Commentaries 6 Almudimeegh A, Rioux C, Ferrand H et al. Drug reaction with eosinophilia and systemic symptoms, or virus reactivation with eosinophilia and systemic symptoms as a manifestation of immune reconstitution inflammatory syndrome in a patient with HIV? Br J Dermatol 2014; 171:895–8. 7 Ishida T, Kano Y, Mizukawa Y, Shiohara T. The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome. Allergy 2014; 69:798–805.
Importance of genotype–phenotype correlation in xeroderma pigmentosum DOI: 10.1111/bjd.13577
ORIGINAL ARTICLE, p 1096 Xeroderma pigmentosum (XP) is a rare disorder of DNA repair, characterized by progressive pigmentary changes at exposed sites and a significantly increased risk of ultraviolet radiation (UVR)-induced skin cancers. About 50% of affected individuals are photosensitive, with an exaggerated and prolonged sunburn response on minimal exposure, and about 30% develop progressive neurological degeneration.1 XP is divided into eight complementation groups, XP-A through to XP-G and XP variant, corresponding to the affected DNA repair gene. The majority of patients are mutated in one of seven genes – XPA, XPB, XPC, XPD, XPE and XPG – whose products are involved in nucleotide excision repair of UVR and other types of DNA damage. However, about 20% of patients, with XP variants, have normal nucleotide excision repair but are defective in DNA polymerase eta, a specialized DNA polymerase required to replicate DNA past unrepaired UVRinduced lesions.2 Historically, XP was considered a single disease with similar features across the different complementation groups. However, it is now becoming evident that patients with XP are a clinically heterogeneous group with wide variability in clinical features both between and within XP complementation groups, in part explained by the precise nature of the pathogenic mutation(s). One example of this is presented in the recent report in the BJD showing that acute and severe sunburn on minimal sun exposure, once considered a cardinal presenting feature of XP, occurs in only around 50% of patients and those with XP-C, XP-E and XP variant have sunburn reactions normal for their skin type.3 Moreover, the presence of abnormal sunburn reactions in patients predicts the complementation groups at risk of neurological degeneration.4 The detailed clinical and molecular study of patients with XP is important in order to explain these differences in the clinical phenotype. However, XP is rare, with only about 23
© 2015 British Association of Dermatologists
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cases per million live births in Western Europe,5 and therefore clinical and academic international collaborations are essential in the study of this disease. In this issue of BJD, Sun et al.6 present the first paper on genotype–phenotype correlation findings in Chinese Han patients with XP. The clinical features and pathogenic mutations are presented in 12 affected individuals from 12 unrelated families, specifically three with XP-A, four with XP-C, two with XP-G and three with XP variant. The proportion of cases across the different complementation groups is similar to that in the U.K., where there are 84 patients under follow-up: 16 with XP-A, two XP-B, 28 XP-C, 14 XP-D, four XP-E, three XP-F, five XP-G and 12 XP variant. The authors have attempted to find genotype–phenotype correlations in their cohort of Chinese Han patients; however, they were unable to come to any firm conclusions because of the small numbers of affected individuals described. This paper highlights a number of important issues. 1 In the study of rare disorders, international collaborations are essential. Teams of specialist physicians and scientists from around the world need to collate data in order to study larger cohorts of patients and to come to more meaningful, useful and robust conclusions. 2 To understand the heterogeneity of clinical features across and within complementation groups in XP, detailed or ‘deep phenotyping’ is needed. The analysis of phenotype plays a key role in clinical practice and medical research, and yet phenotypic descriptions in medical publications are often not detailed or precise enough. 3 The introduction of an international database in order to capture deep phenotypic data on patients with XP worldwide, and to correlate the data with genomic variations is essential in the study of this and other rare disorders. Over 10 years ago, the Human Genome Project, the world’s largest international biological collaboration, transformed medical science with the sequencing of the complete human genome. This has brought new approaches to diagnosis and drug design. Now the 100 000 genome project in England will decode 100 000 human genomes including in patients with rare diseases. These detailed genetic data must be supported by deep phenotypic data in order for them to be useful in the understanding of disease pathogenesis and development of potential treatments. Now that the Human Genome Project is complete, it is time for the Human Phenome Project. Conflicts of interest None declared. UK National XP Service, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Trust, London, U.K. E-mail: [email protected]
H. FASSIHI
British Journal of Dermatology (2015) 172, pp844–860
860 Commentaries
References 1 Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987; 123:241–50. 2 Cleaver JE, Lam ET, Revet I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet 2009; 10:756–68. 3 Sethi M, Lehmann AR, Fawcett H et al. Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions. Br J Dermatol 2013; 169:1279–87.
British Journal of Dermatology (2015) 172, pp844–860
4 Totonchy MB, Tamura D, Pantell MS et al. Auditory analysis of xeroderma pigmentosum 1971–2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration. Brain 2013; 136:194–208. 5 Kleijer WJ, Laugel V, Berneburg M et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst) 2008; 7:744–50. 6 Sun Z, Zhang J, Guo Y et al. Genotype–phenotype correlation of xeroderma pigmentosum in Chinese Han population. Br J Dermatol 2015; 172:1096–1102.
