Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.

BACKGROUND: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). OBJECTIVES: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. METHODS: This was a consensus expert review. RESULTS: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. CONCLUSIONS: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.

Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines.

This article summarizes recommendations reached following a systematic literature review and expert consensus on the diagnosis and management of cutaneous squamous cell carcinomas in people with epidermolysis bullosa. The guidelines are intended to help inform decision making by clinicians dealing with this complex complication of a devastating disease.

[Mucosal manifestations of epidermolysis bullosa : Clinical presentation and management]. / Schleimhautbeteiligung bei Epidermolysis bullosa : Klinik und Therapiemaßnahmen.

Mucosal lesions occur with different prevalence and severity in all subtypes of hereditary epidermolysis bullosa (EB), a group of rare genodermatoses. They are associated with increased morbidity and mortality, especially in severe junctional and dystrophic subtypes. Despite progress in clinical approaches to curative therapy, the management of these patients is still primarily symptom-oriented. Current recommendations mainly rely on expert opinion and experience from health care professionals of specialized centers, since the rarity of this disease largely limits the availability and feasibility of randomized controlled trials. Accurate preventive and supportive care measures, however, can significantly lessen symptoms, avoid/ameliorate complications, and enhance the quality of life of these patients.

[Anesthesiological aspects in patients with epidermolysis bullosa]. / Anästhesiologische Aspekte bei Patienten mit Epidermolysis bullosa.

Epidermolysis bullosa causes blistering due to altered structural proteins of the dermoepidermal junction, resulting in scarring and strictures of the skin and mucous membranes. Affected individuals typically require frequent surgical interventions due to burdensome symptoms and complications of the disease. The anesthesiological management of these patients is inherently challenging. This review article summarizes the relevant features of this patient cohort and provides practical recommendations for care.

[Hereditary blistering diseases. Symptoms, diagnosis and treatment of epidermolysis bullosa]. / Erbliche blasenbildende Erkrankungen. Klinik, Diagnostik und Therapie der Epidermolyis bullosa.

Hereditary epidermolysis bullosa (EB) is a term for a heterogeneous group of rare genetic disorders characterized by marked fragility of the skin and mucous membranes following minor trauma. Significant progress has been made in understanding the molecular basis of EB, which has far-reaching implications for an improved classification with consequences for prognosis, genetic counseling, DNA-based prenatal and preimplantation testing, and the development of future treatments including gene therapy. Besides mucocutaneous changes, EB leads to a number of systemic manifestations whose management requires multidisciplinary access. Extracutaneous complications include ophthalmologic, dental, gastrointestinal, pulmonary, urogenital, hematologic, and nutritional problems. This article reviews the progress that has been made in the understanding of the molecular basis of EB, clinical aspects of major EB subtypes, and the management of patients suffering from EB, and it gives an outlook on molecular therapy projects such as gene, cell, vector, and protein therapies.

Epidermolysis bullosa naevi reveal a distinctive dermoscopic pattern.

BACKGROUND: Large, asymmetrical and irregularly pigmented naevi in patients with epidermolysis bullosa (EB) have been reported often to mimic cutaneous melanoma clinically. OBJECTIVES: As the biological course of these peculiar moles is benign, we assessed EB naevi with a dermatoscope to determine whether they could be reliably differentiated from cutaneous melanoma. METHODS: We evaluated digital dermoscopic images of 23 EB naevi from 11 patients with EB and analysed these pigmented lesions according to pattern analysis, ABCD rule of dermoscopy and the seven-point checklist. RESULTS: Melanoma-associated dermoscopic criteria such as multicomponent pattern (20 of 23), atypical pigment network (17 of 23), irregular dots/globules (16 of 23), irregular pigmentation (22 of 23) and an atypical vascular pattern (seven of 23) were frequently seen in EB naevi. In contrast, other criteria frequently associated with melanoma progression, such as irregular streaks, blue-whitish veil, regression structures (blue-whitish areas) or black dots, were rarely seen. Most lesions gave false-positive results when the scores of the dermoscopic diagnostic algorithms were calculated. CONCLUSIONS: Recurring dermoscopic structures in EB naevi reveal a distinctive dermoscopic pattern of this recently defined entity. Although EB naevi represent an exception to dermoscopic diagnostic algorithms, their dermoscopic evaluation most often allows us to estimate their benign nature. Nevertheless, as an unequivocal discrimination from malignant melanoma in vivo is sometimes not possible, regular clinical follow up of EB naevi with histopathological evaluation of highly suspicious lesions is mandatory.

