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BACKGROUND: Photodiagnostic investigations are essential for the accurate diagnosis of abnormal cutaneous photosensitivity and provide important information for the management of patients with photodermatoses (cutaneous photosensitivity disorders). Although photodiagnosis has been undertaken since the early 1970s, specialist services in the United Kingdom (UK) and Republic of Ireland are limited and there is no formal guidance on diagnostic approach. Indeed, there is a limited literature in this area of methodology and diagnostic practice. OBJECTIVES: The primary objective was to undertake a British Photodermatology Group Workshop to review the role and activities of specialist centres in the UK and Republic of Ireland in order to ascertain whether there were consensus practices. Secondary objectives were to identify key priorities for service, training and research. METHODS: An initial detailed survey review of current activities was undertaken prior to the Workshop and data from this survey were used to inform discussion at the Workshop, which was attended by key photodermatology experts from the UK and Republic of Ireland. RESULTS/CONCLUSIONS: We have undertaken a detailed review of current Photodiagnostic Services in the UK and Republic of Ireland and report on our findings from the 12 centres and we have identified key areas of consensus practice. This is an important step in the process of standardising and optimising procedures and protocols and defining minimum clinical standards for photodiagnostic investigations, which are of such diagnostic importance in Dermatology.
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Dermatopatias , Humanos , Irlanda , Inquéritos e Questionários , Reino UnidoAssuntos
Carcinoma Basocelular , Neoplasias Faciais , Neoplasias Cutâneas , Xeroderma Pigmentoso , Carcinoma Basocelular/cirurgia , Criança , Neoplasias Faciais/cirurgia , Humanos , Cirurgia de Mohs , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgia , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/cirurgiaRESUMO
Although erythropoietic protoporphyria (EPP) is relatively uncommon, affecting approximately 1 in 140 000 individuals in the U.K., it is an important disease not to miss owing to the risk of acute severe liver disease in 2% of cases. EPP occurs with clinical and histological changes in the skin associated with free-radical-associated dermal vascular damage. This also mediates the painful photosensitivity. Severe and disfiguring hyaline deposition is extremely rare. We demonstrate that severe EPP can cause disfiguring hyaline infiltration of the skin on the hands and face, which sheds light on the mechanism of photosensitivity in EPP; it must also be differentiated from conditions such as lipoid proteinosis.
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Dermatoses Faciais/etiologia , Hialina/metabolismo , Transtornos de Fotossensibilidade/etiologia , Protoporfiria Eritropoética/complicações , Dermatoses Faciais/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/metabolismo , Protoporfiria Eritropoética/metabolismoAssuntos
Transtornos de Fotossensibilidade/etiologia , Luz Solar/efeitos adversos , Urticária/etiologia , Idade de Início , Pré-Escolar , Feminino , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Lactente , Masculino , Transtornos de Fotossensibilidade/tratamento farmacológico , Resultado do Tratamento , Urticária/tratamento farmacológicoAssuntos
Terapia PUVA/métodos , Transtornos de Fotossensibilidade/tratamento farmacológico , 5-Metoxipsoraleno/administração & dosagem , 5-Metoxipsoraleno/efeitos adversos , Adulto , Esquema de Medicação , Feminino , Humanos , Masculino , Metoxaleno/administração & dosagem , Metoxaleno/efeitos adversos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: 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. OBJECTIVES: To examine sunburn reactions in a cohort of patients with XP and correlate this to the complementation group. METHODS: Sixty patients with XP attending the U.K. National XP Service from 2010 to 2012 were studied. Their history of burning after minimal sun exposure was assessed using a newly developed sunburn severity score. The age at which the first skin cancer was histologically diagnosed in each patient, and the presence of any neurological abnormality, was also recorded. RESULTS: Sunburn severity scores were abnormally high in patients with XP-A, XP-D, XP-F and XP-G compared with non-XP controls. There was no significant difference in sunburn score of patients with XP-C, XP-E and XP-V compared with controls (P > 0·05). Patients with XP-C, XP-E and XP-V were more likely to have skin cancer diagnosed at an earlier age than those with severe sunburn on minimal sun exposure. In addition, patients with XP with severe sunburn had an increased frequency of neurological abnormalities. CONCLUSIONS: Not all patients with XP have a history of severe and prolonged sunburn on minimal sun exposure. The normal sunburn response of patients with XP-C, XP-E and XP-V may relate to the preservation of transcription-coupled DNA repair in these groups. Those with a history of severe sunburn on minimal sun exposure developed their first skin cancer at an older age compared with patients with XP-C, XP-E and XP-V, but they had an increased frequency of neurological abnormalities. Physicians need to be aware that about half of all patients with XP will present without a history of abnormal sunburn.
