Minireview Submitted: 23.4.2014 Accepted: 13.6.2014 Conflict of interest None.
Janin Lehmann, Steffen Schubert, Steffen Emmert Department of Dermatology, Venereology, and Allergology, University Hospital at the Georg August University Göttingen, Göttingen, Germany
DOI: 10.1111/ddg.12419
Xeroderma pigmentosum: Diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches
Summary Xeroderma pigmentosum (XP) is an autosomal recessive disease, caused by a gene defect in the nucleotide-excision-repair (NER) pathway or in translesional DNA synthesis. At the age of eight, patients already develop their first skin cancers due to this DNA repair defect. In contrast, in the Caucasian population the first tumor formation in UV exposed skin regions occurs at a mean age of 60. The clinical picture among patients suffering from XP is highly diverse and includes signs of accelerated skin aging, and UV-induced skin cancers, as well as ophthalmologic and neurological symptoms. Patients should therefore receive interdisciplinary care. This includes dermatologists, ophthalmologists, ENT specialists, neurologists, and human geneticists. Patients with XP are clinically diagnosed, but this may be supported by molecular-genetic and functional analyses. These analyses allow pinpointing the exact disease-causing gene defect (complementation group assignment, detection of the type and location of the mutation within the gene). The resulting information is already relevant to predict the course of disease and symptoms and probably will be utilized for individualized therapeutic approaches in the future. Recently, enhanced repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons by certain antibiotics could be demonstrated.
DNA repair Nucleotide excision repair (NER) plays an essential role in eliminating UV-induced DNA damage and thus preventing skin cancer. Damage recognition in NER is divided into two signaling pathways: global genomic repair (GGR) and transcription coupled repair (TCR). The basic mechanism of DNA repair always follows the same pattern and can be classified in the following consecutive steps: damage demarcation, unwinding of the DNA double helix around the lesion, damage verification, incision of the damage-containing DNA strand, removal of the damaged oligonucleotide, and filling of the single-strand DNA gap by a newly synthesized oligonucleotide (Figure 1) [1].
Patients with xeroderma pigmentosum (XP) exhibit defective NER caused by a genetic defect in one of the components involved in the repair cascade. So far, seven different clinical XP complementation groups have been identified, XP-A to XP-G (mutations in genes XPA–XPG). By contrast, XP Variant patients, representing approximately 10 % of all XP patients, display mutations in the translesional polymerase η gene (Pol H) [2]. Mutations in XP genes are responsible for at least six different clinical entities: 1) xeroderma pigmentosum, 2) XP with neurologic symptoms, 3) trichothiodystrophy (TTD), 4) XP with trichothiodystrophy symptoms (XP/TTD complex), 5) XP with Cockayne syndrome (CS) symptoms (XP/CS
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
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Minireview Diagnostics and therapy of xeroderma pigmentosum
damage sensors XPC or XPE (DDB complex) is not associated with progressive neurologic symptoms.
Epidemiology and genetics
Figure 1 The nucleotide excision repair (NER) pathway. In the global genome, XPC and XPE recognize DNA damage and initiate the NER cascade (GGR). In actively transcribed genes, polymerase II (stalled by DNA damage) along with CSA and CSB are thought to initiate the NER cascade (TCR). As components of the 10-unit multiprotein complex TFIIH (transcription factor II H), XPB and XPD demarcate DNA damage through their helicase activity. TTD-A is also a component of the TFIIH complex. XPF and XPG (endonucleases) remove the damage containing DNA strand. Using the complementary DNA strand as template, polymerases and ligases fill the resultant gap. RPA: replication protein A. From: Emmert S. Xeroderma Pigmentosum, Cockayne syndrome, Trichothiodystrophy – Defects in DNA Repair and Carcinogenesis. In: Allgayer H, Rehder H, Fulda S (eds). Hereditary Tumors. 2009: 421–39, Copyright Wiley-VCH Verlag GmbH & Co KGaA. Reproduced with permission.