The European Multiple System Atrophy-Study Group (EMSA-SG).

Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

[Outcome after artificial amniotic fluid instillation in early oligohydramnios]. / Outcome nach artifizieller Fruchtwasser-Instillation (AFI) bei früher Oligohydramnie.

We report on the foetal outcome of 50 pregnancies with severe oligohydramnios in the second and early third trimesters in which artificial fluid instillation (AFI) had been performed. Through the AFI, rapid diagnosis was possible or was made easier or additional malformations were detected or could be excluded. The AFI-associated risk was an induction of labour and a possible iatrogenic rupture of membranes in 3/50 cases. A total of 47 pregnancies could be evaluated to the end, 37 ended in intrauterine death, spontaneous abortion or, in case of a diagnosed lethal malformation, in induced abortion. Ten babies were born alive, but within a period of six months 6 of them died. From the total group, 4 children (8%) are alive and healthy. Survivors are from pregnancies with PROM, with severe IUGR or from the group of idiopathic oligohydramnios. Twenty-seven foetuses had structural, chromosomal or functional anomalies (urogenital, intestinal, heart, skeletal, central nervous, complex malformations). Our data demonstrate a poor prognosis in case of early oligohydramnios. AFI enables early and correct diagnosis. It provides a better basis for counselling and managing of these pregnancies. The risk of AFI with possible induction of labour and iatrogenic rupture of membranes has to be considered both in indication and counselling. However, the risk is limited with regard to the very poor prognosis even without invasive diagnosis.

[Liver cirrhosis in autopsy material within 48 years. I. Changes of prevalence, regional differences (author's transl)]. / Die Leberzirrhose im Autopsiegut von 48 Jahren. I. Häufigkeitsänderungen, regionale Unterschiede.

Comparative studies on a total of 41628 autopsies from the Institutes of Pathology of Wuppertal and Tuebingen revealed a 2,97 fold increase of liver cirrhosis in Wuppertal and 2,29 fold rise of prevalence in Tuebingen between 1946 and 1975. In Tuebingen this increasing prevalence preponderates in men, in Wuppertal in women. Thus, between 1964-1975 in Tuebingen the prevalence of liver cirrhosis in men exceeds liver cirrhosis in women 2,1 fold, in Wuppertal 1,1 fold only. After World War II a considerable increase was observed in both Institutes within 25 years, which reached a maximum with 8,2% of all adults in Tuebingen in 1969 and 11,8% in 1972 in Wuppertal, especially owing to an increase of portal cirrhosis. Since then no further rise has been noticed.

[Liver cirrhosis in autopsy material within 48 years. II. Causes of death, liver cell carcinoma, weights of liver and spleen (author's transl)]. / Die Leberzirrhose im Autopsiegut von 48 Jahren. II. Todesursachen. Leberkarzinome, Leber- und Milzgewichte.

Post mortems of 2289 patients with liver cirrhosis revealed that 37% died of causes related directly to cirrhosis i.e. liver failure or hemorrhage from oesophageal varices. Patients who died of ruptured oesophageal varices in 82% have splenomegaly and most frequently hepatomegaly. Livercell carcinomas were recognized in 7,5% of cirrhotic livers, increasing to 10% in 1976-1978. This rise particularly is conspicuous in women. Liver carcinoma is 4,5 times more frequent in postnecrotic than in portal cirrhosis.