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Queimadura Solar/patologia , Xeroderma Pigmentoso/patologia , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/etnologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etnologia , Doenças do Sistema Nervoso/mortalidade , Doenças do Sistema Nervoso/patologia , Neoplasias Cutâneas/etnologia , Neoplasias Cutâneas/patologia , Queimadura Solar/etnologia , Queimadura Solar/mortalidade , Xeroderma Pigmentoso/etnologia , Xeroderma Pigmentoso/mortalidade , Adulto JovemRESUMO
Xeroderma pigmentosum (XP), a rare genetic skin condition, causes ultraviolet (UV)-induced neoplasms and possible neurological deficits including sensorineural hearingloss. We present the first case in literature of bilateral cochlear implantation (CI) in a patient with XP-D with neurodegeneration. Multi-disciplinary team members (national XP team, dermatologist, anaesthetist, theatre team, biophysicists) were involved. UV exposure from equipment and areas where the 14-year-old patient would track was measured. Maximum possible surgery was performed under operating headlights to limit higher-UV microscope exposure. Its bulb light intensity was reduced to achieve safe UV level (0-10 µW/cm2). Skin was protected under surgical drapes. Challenges included drilling unpredicted hard thick bone under low-intensity light and requiring bulkier Nucleus®-7 processor due to unanticipated increased scarring. A delayed left facial weakness was resolved with steroids. He is undergoing hearing rehabilitation. This highlights challenges of CI in XP. Its impact in preserving cognition and on neurodegeneration should also be observed.
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BACKGROUND: Herlitz junctional epidermolysis bullosa (HJEB) is a severe, life-threatening, autosomal recessive blistering skin disease for which no cure is currently available. Prenatal diagnosis for couples at risk is feasible through fetal skin biopsy or analysis of DNA extracted from chorionic villi, but these methods can be applied only after pregnancy has been established. An alternative approach, which involves the analysis of single cells from embryos prior to establishment of pregnancy, is preimplantation genetic diagnosis (PGD). Until now, its clinical uptake has been hindered by lengthy delays in establishing mutation-specific protocols, and by the small amount of template DNA that can be obtained from a single cell. A new method that addresses these problems, preimplantation genetic haplotyping (PGH), relies on whole genome amplification followed by haplotyping of multiple polymorphic markers using standard DNA-based polymerase chain reaction (PCR) assays. OBJECTIVES: To design and validate a generic PGH assay for HJEB and to transfer this into clinical practice. MATERIALS AND METHODS: We established a multiplex PCR-based PGH assay involving 16 markers within and flanking the LAMB3 gene (the most frequently mutated gene in HJEB). The assay was then validated in 10 families with at least one previously affected offspring. After licensing by the Human Fertilisation and Embryology Authority (HFEA), the new test was used for PGD in a couple at risk of HJEB. RESULTS: The chromosome 1 LAMB3 markers within the assay were shown to be of sufficient heterogeneity to have widespread application for preimplantation testing of HJEB. In one couple that were heterozygous carriers of nonsense mutations in LAMB3, we used the new assay to identify unaffected embryos in a series of PGD cycles. Pregnancy was established in the third PGD cycle and a healthy, unaffected child was born. DNA analysis of cord blood confirmed the predicted single-cell mutation status of wild-type LAMB3 alleles. CONCLUSIONS: PGH represents a major step forward in widening the scope and availability of preimplantation testing for serious mapped single-gene disorders. We have established a generic test that is suitable for the majority of couples at risk of HJEB.