complex), and 6) cerebro-oculo-facio-skeletal (COFS) syndrome [3]. XP with neurologic symptoms or XP/CS complex may develop in patients with mutations in the XPA, XPB, XPD, XPF or XPG genes [3–5]. On the other hand, failure of the
868
Xeroderma pigmentosum is a rare autosomal recessive genetic disorder with a worldwide prevalence of 1 in 1,000,000, spanning all ethnic groups [2]. Certain geographical regions such as Japan (1 in 22,000) or Northern Africa, however, show a far greater prevalence, primarily due to isolation, cultural influences, or less mobility. For example, almost 1% of the Japanese population carry one of several founder mutations in the XPA gene [6]. Worldwide, XP-C represents the most common complementation group (Table 1). Here again, some isolated regions reveal a greater prevalence (Mayotte region [Indian Ocean], Northern Africa), and microsatellite analysis has shown a founder mutation among the Northern African population [7]. With respect to the XP-D complementation group, there have also been reports on a founder mutation among Iraqi families of Jewish descent, resulting in a very mild form of XP [8]. However, much more common is a classic hotspot for mutations in the XPD gene (amino acid substitution at position 683) [9]. The kind of amino acid substitution at this particular position has a substantial causal effect on disease severity in XP. XP-F and XP-G patients, described in Japan as well as Europe and the USA, are very rare. By comparison, individuals showing the XP Variant (XPV), primarily found in Europe and the USA, constitute a relatively large percentage of all XP patients [3]. Interestingly, XPV patients exhibit the same clinical XP picture, although, unlike the other seven XP complementation groups, this variant is not characterized by defective DNA repair, but by failure of error-free translesional synthesis past DNA photoproducts [1].
Clinical picture Unlike frequently reported, only approximately 60% of XP patients show increased sunlight sensitivity in terms of severe sunburn following minor UV exposure, which usually represents the most conspicuous XP symptom during the first weeks of life. The remaining 40 % of patients, on the other hand, do not display any considerable sensitivity to sunlight (especially not complementation groups XP-C, XP-E, and XPV). Irrespectively, however, all patients exhibit hyperpigmentation in sun-exposed areas at an early age(Figure 2). Poikilodermic skin lesions as sign of premature skin aging may be observed by the age of 3 to 5. At an average age of 8, XP patients start developing various skin cancers such as basal cell and squamous cell
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
Minireview Diagnostics and therapy of xeroderma pigmentosum
Table 1 Xeroderma pigmentosum: complementation groups, affected genes, and prevalence [10]. Complementation group
Affected gene
Percentage of XP patients worldwide
XP A (MIM: 278700)
XPA (MIM: 611153)
9%
XP B (MIM: 610651)
XPB (MIM: 133510)
1%
XP C (MIM: 278720)
XPC (MIM: 278720)
43 %
XP D (MIM: 278730)
XPD (MIM: 126340)
28 %
XP E (MIM: 278740)
DDB1 (MIM: 600045), DDB2 (MIM: 600811)
3%
XP F (MIM: 278760)
XPF (MIM: 133520)
Janin Lehmann, Steffen Schubert, Steffen Emmert Department of Dermatology, Venereology, and Allergology, University Hospital at the Georg August University Göttingen, Göttingen, Germany
DOI: 10.1111/ddg.12419
Xeroderma pigmentosum: Diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches
Summary Xeroderma pigmentosum (XP) is an autosomal recessive disease, caused by a gene defect in the nucleotide-excision-repair (NER) pathway or in translesional DNA synthesis. At the age of eight, patients already develop their first skin cancers due to this DNA repair defect. In contrast, in the Caucasian population the first tumor formation in UV exposed skin regions occurs at a mean age of 60. The clinical picture among patients suffering from XP is highly diverse and includes signs of accelerated skin aging, and UV-induced skin cancers, as well as ophthalmologic and neurological symptoms. Patients should therefore receive interdisciplinary care. This includes dermatologists, ophthalmologists, ENT specialists, neurologists, and human geneticists. Patients with XP are clinically diagnosed, but this may be supported by molecular-genetic and functional analyses. These analyses allow pinpointing the exact disease-causing gene defect (complementation group assignment, detection of the type and location of the mutation within the gene). The resulting information is already relevant to predict the course of disease and symptoms and probably will be utilized for individualized therapeutic approaches in the future. Recently, enhanced repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons by certain antibiotics could be demonstrated.
DNA repair Nucleotide excision repair (NER) plays an essential role in eliminating UV-induced DNA damage and thus preventing skin cancer. Damage recognition in NER is divided into two signaling pathways: global genomic repair (GGR) and transcription coupled repair (TCR). The basic mechanism of DNA repair always follows the same pattern and can be classified in the following consecutive steps: damage demarcation, unwinding of the DNA double helix around the lesion, damage verification, incision of the damage-containing DNA strand, removal of the damaged oligonucleotide, and filling of the single-strand DNA gap by a newly synthesized oligonucleotide (Figure 1) [1].
