignant melanoma, internal malignancy and mortality in xeroderma pigmentosum patients. Br J Dermatol 1987; 117: 457-61.

7
Kobayashi M, Satoh Y, Irimajiri T, Mitoh Y, Kozuka T, Sato K, Ichihashi M, Nakanishi T. Skin tumors of xeroderma pigmentosum (I). J Dermatol 1982; 9: 319-22.

8
Tullis GD, Lynde CW, McLean DI, Stewart WD. Multiple melanomas occurring in a patient with xeroderma pigmentosum. J Am Acad Dermatol 1984; 11: 364-8.

9
De Silva BD, Nawroz I, Doherty VR. Angiosarcoma of the head and neck associated with xeroderma pigmentosum variant. Br J Dermatol 1999; 141: 166-7.

10
Robbins JH, Brumback RA, Moshell AN. Clinically asymptomatic xeroderma pigmentosum neurological disease in an adult: evidence for a neurodegeneration in later life caused by defective DNA repair. Eur Neurol 1993; 33: 188-90.

11
Robbins JH. Xeroderma pigmentosum. Defective DNA repair causes skin cancer and neurodegeneration. JAMA 1988; 60: 384-8.

12
Rolig RL, McKinnon PJ. Linking DNA damage and neurodegeneration. Trends Neurosci 2000; 23: 417-24.

13
De Sanctis C, Caccione A. L’idiozia xerodermica. Riv Sper Freniat 1932; 56: 269-92.

14
Nakamura T, Ono T, Yoshimura K, Arao T, Kondo S, Ichihashi M, Matsumoto A, Fujiwara Y. Malignant schwannoma associated with xeroderma pigmentosum in a patient belonging to complementation group D. J Am Acad Dermatol 1991; 25: 349-53.

15
Goyal JL, Rao VA, Srinivasan R, Agrawal K. Oculocutaneous manifestations in xeroderma pigmentosa. Br J Ophthalmol 1994; 78: 295-7.

16
Vivian AJ, Ellison DW, McGill JI. Ocular melanomas in xeroderma pigmentosum. Br J Ophthalmol 1993; 77: 597-8.

17
Jalali S, Boghani S, Vemuganti GK, Ratnakar KS, Rao GN. Penetrating keratoplasty in xeroderma pigmentosum. Case reports and review of the literature. Cornea 1994; 13: 527-33.

18
Schroeder TM. Relationship between chromosomal instability and leukemia. Hämatol Bluttransfus 1974; 14: 94-6.

19
Tateishi S, Mori S, Sugano T, Hori N, Ohtsuka E, Yamaizumi M. Separation of protein factors that correct the defects in the seven complementation groups of xeroderma pigmentosum cells. J Biochem 1995; 118: 819-24.

20
Copeland NE, Hanke CW, Michalak JA. The molecular basis of xeroderma pigmentosum. Dermatol Surg 1997; 23: 447-55.

21
Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei DD, Groshen S, Lenz HJ. A xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 2001; 61: 8654-8.

22
Wolff S, Bodycote J, Thomas GH, Cleaver JE. Sister chromatid exchange in xeroderma pigmentosum cells that are defective in DNA excision repair or post-replication repair. Genetics 1975; 81: 349-55.

23
Maeda T, Sato K, Minami H, Taguchi H, Yoshikawa K. PCR-RFLP analysis as an aid to genetic counseling of families of Japanese patients with group A xeroderma pigmentosum. J Invest Dermatol 1997; 109: 306-9.

24
Balajee AS, Bohr VA. Genomic heterogeneity of nucleotide excision repair. Gene 2000; 250: 15-30.

25
de Boer J, Hœijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis 2000; 21: 453-60.

26
Trosko JE, Krause D, Isoun M. Sunlight-induced pyrimidine dimers in human cells in vitro. Nature 1970; 22: 8358-9.

27
Chan GL, Doetsch PW, Haseltine WA. Cyclobutane pyrimidine dimers and (6-4) photoproducts block polymerization by DNA polymerase I. Biochemistry 1985; 24: 5723-8.

28
Hœijmakers JH, Egly JM, Vermeulen W. TFIIH: a key component in multiple DNA transactions. Curr Opin Genet Dev 1996; 6: 26-33.

29
de Gruijl FR, van Kranen HJ, Mullenders LH. UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer. J Photochem Photobiol B 2001; 63: 19-27.

30
van Steeg H, Mullenders LH, Vijg J. Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice. Mutat Res 2000; 450: 167-80.

31
Sato M, Nishigori C, Lu Y, Zghal M, Yagi T, Takebe H. Far less frequent mutations in ras genes than in the p53 gene in skin tumors of xeroderma pigmentosum patients. Mol Carcinog 1994; 11: 98-105.

32
Norris PG, Limb GA, Hamblin AS, Hawk JL. Impairment of natural-killer-cell activity in xeroderma pigmentosum. N Engl J Med 1988; 319: 1668-9.

33
Ahrens C, Grewe M, Berneburg M, Grether-Beck S, Quilliet X, Mezzina M, Sarasin A, Lehmann AR, Arlett CF, Krutmann J. Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals. Proc Natl Acad Sci U S A 1997; 94: 6837-41.

34
Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology 2000; 55: 1442-9.

35
Broughton BC, Berneburg M, Fawcett H, et al. Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene. Hum Mol Genet 2001; 10: 2539-47.

36
Berneburg M, Lowe JE, Nardo T, Araujo S, Fousteri MI, Green MH, Krutmann J, Wood RD, Stefanini M, Lehmann AR. UV damage causes uncontrolled DNA breakage in cells from patients with combined features of XP-D and Cockayne syndrome. EMBO J 2000; 19: 1157-66.

37
Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol 2001; 44: 891-920, quiz 921-4.

38
Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev 2001; 15: 15-23.

39
Scott RJ, Itin P, Kleijer WJ, Kolb K, Arlett C, Muller H. Xeroderma pigmentosum-Cockayne syndrome complex in two patients: absence of skin tumors despite severe deficiency of DNA excision repair. J Am Acad Dermatol 1993; 29: 883-9.

40
Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988; 318: 1633-7.

41
Braun-Falco O., Galosi A, Dorn M. Tumorprophylaxe bei Xeroderma Pigmentosum mit aromatischem Retinoid (Ro-9359). Hautarzt 1982; 33: 445-8.

42
Gleason MC. Xeroderma pigmentosum - five-year arrest after total resurfacing of the face. Plast Reconstr Surg 1970; 46: 577-81.

43
König A, Friederich HC, Hoffmann R, Happle R. Dermabrasion for the treatment of xeroderma pigmentosum. Arch Dermatol 1998; 134: 241-2.

44
Stege H, Roza L, Vink AA, Grewe M, Ruzicka T, Grether-Beck S, Krutmann J. Enzyme plus light therapy to repair DNA damage in ultraviolet-B-irradiated human skin. Proc Natl Acad Sci U S A 2000; 97: 1790-5.

45
Tanaka K, Sekiguchi M, Okada Y. Restoration of ultraviolet-induced unscheduled DNA synthesis of xeroderma pigmentosum cells by the concomitant treatment with bacteriophage T4 endonuclease V and HVJ (Sendai virus). Proc Natl Acad Sci U S A 1975; 72: 4071-5.

46
Spirito F, Meneguzzi G, Danos O, Mezzina M. Cutaneous gene transfer and therapy: the present and the future. J Gene Med 2001; 3: 21-31.

47
Khavari PA. Gene therapy for genetic skin disease. J Invest Dermatol 1998; 110: 462-7.