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Moléculas de Adesão Celular/genética , Epidermólise Bolhosa Juncional/diagnóstico , Haplótipos , Diagnóstico Pré-Implantação/métodos , Cromossomos Humanos 1-3/genética , Epidermólise Bolhosa Juncional/genética , Feminino , Marcadores Genéticos , Humanos , Reação em Cadeia da Polimerase/métodos , Gravidez , CalininaRESUMO
BACKGROUND: Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) is a severe inherited blistering skin disorder caused by mutations in the anchoring fibril type VII collagen gene, COL7A1. There is currently no effective treatment but DNA-based prenatal testing in families at risk of recurrence is possible, mostly involving chorionic villus sampling at 10-11 weeks' gestation. OBJECTIVES: An alternative method, for avoiding recurrence of HS-RDEB, is preimplantation genetic diagnosis (PGD). This involves DNA analysis of single blastomeres extracted from late cleavage stage embryos following in vitro fertilisation. METHODS: To establish PGD for HS-RDEB, we designed and optimised a sensitive single cell semi-duplex polymerase chain reaction (PCR) assay for two highly polymorphic dinucleotide repeat microsatellite markers, D3S1581 (telomeric) and D3S1289 (centromeric), close to the COL7A1 gene. RESULTS: We demonstrated high PCR efficiency, low allele drop out rates and no contamination in testing this assay on 50 single buccal cells of known heterozygous genotype and 13 research blastomeres from donated embryos. CONCLUSIONS: This semi-duplex PCR method provides robust, reproducible and informative amplification results for single cells. Moreover, this test has now been approved for clinical application by the UK Human Fertilisation and Embryology Authority (HFEA). As such, the development of PGD for HS-RDEB broadens the range of prenatal testing options and personal choice for couples at reproductive risk of this severe genetic skin disease.
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Colágeno/genética , Repetições de Dinucleotídeos , Epidermólise Bolhosa Distrófica/diagnóstico , Reação em Cadeia da Polimerase , Diagnóstico Pré-Implantação/métodos , Sequência de Bases , Feminino , Humanos , Masculino , Dados de Sequência Molecular , GravidezRESUMO
Kindler syndrome (KS) is a rare inherited skin disorder with blistering and poikiloderma as its main clinical features. It is caused by loss-of-function mutations in the C20orf42 (KIND1) gene which encodes kindlin-1, an actin cytoskeleton-focal contact-associated protein which is predominantly expressed in keratinocytes. We investigated the molecular basis of KS in a 16-year-old Indian boy who had additional clinical findings, including scleroatrophic changes of the hands and feet, pseudoainhum and early onset of squamous cell carcinoma on his foot. Immunostaining for kindlin-1 in the patient's skin was completely absent and sequencing of C20orf42 (KIND1) genomic DNA showed a homozygous splice-site mutation at the -6 position, IVS9-6T-->A. Amplification and sequencing of cDNA from the skin revealed aberrant splicing with either deletion of exon 10 or deletion of exons 9, 10 and 11, both of which involve loss of the pleckstrin homology domain of kindlin-1 that is thought to play a role in cytoskeletal attachment and integrin-mediated cell signalling. Pathogenic splice-site mutations at the -6 position are unusual and have rarely been reported for any genetic disorder. Collectively, these findings extend the spectrum of clinical and molecular abnormalities in this rare genodermatosis.
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Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Dermatopatias Genéticas/patologia , Adolescente , Evolução Fatal , Humanos , Masculino , Sítios de Splice de RNA/genética , Dermatopatias Genéticas/genética , SíndromeRESUMO
Maintenance of an intact epidermis depends on secure adhesion between adjacent keratinocytes, and between basal keratinocytes and the underlying epidermal basement membrane. The major adhesion units that achieve this are the hemidesmosomes and desmosomes, but when these structures are disrupted, e.g., by gene mutations or autoantibodies, the resilience of the epidermis is lost and blisters develop. Recently, there have been considerable advances in our knowledge of the proteins and glycoproteins that contribute to maintaining keratinocyte adhesion via hemidesmosomes and desmosomes, as well as new insights into the molecular pathogenesis of several inherited and autoimmune blistering skin diseases. These new basic scientific data are clinically relevant, helping to improve patient management and to provide a rationale for developing better and more specific treatments for patients with inherited or acquired blistering skin diseases. In addition, there have also been improvements in our understanding of the organization and assembly of these adhesion structures, and their involvement in signalling pathways, intricately linked to skin development, wound healing and tumour invasion. This review provides an update on the structure and organization of hemidesmosomes and desmosomes, and on the molecular pathology of their various components that result in bullous skin diseases.
