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Patients with classic hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.

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.

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK., (© The Author(s). CED © 2012 British Association of Dermatologists.)

UVB readily induces cyclobutane pyrimidine dimers, mainly thymine dimers (TTs), and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) in DNA. These lesions result in "UVB signature mutations" found in skin cancers. We have investigated the induction of TTs and 6-4PPs in human skin in vivo by broadband UVA1, and have compared this with comparable erythemal doses of monochromatic UVB (300 nm). In vitro and ex vivo studies have shown the production of TTs, without 6-4PPs, by UVA1. We show that UVA1 induces TTs, without 6-4PPs, in the epidermis of healthy volunteers in vivo, whereas UVB induced both photoproducts. UVB induced more TTs than UVA1 for the same level of erythema. The level of UVA1-induced TTs increased with epidermal depth in contrast to a decrease that was seen with UVB. UVA1- and UVB-induced TTs were repaired in epidermal cells at a similar rate. The mechanism by which UVA1 induces TTs is unknown, but a lack of intra-individual correlation between our subjects' UVB and UVA1 minimal erythema doses implies that UVA1 and UVB erythema occur by different mechanisms. Our data suggest that UVA1 may be more carcinogenic than has previously been thought.

Background: Polymorphic light eruption and erythropoietic protoporphyria (EPP) have been demonstrated to have a moderate and large impact on the quality of life (QoL) of patients, respectively. However, there is little information available about the impact of other photodermatoses on QoL., Objectives: To assess and compare the impact of all forms of photodermatoses on patients' QoL using the standard 1-week Dermatology Life Quality Index (DLQI) questionnaire and a modified questionnaire to assess the impact over the previous year., Methods: All patients with photodermatoses seen between 2001 and 2005 at five U.K. photobiology centres were contacted by post on the same day during a forecasted sunny week across the U.K. and asked to complete DLQI questionnaires., Results: A total of 1877 patients were contacted. Seven hundred and ninety-seven (42%) patients replied, with a range from 30% to 48% for the five individual centres. Nearly two-thirds of patients with actinic prurigo (AP) and more than one-third of patients with photoaggravated dermatoses (PAD), chronic actinic dermatitis, EPP and solar urticaria had a DLQI of > 10, confirming a very large effect of the disorders on QoL. Of the cutaneous porphyrias, both variegate porphyria (median DLQI 3) and porphyria cutanea tarda (median DLQI 1.5) had a much lower impact on QoL than EPP., Conclusion: This is the first large-scale study to attempt to measure the impact of a range of photodermatoses on QoL. Photodermatoses have a major impact on QoL. This impact is highest in AP and PAD.

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. In this review, I will try to explain why porphyrias occur, why they present as they do in the clinic, and provide a checklist for treating patients with porphyria.

We report a patient aged 73 years, who developed erythropoietic protoporphyria with typical photosensitivity, at the same time as she was diagnosed as having myelodysplastic syndrome. The myelodysplastic clone in her bone marrow completely lacked one of the two copies of chromosome 18. As chromosome 18 is the locus of the ferrochelatase gene, we postulate that this chromosomal deletion led to reduced synthesis of the enzyme in the bone marrow clone, so causing the porphyria. The nature of the remaining ferrochelatase allele was examined by polymorphism analysis and we discuss the insights that this patient's genotype may reveal about the pathogenesis of porphyria in myelodysplasia.

It has recently been shown that most cases of clinically overt erythropoietic protoporphyria (EPP) result from coinheritance of a mutated ferrochelatase gene and a commonly occurring low-expression normal variant allele. The identification of two polymorphic variant sequences associated with this low-expression allele now enables improved predictive counselling for couples where one partner has EPP. We describe a patient and his spouse in whom we have used such genetic analysis to provide an accurate estimate of the chance that their future offspring may suffer from EPP.

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.

Porphyria cutanea tarda (PCT), the commonest of all porphyrias, is usually characterized by blisters and fragility of skin in light-exposed areas. It can be clinically indistinguishable from other disorders including variegate porphyria and the diagnosis can only be made by rigorous biochemical analysis. PCT does not cause acute attacks of porphyria. It is usually an acquired condition caused by inhibition of the uroporphyrinogen decarboxylase enzyme in the liver. Hereditary haemochromatosis, hepatitis C virus infection, alcohol, oestrogens and a family history of PCT are the major risk factors for the condition and should be searched for specifically in all patients. Liver disease, including hepatocellular carcinoma, is common in patients with PCT, and should be investigated for at presentation by means of a liver biopsy where possible. Patients with severe hepatic pathology or longstanding untreated PCT need to be monitored for the development of hepatocellular carcinoma in the long term. Low dose twice weekly chloroquine is the mainstay of treatment, but venesection should be used in patients with severe iron overload or hepatitis C-related liver disease. Subsequently, long-term follow-up is needed in all patients to monitor for relapse.

Phototherapy is a popular and effective treatment for many patients with skin diseases. However, repeated journeys to hospital for phototherapy can be inconvenient and expensive. If it were available, many patients might prefer home-based phototherapy as long as it was safe and effective. Indeed, many psoriasis patients already self-treat with ultraviolet A sunbeds at home. This report represents a consensus view from a British Photodermatology Group workshop held in December 1996, the purpose of which was to examine the potential role of home-based phototherapy in dermatological practice. We conclude that home-based therapy represents a suboptimal treatment with greater attendant risks than phototherapy in a hospital environment. The level of medical supervision of the home treatment is crucial to its safety and effectiveness. Until further studies are forthcoming, home phototherapy should be largely restricted to those with overwhelming difficulties in attending hospital.