© 2015 British Association of Dermatologists
Importance of genotype–phenotype correlation in xeroderma pigmentosum DOI: 10.1111/bjd.13577
ORIGINAL ARTICLE, p 1096 Xeroderma pigmentosum (XP) is a rare disorder of DNA repair, characterized by progressive pigmentary changes at exposed sites and a significantly increased risk of ultraviolet radiation (UVR)-induced skin cancers. About 50% of affected individuals are photosensitive, with an exaggerated and prolonged sunburn response on minimal exposure, and about 30% develop progressive neurological degeneration.1 XP is divided into eight complementation groups, XP-A through to XP-G and XP variant, corresponding to the affected DNA repair gene. The majority of patients are mutated in one of seven genes – XPA, XPB, XPC, XPD, XPE and XPG – whose products are involved in nucleotide excision repair of UVR and other types of DNA damage. However, about 20% of patients, with XP variants, have normal nucleotide excision repair but are defective in DNA polymerase eta, a specialized DNA polymerase required to replicate DNA past unrepaired UVRinduced lesions.2 Historically, XP was considered a single disease with similar features across the different complementation groups. However, it is now becoming evident that patients with XP are a clinically heterogeneous group with wide variability in clinical features both between and within XP complementation groups, in part explained by the precise nature of the pathogenic mutation(s). One example of this is presented in the recent report in the BJD showing that acute and severe sunburn on minimal sun exposure, once considered a cardinal presenting feature of XP, occurs in only around 50% of patients and those with XP-C, XP-E and XP variant have sunburn reactions normal for their skin type.3 Moreover, the presence of abnormal sunburn reactions in patients predicts the complementation groups at risk of neurological degeneration.4 The detailed clinical and molecular study of patients with XP is important in order to explain these differences in the clinical phenotype. However, XP is rare, with only about 23
© 2015 British Association of Dermatologists
859
cases per million live births in Western Europe,5 and therefore clinical and academic international collaborations are essential in the study of this disease. In this issue of BJD, Sun et al.6 present the first paper on genotype–phenotype correlation findings in Chinese Han patients with XP. The clinical features and pathogenic mutations are presented in 12 affected individuals from 12 unrelated families, specifically three with XP-A, four with XP-C, two with XP-G and three with XP variant. The proportion of cases across the different complementation groups is similar to that in the U.K., where there are 84 patients under follow-up: 16 with XP-A, two XP-B, 28 XP-C, 14 XP-D, four XP-E, three XP-F, five XP-G and 12 XP variant. The authors have attempted to find genotype–phenotype correlations in their cohort of Chinese Han patients; however, they were unable to come to any firm conclusions because of the small numbers of affected individuals described. This paper highlights a number of important issues. 1 In the study of rare disorders, international collaborations are essential. Teams of specialist physicians and scientists from around the world need to collate data in order to study larger cohorts of patients and to come to more meaningful, useful and robust conclusions. 2 To understand the heterogeneity of clinical features across and within complementation groups in XP, detailed or ‘deep phenotyping’ is needed. The analysis of phenotype plays a key role in clinical practice and medical research, and yet phenotypic descriptions in medical publications are often not detailed or precise enough. 3 The introduction of an international database in order to capture deep phenotypic data on patients with XP worldwide, and to correlate the data with genomic variations is essential in the study of this and other rare disorders. Over 10 years ago, the Human Genome Project, the world’s largest international biological collaboration, transformed medical science with the sequencing of the complete human genome. This has brought new approaches to diagnosis and drug design. Now the 100 000 genome project in England will decode 100 000 human genomes including in patients with rare diseases. These detailed genetic data must be supported by deep phenotypic data in order for them to be useful in the understanding of disease pathogenesis and development of potential treatments. Now that the Human Genome Project is complete, it is time for the Human Phenome Project. Conflicts of interest None declared. UK National XP Service, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Trust, London, U.K. E-mail: [email protected]
H. FASSIHI
British Journal of Dermatology (2015) 172, pp844–860
860 Commentaries
References 1 Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987; 123:241–50. 2 Cleaver JE, Lam ET, Revet I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet 2009; 10:756–68. 3 Sethi M, Lehmann AR, Fawcett H et al. Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions. Br J Dermatol 2013; 169:1279–87.
British Journal of Dermatology (2015) 172, pp844–860
4 Totonchy MB, Tamura D, Pantell MS et al. Auditory analysis of xeroderma pigmentosum 1971–2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration. Brain 2013; 136:194–208. 5 Kleijer WJ, Laugel V, Berneburg M et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst) 2008; 7:744–50. 6 Sun Z, Zhang J, Guo Y et al. Genotype–phenotype correlation of xeroderma pigmentosum in Chinese Han population. Br J Dermatol 2015; 172:1096–1102.
© 2015 British Association of Dermatologists
