Jemima E. Mellerio

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB

BACKGROUND Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. OBJECTIVE We sought to arrive at a new consensus of the classification of EB subtypes. RESULTS We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. LIMITATIONS As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. CONCLUSION This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

Extracutaneous manifestations and complications of inherited epidermolysis bullosa: Part I. Epithelial associated tissues

Based upon case reports and small case series, it has been known for many years that some types and subtypes of inherited epidermolysis bullosa (EB) may be at risk for developing one or more extracutaneous complications. Many of these are associated with considerable morbidity; some may result in death. Only over the past few years have there been data generated from large, well characterized cohorts. However, these data, to date, have been published almost exclusively in the nondermatologic literature. Our objective is to provide dermatologists with a comprehensive review of each major extracutaneous complication with a summary of the pertinent literature and recommendations for evaluation and optimal management. Part I highlights epithelial associated tissues, and part II addresses other organs. Based on these reviews, the readership should gain a greater understanding of the types of complications that may occur, when they are most likely to develop, and the range of medical and surgical interventions that are currently available. It should also be possible for the reader to develop surveillance strategies based on an understanding of the published evidence-based data. The breadth and range of severity of complications that arise in some EB types and subtypes within the external eye, ear, nose, upper airway, and gastrointestinal and genitourinary tracts suggest that optimal management must be multidisciplinary. Given the unique knowledge that dermatologists have of this disease, we believe that the care of the EB patient should be under the direction of his or her dermatologist, who can best assist in timely referrals to those specialists who are most experienced in the care of specific extracutaneous problems.

Extracutaneous manifestations and complications of inherited epidermolysis bullosa: Part II. Other organs

It is well known, primarily via case reports and limited case series, that nonepithelial tissues may become injured in patients with epidermolysis bullosa. Only recently, however, have there been data generated from large, well characterized cohorts. Our objective is to provide dermatologists with a comprehensive review of each of these major extracutaneous complications, with a summary of the pertinent literature and evidence-based recommendations for surveillance, evaluation, and management. Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth, and for the development of squamous cell carcinoma, basal cell carcinoma, or malignant melanoma. If untreated, significant morbidity or mortality may result.

Prenatal diagnosis for severe inherited skin disorders: 25 years' experience

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 Johns 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).

A consensus approach to wound care in epidermolysis bullosa

BACKGROUND Wound care is the cornerstone of treatment for patients with epidermolysis bullosa (EB); however, there are currently no guidelines to help practitioners care for these patients. OBJECTIVES The objective of this study was to generate a list of recommendations that will enable practitioners to better care for patients with EB. METHODS An expert panel generated a list of recommendations based on the best evidence available. The recommendations were translated into a survey, and sent to other EB experts to generate consensus using an online-based modified Delphi method. The list was refined and grouped into themes and specific recommendations. RESULTS There were 15 respondents (45% response rate), with significant experience in the EB field (>10 years [67%]). Respondents included physicians (67%), nurses (17%), and allied health professionals (7%). There was more than 85% agreement for all the proposed items. These were further refined and grouped into 5 main themes (assessment and management of factors that impair healing, patient-centered concerns, local wound care, development of an individualized care plan, and organizational support) and 17 specific recommendations. LIMITATIONS There is a paucity of scientific evidence with most recommendations based on expert opinion. CONCLUSIONS These recommendations will provide practitioners with a framework for caring for these patients. Additional scientific research including effectiveness studies for everyday practice and expert consensus, may further refine these recommendations.

Gastrointestinal complications of epidermolysis bullosa in children

Background  Epidermolysis bullosa (EB) is a group of inherited disorders characterized by skin and mucous membrane fragility. Gastrointestinal (GI) complications have been described in many types of EB and are responsible for significant morbidity.

Recessive epidermolysis bullosa simplex associated with plectin mutations: infantile respiratory complications in two unrelated cases

Plectin is a 500kDa protein involved in cytoskeleton‐plasma membrane attachment with a wide tissue distribution including cutaneous and airway epithelia, muscle and neuronal tissue. Recently, mutations in the gene encoding plectin (PLECI) have been implicated in the pathogenesis of an autosomal recessive variant of epidermolysis bullosa simplex in which cutaneous blistering starting in the neonatal period is associated with muscular dystrophy in later life. In this study, we report two unrelated patients, both of consanguineous parentage, who presented with cutaneous blistering and a hoarse cry from birth. Both experienced inspiratory stridor and respiratory distress, necessitating emergency tracheostomy in one case. Immunoreactivity to monoclonal antibodies against plectin was absent or markedly reduced in skin biopsies from both patients. Electron microscopy revealed a low intraepidermal plane of cleavage and hypoplastic hemidesmosomes with a reduced association with keratin intermediate filaments. Direct sequencing of PLEC1 in each case demonstrated two novel homozygous frameshift deletion mutations. 5069del19 and 5905del2, which both create downstream premature termination codons. Although currently neither patient has symptoms of muscle disease, the identification of mutations in PLEC1 may be predictive for the future development of muscular dystrophy. Recessive epidermolysis bullosa simplex resulting form abnormalities in plectin should be considered in the differential diagnosis of cutaneous blistering, hoarseness and stridor in infancy.

Fibroblast cell therapy enhances initial healing in recessive dystrophic epidermolysis bullosa wounds: results of a randomized, vehicle-controlled trial.

Fibroblast cell therapy can modify disease biology in recessive dystrophic epidermolysis bullosa (RDEB) although whether it improves wound healing is not clear.

α6β4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia

Junctional epidermolysis bullosa with pyloric atresia (JEB‐PA) (MIM 226730) is an autosomal recessive disorder resulting from mutations in the genes encoding α6β4 integrin (ITGA6 and ITGB4). Clinically, it is characterized by mucocutaneous fragility and gastrointestinal atresia, which most commonly affects the pylorus. Additional features of JEB‐PA include involvement of the urogenital tract, aplasia cutis and failure to thrive. While most affected individuals have a poor prognosis resulting in death in infancy, others have milder clinical features and a better prognosis. We report two previously undescribed homozygous ITGB4 mutations in two unrelated families, which resulted in severe skin blistering, pyloric atresia and lethality in infancy. Delineation of the mutations was used to undertake DNA‐based prenatal diagnosis in subsequent pregnancies at risk for recurrence in both families. We review all previously published ITGA6 and ITGB4 mutation reports to help define genotype–phenotype correlation in this rare genodermatosis.

Desmosomal genodermatoses: Desmosomal genodermatoses

Desmosomes are intercellular junctions that contribute to cell–cell adhesion, signalling, development and differentiation in various tissues, including the skin. Composed of a network of transmembranous and intracellular plaque proteins, pathogenic autosomal dominant or recessive mutations have been reported in 10 different desmosomal genes, resulting in a spectrum of phenotypes variably affecting skin, hair and heart. This review summarizes the molecular pathology and phenotypes that predominantly affect the skin/hair. Recent desmosomal genodermatoses described include lethal congenital epidermolysis bullosa (plakoglobin), cardiomyopathy with alopecia and palmoplantar keratoderma (plakoglobin), hypotrichosis with scalp vesicles (desmocollin 3), and generalized peeling skin disease (corneodesmosin). Understanding the range of clinical phenotypes in combination with knowledge of the inherent desmosome gene mutation(s) is helpful in managing and counselling patients, as well as providing insight into the biological function of specific components of desmosomes in skin and other tissues.