The porphyrias are a group of disorders caused by deficient activity of the enzymes responsible for the biosynthesis of haem. The skin is one of the major organs involved in most of these diseases because the porphyrins which accumulate are phototoxic. The common cutaneous porphyrias are variegate porphyria, porphyria cutanea tarda, congenital erythropoietic porphyria and erythropoietic protoporphyria, each caused by a different enzyme deficiency causing a distinctive pattern of porphyrin accumulation and typical clinical features. The genes encoding these enzymes have all been cloned recently, enabling the genetic defects underlying these disorders to be elucidated. The factors triggering sporadic porphyria cutanea tarda in predisposed individuals are now becoming clear: hepatic iron overload is required to induce the hepatic enzyme defect and many patients are haemochromatosis gene carriers. Hepatitis B, C, and HIV virus infection also contribute to disease expression. In erythropoietic protoporphyria, up to 5% of patients develop liver failure. It is now clear that some of these patients suffer from a different recessively transmitted form of the disease: this finding may make it possible to identify these patients at an earlier stage. Gene therapy holds particular promise as a future therapy and has successfully been used to correct enzyme defects in vitro. Bone marrow transplantation has also been tried in patients with congenital erythropoietic porphyria. The joints are not involved by porphyria. However, some non-steroidal inflammatory drugs prescribed by rheumatologists have phototoxic properties similar to uroporphyrin. These drugs cause a syndrome clinically and histologically indistinguishable from porphyria cutanea tarda which is known as pseudoporphyria.

We report a 20-year-old female patient with telangiectasia macularis eruptiva perstans characterised by telangiectatic macular lesions and episodic flushing, two lesions of which were successfully treated by laser. Two clinically different forms of cutaneous mastocytosis have both been previously described as telangiectasia macularis eruptiva perstans, and we now propose that this term be restricted to cutaneous mastocytosis characterised by the typical telangiectatic macules.

Human protoporphyria results from mutations in the ferrochelatase gene. Heritable deficiency of ferrochelatase causes overproduction of protoporphyrin IX, principally in the erythron. Photosensitivity is a universal feature of protoporphyria but hepatic clearance of the hydrophobic protoporphyrin molecule with excretion in bile may lead to precipitation within biliary pathways. Thus cholestatic injury and protoporphyrin gallstones occur. Minor hepatic abnormalities are frequent, but at least 30 patients have been reported with a progressive liver disease that requires transplantation. Fulminant hepatic disease appears to be recessively inherited in some pedigrees. Hazards of liver transplantation include tissue photolysis, hemolysis, and an unexplained neurological syndrome, but most of the 15 patients reported after transplantation have survived for several months to > 6 years. Aspects of protoporphyria, its pathogenesis and contemporary therapeutic strategies are considered, with emphasis on hepatic sequelae.

Erythropoietic protoporphyria is caused by inherited deficiency of the haem synthetic enzyme ferrochelatase, and is characterized by lifelong photosensitivity. About 5% of patients also develop rapidly progressive liver failure. Inheritance is considered to be autosomal dominant, with transmission of a single ferrochelatase defect from one parent. We describe a family in which two siblings with protoporphyria suffered from severe photosensitivity and developed hepatic failure requiring liver transplantation. Their asymptomatic parents were heterozygous for distinct ferrochelatase gene mutations (exon 10 donor site a(+3)-->g and 1088T-->G). Both mutations disrupt splicing of the transcript and cause partial deficiency of ferrochelatase. The affected offspring were compound heterozygotes for these mutations. These patients suffered from an autosomal recessive form of protoporphyria characterized by severe photosensitivity and cholestatic liver disease in adolescence. We postulate that hepatic failure in erythropoietic protoporphyria may in some cases represent an autosomal recessive type of ferrochelatase deficiency distinct from the purely dermatological disorder. Studies of disease inheritance in families affected by protoporphyria may help identify those predisposed to develop severe liver complications, a distinction not currently possible.

Erythropoietic protoporphyria is an inherited disorder caused by deficient activity of the enzyme ferrochelatase. We have examined the ferrochelatase gene in an 11-year-old female with protoporphyria and have found that she is heterozygous for a mutation at a conserved residue in the exon 3 donor splice site consensus sequence (T(+2)-->G). This is inherited from her father, who also has deficient ferrochelatase activity. As a consequence of the mutation, ferrochelatase transcripts are aberrantly spliced and give rise to mRNA molecules in which sequences corresponding to exon 3 are absent. This leads to the expression of a ferrochelatase protein lacking a central region of 40 amino acids.

The activation of trypsinogen to trypsin in the small intestine can occur by the action of enterokinase or, alternatively, as an autocatalytic process catalysed by trypsin itself. We have found that bile salts and human bile cause a significant enhancement of the autocatalytic activation of trypsinogen. This effect is dependent on the calcium ion concentration and is most marked around pH 5.4 and 7.8. An optimum concentration exists for each bile salt at which the greatest enhancement occurs. At this concentration, certain bile salts have been shown to produce activation effects of up to 55-fold. It is suggested that this activation of the autocatalytic process by bile plays an important role in protein digestion in the small intestine, since it has been shown previously that duodenal trypsin levels are abnormally low in patients with an impairment of bile secretion.