Robert Sarkany

Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

Photopatch testing: recommendations for a European photopatch test baseline series.

In order to establish a consensus recommendation for performing photopatch testing, a photopatch test taskforce group was established under the joint umbrella of the European Society for Contact Dermatitis and the European Society for Photodermatology in 2000. After proposing the most adequate methodology in 2004 and completing a European multicentre photopatch test study in 2011, this taskforce is recommending a list of photoallergens that should form part of a baseline series for photopatch testing in Europe. It contains mainly ultraviolet filters and drugs, mostly non‐steroidal anti‐inflammatory drugs. The choice of chemicals was based on the results of a recent multicentre study, previous published cases of photoallergy, and use of the substances in the European market.

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

Significance Xeroderma pigmentosum (XP) is a genetic disorder caused by defective repair of DNA damage. Affected patients are mutated in one of eight genes and develop skin pigmentation changes, skin cancers, ocular surface abnormalities, and, in some cases, acute sunburn and neurodegeneration. The XP proteins are involved in different steps in the repair of DNA damage. Examination of 89 patients, the largest reported cohort under long-term follow-up, by the same multidisciplinary team of clinicians and scientists has revealed unexpected clinical heterogeneity dependent on the affected gene and the exact mutation. Our findings provide new insights into the mechanisms of carcinogenesis, ocular surface disease, and neurodegeneration, as well as providing improved clinical management and more definitive prognostic predictions. Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.

Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of DNA repair. It is divided into eight complementation groups: XP‐A to XP‐G (classical XP) and XP variant (XP‐V). Severe and prolonged sunburn reactions on minimal sun exposure have been considered a cardinal feature of classical XP. However, it has recently become clear that not all patients have abnormal sunburn reactions.

Making sense of the porphyrias

Patients with cutaneous porphyrias can be worrying for dermatologists. The diseases are rare enough to be unfamiliar, are associated with internal diseases, can have genetic implications, and are associated with incomprehensible biochemical pathways.

Upregulation of MMP12 and Its Activity by UVA1 in Human Skin: Potential Implications for Photoaging

UVA1 constitutes around 75% of the terrestrial UV radiation, and most of the output of artificial tanning sources. However, the molecular effects of UVA1 in human skin in vivo are surprisingly poorly understood. We have examined time-dependent whole-genome expression, along with mRNA and protein changes in the skin after one minimal erythema dose of spectrally pure UVA1 (50 J cm(-2)) and 300 nm UVB (30 mJ cm(-2)). After 24 hours, the genes induced to the greatest extent were those involved in extracellular matrix remodeling with both UVA1 (P=5.5e-7) and UVB (P=2.9e-22). UVA1 and UVB caused different effects on matrix metalloproteinase (MMP) expression: UVB induced MMP1, MMP3, and MMP10 mRNA at 24 hours to a much greater extent than UVA1. MMP12 induction by UVA1 at 6 hours is marked and much greater than that by UVB. We have found that MMP12 mRNA induction by UVA1 resulted in expression of MMP12 protein, which is functional as an elastase. This induction of elastase activity did not occur with UVB. We hypothesize that the UVA1 induction of MMP12 mediates some of its photoaging effects, particularly by contributing to elastin degeneration in late solar elastosis. MMP12 is a good marker of UVA1 exposure.

Determinants of vitamin D status in long‐term renal transplant patients

In this study, we explored the determinants of vitamin D status in a large cohort of stable, Long‐term renal transplant (RTx) patients. Serum 25(OH)D concentrations, and bone biochemistry parameters, were retrospectively analyzed from 266 RTx patients (>10 yr post‐engraftment) presenting to clinic over the course of a year. Forty‐five percent of the cohort were vitamin D deficient (<37.5 nM), 38% insufficient (37.5 75–nM), and 17% sufficient (>75 nM). Serum 25(OH)D concentrations were higher in patients presenting in summer (p < 0.001) and in more active patients (p < 0.05). RTx patients with non‐melanoma skin cancer (NMSC) (n = 45) had higher 25(OH)D concentrations than patients without NMSC (n = 221; p < 0.05) despite these patients being older, having worse eGFR, transplanted for longer, and less active physically (p < 0.05). Lower 25(OH)D concentrations were associated with higher PTH concentrations (p < 0.05) which, in the setting of widespread hypovitaminosis, suggests that secondary hyperparathyroidism was common in this cohort. In conclusion, season and activity status are important determinants of vitamin D status. We report, for the first time, that NMSC is associated with higher 25(OH)D, probably through increased UV radiation exposure. Long‐term RTx patients may benefit from oral vitamin D supplementation, but this requires a randomized controlled trial to confirm.