Patients with xeroderma pigmentosum (XP) exhibit defective NER caused by a genetic defect in one of the components involved in the repair cascade. So far, seven different clinical XP complementation groups have been identified, XP-A to XP-G (mutations in genes XPA–XPG). By contrast, XP Variant patients, representing approximately 10 % of all XP patients, display mutations in the translesional polymerase η gene (Pol H) [2]. Mutations in XP genes are responsible for at least six different clinical entities: 1) xeroderma pigmentosum, 2) XP with neurologic symptoms, 3) trichothiodystrophy (TTD), 4) XP with trichothiodystrophy symptoms (XP/TTD complex), 5) XP with Cockayne syndrome (CS) symptoms (XP/CS
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
867
Minireview Diagnostics and therapy of xeroderma pigmentosum
damage sensors XPC or XPE (DDB complex) is not associated with progressive neurologic symptoms.
Epidemiology and genetics
Figure 1 The nucleotide excision repair (NER) pathway. In the global genome, XPC and XPE recognize DNA damage and initiate the NER cascade (GGR). In actively transcribed genes, polymerase II (stalled by DNA damage) along with CSA and CSB are thought to initiate the NER cascade (TCR). As components of the 10-unit multiprotein complex TFIIH (transcription factor II H), XPB and XPD demarcate DNA damage through their helicase activity. TTD-A is also a component of the TFIIH complex. XPF and XPG (endonucleases) remove the damage containing DNA strand. Using the complementary DNA strand as template, polymerases and ligases fill the resultant gap. RPA: replication protein A. From: Emmert S. Xeroderma Pigmentosum, Cockayne syndrome, Trichothiodystrophy – Defects in DNA Repair and Carcinogenesis. In: Allgayer H, Rehder H, Fulda S (eds). Hereditary Tumors. 2009: 421–39, Copyright Wiley-VCH Verlag GmbH & Co KGaA. Reproduced with permission.
complex), and 6) cerebro-oculo-facio-skeletal (COFS) syndrome [3]. XP with neurologic symptoms or XP/CS complex may develop in patients with mutations in the XPA, XPB, XPD, XPF or XPG genes [3–5]. On the other hand, failure of the
868
Xeroderma pigmentosum is a rare autosomal recessive genetic disorder with a worldwide prevalence of 1 in 1,000,000, spanning all ethnic groups [2]. Certain geographical regions such as Japan (1 in 22,000) or Northern Africa, however, show a far greater prevalence, primarily due to isolation, cultural influences, or less mobility. For example, almost 1% of the Japanese population carry one of several founder mutations in the XPA gene [6]. Worldwide, XP-C represents the most common complementation group (Table 1). Here again, some isolated regions reveal a greater prevalence (Mayotte region [Indian Ocean], Northern Africa), and microsatellite analysis has shown a founder mutation among the Northern African population [7]. With respect to the XP-D complementation group, there have also been reports on a founder mutation among Iraqi families of Jewish descent, resulting in a very mild form of XP [8]. However, much more common is a classic hotspot for mutations in the XPD gene (amino acid substitution at position 683) [9]. The kind of amino acid substitution at this particular position has a substantial causal effect on disease severity in XP. XP-F and XP-G patients, described in Japan as well as Europe and the USA, are very rare. By comparison, individuals showing the XP Variant (XPV), primarily found in Europe and the USA, constitute a relatively large percentage of all XP patients [3]. Interestingly, XPV patients exhibit the same clinical XP picture, although, unlike the other seven XP complementation groups, this variant is not characterized by defective DNA repair, but by failure of error-free translesional synthesis past DNA photoproducts [1].
Clinical picture Unlike frequently reported, only approximately 60% of XP patients show increased sunlight sensitivity in terms of severe sunburn following minor UV exposure, which usually represents the most conspicuous XP symptom during the first weeks of life. The remaining 40 % of patients, on the other hand, do not display any considerable sensitivity to sunlight (especially not complementation groups XP-C, XP-E, and XPV). Irrespectively, however, all patients exhibit hyperpigmentation in sun-exposed areas at an early age(Figure 2). Poikilodermic skin lesions as sign of premature skin aging may be observed by the age of 3 to 5. At an average age of 8, XP patients start developing various skin cancers such as basal cell and squamous cell
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
Minireview Diagnostics and therapy of xeroderma pigmentosum
Table 1 Xeroderma pigmentosum: complementation groups, affected genes, and prevalence [10]. Complementation group
Affected gene
Percentage of XP patients worldwide
XP A (MIM: 278700)
XPA (MIM: 611153)
9%
XP B (MIM: 610651)
XPB (MIM: 133510)
1%
XP C (MIM: 278720)
XPC (MIM: 278720)
43 %
XP D (MIM: 278730)
XPD (MIM: 126340)
28 %
XP E (MIM: 278740)
DDB1 (MIM: 600045), DDB2 (MIM: 600811)
3%
XP F (MIM: 278760)
XPF (MIM: 133520)