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Desmossomos/patologia , Hemidesmossomos/patologia , Dermatopatias Vesiculobolhosas/patologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Adesão Celular , Desmossomos/genética , Desmossomos/imunologia , Epiderme/imunologia , Epiderme/patologia , Hemidesmossomos/genética , Hemidesmossomos/imunologia , Humanos , Dermatopatias Vesiculobolhosas/genética , Dermatopatias Vesiculobolhosas/imunologiaRESUMO
Skin fragility-ectodermal dysplasia syndrome is an autosomal recessive disorder caused by loss-of-function mutations in the desmosomal protein, plakophilin 1. Clinically, there may be considerable morbidity from extensive skin erosions and painful fissures on the palms and soles. In the absence of any specific treatment, prenatal diagnosis is an option for couples at reproductive risk of recurrence. In 2000, we developed and applied a single cell nested polymerase chain reaction protocol to test one couple for compound heterozygous plakophilin 1 gene mutations by preimplantation genetic diagnosis (PGD). Although pregnancy was established, an unrelated trisomy 22 led to a spontaneous abortion. However, eight embryos of known genetic status were cryopreserved at that stage, and we planned to undertake subsequent frozen embryo replacement cycles that might lead to the birth of an unaffected child in this family. Embryo cryopreservation was carried out in June 2000 using standard protocols in a three-step freezing procedure. Four embryos were thawed in March 2003, one of which was viable and was used in a frozen embryo replacement cycle, but pregnancy did not occur. The remaining four embryos were thawed in February 2004, two of which were viable (both carriers of the paternal mutation) and these were used in a second frozen embryo replacement cycle, and a singleton pregnancy was established. The child's plakophilin 1 genotype was assessed by direct nucleotide sequencing across the site of both potential mutations. Following two frozen embryo replacement cycles, and almost 4 years after the initial embryo biopsy and mutation analysis, a pregnancy was achieved that progressed to term with the birth of a healthy baby girl. Nucleotide sequencing of cord blood DNA, taken immediately after delivery, showed that the child was a heterozygous carrier of the paternal mutation but not of the maternal mutation. This case demonstrates the value of embryo cryopreservation, which can increase the number of embryo replacement procedures and hence the cumulative pregnancy rate per retrieval cycle. Moreover, this is the first report of successful full-term pregnancy and birth of a healthy baby following exclusion of a severe genodermatosis by PGD. The successful outcome of PGD in this case illustrates what is technically possible for couples at risk of recurrence of a severe inherited skin disease.
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Displasia Ectodérmica/diagnóstico , Diagnóstico Pré-Implantação/métodos , Adulto , Sequência de Bases , Criopreservação/métodos , Displasia Ectodérmica/genética , Transferência Embrionária , Feminino , Genótipo , Heterozigoto , Humanos , Recém-Nascido , Dados de Sequência Molecular , Placofilinas/genética , Reação em Cadeia da Polimerase/métodos , GravidezRESUMO
BACKGROUND: Over the last 25 years there have been major advances in methods for prenatal testing of inherited skin disorders. Since 1979, our group at the St John's Institute of Dermatology has performed 269 prenatal diagnoses, using a variety of approaches, including fetal skin biopsy (FSB), chorionic villus sampling (CVS) and preimplantation genetic diagnosis (PGD). OBJECTIVES: This study was designed to review the clinical indications, testing procedures and laboratory analyses for all prenatal tests conducted at St John's over this period. METHODS: FSBs were examined for morphological and, when relevant or feasible, immunohistochemical abnormalities. The DNA-based tests involved screening by nucleotide sequencing, restriction enzyme digests or, in a few cases, by linkage analysis. Results Of the 269 tests, 191 were FSB, 76 were CVS and two were PGD. The major indications for FSB were epidermolysis bullosa (EB) (138 cases, including 88 junctional and 48 dystrophic), ichthyoses (37 cases, including 22 tests for harlequin ichthyosis) and oculocutaneous albinism (12 cases). Of the CVS procedures, 75 were for EB (40 junctional, 35 dystrophic) and one was for the EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome. Both of the PGD procedures were for the skin fragility-ectodermal dysplasia syndrome. All tests provided accurate diagnoses and the fetal loss rate was approximately 1% for both FSB and CVS. CONCLUSIONS: The development of prenatal testing has proved to be of great benefit for individuals or couples at risk of having children with severe inherited skin disorders and, in the absence of a cure, prenatal testing along with appropriate counselling has become an important translational benefit of basic research and an integral part of clinical management.