Erythropoietic protoporphyria (EPP) at 40. Where are we now

Since Professor Magnus first defined erythropoietic protoporphyria (EPP) in 1961, there has been considerable progress in the understanding this disease. The past decade has been a period of spectacular progress in understanding the genetics and pathogenesis of the disease by molecular investigation. However, progress in therapy for EPP has been slower, and has been dogged by difficulty in assessing treatment efficacy in patients. We are now entering an era in which advances in molecular genetics are directly affecting patient management. This review summarises laboratory and clinical progress in EPP in the past 40 years, and assesses the potential impact of molecular biology on clinical practice.

Clinical ultraviolet dosimetry with a CCD monochromator array spectroradiometer

Single monochromator charge-coupled device (CCD) array spectroradiometers have the advantage of ease of use and speed compared with double grating instruments. Their inherently inferior stray-light rejection, however, can critically affect their accuracy in phototherapy and research-related dosimetry applications. This paper shows that without adequate correction the HR4000 (Ocean Optics Inc., Dunedin, USA) array device can overestimate the CIE erythema-weighted irradiance of common phototherapy sources and solar simulator beams by over 100%. A software stray-light correction (Ylianttila et al 2005 Photochem. Photobiol. 81 333-41), using the measured slit function of the HR4000, has been applied to spectra acquired from sources used in phototherapy and photobiology (PUVA, UV21, TL01 and solar simulator). The resulting corrected erythema-weighted irradiance measurements from the HR4000 are within 10% of those from a DM150 double grating spectroradiometer (Bentham Instruments Ltd, Reading, UK). A simple model is considered for combining estimates of measurement uncertainties. The importance of exposure bracketing to improve the dynamic range of the HR4000 is illustrated, along with the difficulty in making direct comparison of spectral values between two instruments due to wavelength scale uncertainties. Comparison with a double grating instrument in a solar simulator beam is examined here as a basis for validating CCD array device measurements. The study demonstrates that the HR4000 array spectroradiometer can provide an adequate level of accuracy for common phototherapy and photobiology applications only where a suitable stray-light correction is carefully applied and where the instruments effective dynamic range is improved.

A Distinct Genotype of XP Complementation Group A: Surprisingly Mild Phenotype Highly Prevalent in Northern India/Pakistan/Afghanistan.

Xeroderma pigmentosum (XP) is a rare inherited disorder of DNA repair. Affected individuals cannot repair ultraviolet radiation (UVR)einduced DNA damage, resulting in an increased skin cancer risk (Bradford et al., 2011), severe sunburn in approximately 50% of patients (Sethi et al., 2013), and progressive neurodegeneration in approximately 30% (Kraemer et al., 1987; Totonchy et al., 2013). XP can result from defects in any of eight genes (XPAeXPG and POLH). XPAeXPG are involved in nucleotide excision repair (NER) of DNA damage (Cleaver et al., 2009). Xeroderma pigmentosum complementation group A (XP-A) patients usually have a severe phenotype, with exaggerated sunburn and early onset of progressive neurodegeneration, which results in death, usually in the second or third decade (Anttinen et al., 2008). XPA protein is required for damage verification in the NER pathway. More than 20 different mutations have been identified in the XPA gene (States et al., 1998; Takahashi et al., 2010). Many of the reported cases come from Japan because of a founder mutation (c.390-1G>C) carried by 1% of the Japanese population (Hirai et al., 2006; Satokata et al., 1990). This mutation results in abnormal splicing of mRNA and subsequent production of truncated, nonfunctioning XPA protein and the typically severe clinical phenotype. Although a diagnosis of XP-A has usually been associated with a poor prognosis, a number of XP-A patients undergoing long-term follow-up at the UK National XP Clinic have a surprisingly mild phenotype. To examine this finding further, a detailed genotype-phenotype study in this cohort was conducted. Neurological analysis included audiometry, nerve conduction studies, brain magnetic resonance imaging and neuropsychometric evaluations. Informed written consent was obtained from all patients. The study was performed in accordance with protocols approved by the Research Ethics Committee of Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London (reference 12/LO/0325). Nineteen of 90 patients being studied at the UK National XP clinic were assigned to complementation group A (Table 1). Twelve of these patients, from eight consanguineous families, displayed a mild XP-A phenotype with no ocular surface disease, delayed onset or lack of skin cancer, and normal neurological and neuropsychometric evaluations (Figure 1aeh). Mean age at assessment was 32 years (range 6e79 years) and mean age at clinical diagnosis was 26 years (range 4e46 years), significantly higher than in the more severely affected XP-A group of patients, who showed progressive neurodegeneration presenting as developmental delay and cognitive impairment, sensorineural hearing loss, microcephaly, neuropathy, and cerebellar signs (Table 1). Remarkably, one of the patients, XP1CB, is aged 79 years without any XP-related neurological problems. He spent the first 30 years of his life in India working mostly outdoors and was only diagnosed clinically at age 46 years. These 12 patients all were homozygous for the mutation c.555þ8A>G, which previously was reported by Sidwell et al. (2006) in a 61-year-old Punjabi woman with no neurological problems. All 12 patients included in this study, as well as the case described by Sidwell et al., originate from a 950-km stretch of land