The Use of Oral Ketamine for Analgesia with Dressing Change in an Infant with Epidermolysis Bullosa: Report of a Case

Abstract: Epidermolysis bullosa (EB) describes a spectrum of disease from occasional bullae and callus formation to a debilitating life‐threatening condition. In this study, we report the use of intravenous ketamine given orally to an infant with a phenotypically severe form of EB simplex, Dowling‐Meara subtype, to achieve analgesia during painful dressing changes.     

Clinical Phenotype of Bart's Syndrome Seen in a Family with Dominant Dystrophic Epidermolysis Bullosa

Background: Bart's syndrome is one type of dominant dystrophic epidermolysis bullosa (EB). It is known that, in some familial cases of dominant dystrophic EB, the symptoms differ depending on the individual. We observed the way Bart's syndrome affected four generations in the same family. The proband was a newborn boy who showed congenital localized absence of skin (CLAS) and bullae on the anterior aspects of both legs. Histologically, the bullae were located subepidermally. The CLAS and bullae disappeared within 4 months after birth, leaving scars. His father retained scarring and scaling from the knees down along the anterior aspect of the legs, and the nails of the toes were either lacking or deformed. His paternal grandmother and great-grandmother also presented deformed nails of the toes, although they had not had CLAS or bullae on the legs at birth. The individuals in this family thus showed some heterogeneity depending on the sex: blistering and CLAS were seen on the legs soon after birth in the male family members, but the female members did not share this pattern of symptoms, suggesting that the expression of symptoms may differ depending on the sex of the affected individual.     

Genetic abnormalities and clinical classification of epidermolysis bullosa

Genetic abnormalities for different subtypes of epidermolysis bullosa (EB) have been described. In dominant simplex type EB, mutations of the K5 or K14 gene lead to disruption of basal cells and the formation of bullae. The recessive simplex types include EB with muscular dystrophy due to abnormal plectin, EB without muscular dystrophy in patients homozygous for K14 gene abnormalities, and skin fragility syndrome, with formation of acantholytic vesicles within the epidermis due to PKP1 gene mutations. In junctional EB, mutations of the laminin 5, type XVII collagen, and alpha 6 beta 4 integrin genes have been reported. Dystrophic type EB is associated with various abnormalities of the type VII collagen gene. A new classification of EB based on these genetic abnormalities has been proposed. However, some concern has been voiced regarding the clinical utility of a classification based solely on genetic abnormalities. Although the reasons are unclear, identical genetic abnormalities have been known to be associated with different clinical features. A classification including a component based on clinical features would therefore be preferable. This article describes recently discovered genetic abnormalities and offers a new classification scheme for EB.     

Bullous pyoderma as a presentation of acute leukaemia

A patient with an unusual bullous pyoderma preceding the onset of acute leukaemia is reported. The initial lesions were purplish bullae, which later formed superficial ulcers and healed with minimal scarring. Histology showed intra-epidermal bullae with a dense polymorphonuclear infiltrate in the epidermis. This eruption is difficult to classify, but fifteen patients with similar skin lesions have been found in the literature, seven of these patients developed acute leukaemia and one had metastatic adenocarcinoma on presentation. We feel that the recognition of these distinctive skin lesions may be important because of their association with internal malignancy.     

Bart''s Syndrome: Microscopic, Ultrastructural, and Immunofluorescent Mapping Features

Bart's syndrome has been clinically described as the association of congenital localized absence of skin (CLAS), epidermolysis bullosa (EB), oral mucosal lesions, and dystrophic nails. Transmission occurs through an autosomal dominant gene with complete penetrance but variable expression. It has been difficult to classify this type of EB because of lack of microscopic and ultrastructural studies on affected family members. This is the first report of microscopic, ultrastructural, and immunofluorescent mapping studies of an affected individual with the complete inherited syndrome initially described by Bart. This study is also the first to document the association of CLAS and dominant dystrophic epidermolysis bullosa by histology, electron microscopy, and immunofluorescent mapping. Our two patients and one other affected family member had diminution or absence of a specific basement membrane antigen as defined by immunofluorescence with a monoclonal antibody (KF-1) in perilesional skin.     

Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment

Epidermolysis bullosa (EB) is a group of genetic disorders in which the skin is abnormally fragile. In EB simplex, the skin cells tend to fall apart because their internal scaffolding of keratin fibres is defective, due to mutations in the genes encoding keratins type 5 or 14 (KRT5 and KRT14). But people with the generalised, severe type of EB simplex (EBS-GS) are sometimes more ill than would be expected just from a mechanical problem with the skin; some even die in infancy, usually from infection. This group from France and Scotland explored the possibility that EBS-GS patients also have a faulty immune system. They re-examined skin specimens taken previously for diagnostic purposes from 17 patients with EBS-GS and also tested fresh skin biopsies and blister fluid from a further 10 patients. They consistently found more inflammatory cells and higher levels of chemicals which promote inflammation (cytokines) than normal. The findings were the same regardless of whether the sample was from blistered or normal-looking skin and whether the fault was in KRT5 or KRT14. Markers for the cytokine Th17 were particularly high, encouraging them to treat three EBS-GS patients with the anti-Th17 drug Apremilast as used in psoriasis. All three reported a dramatic reduction in blisters within the first month, which lasted throughout treatment for up to 10 months, with minimal side-effects. One patient stopped the Apremilast after 7 months because of nausea and the blistering came back 2 days later. This appears to be a promising new approach to treating EBS-GS.     

Paraneoplastic pemphigus: a pustular form during chronic lymphoid leukemia]

BACKGROUND: Paraneoplastic pemphigus is an autoimmune disease of the skin and mucosa described in 1990. The condition is generally associated with lymphoma or chronic lymphoid leukemia. Lesions are often misleading, masquerading as polymorphous erythema or lichen. We report a case of paraneoplastic pemphigus with pustulous skin lesions. CASE REPORT: A 52-year-old man developed over a few weeks time erosive lesions of the oral cavity and lips associated with papulous skin lesions. Secondarily, large-sized pustules, sometimes a hypopion, were observed associated with bullae. The diagnosis of paraneoplastic pemphigus was confirmed by direct immunofluorescence that evidenced IgG deposits within the keratinocytes and along the basal membrane and by indirect immunofluorescence on rat bladder that evidenced circulating antibodies. This paraneoplastic pemphigus was the inaugural sign of chronic lymphoid leukemia. DISCUSSION: Skin lesions described in paraneoplastic pemphigus include: erosion, vesicles, bullae, and psoriasiform, lichen-like, plate-like or vegetative formations. To our knowledge, this is the first report of a pustulous form; clinically similar to Hallopeau pustulous pemphigus.     

Hereditäre Blasen bildende Hauterkrankungen

Epidermolysis bullosa (EB) is a group of genetic skin disorders whose common feature is the formation of blisters following minor trauma. They present with a wide clinical spectrum of manifestations because of a variety of molecular defects. In patients with mild phenotypes, only skin is affected. The most severe EB forms are multiorgan disorders with a poor prognosis. EB arises from abnormalities in proteins of the dermal-epidermal junction. These specialized protein components aggregate to form anchoring complexes, which attach the epidermis to the dermis. Three major EB-forms can be distinguished on the basis of ultrastructural blistering level: EB simplex—epidermolytic, junctional EB—in the lamina lucida and dystrophic EB—dermolytic. To establish a provisional diagnosis for an EB patient, clinical data, family history and morphologic examination of the skin, e.g. by antigen-mapping, are needed. Complete knowledge of the genetic defect provides the basis to a rational genetic counseling and prenatal testing. Treatment of EB is based on wound care; multidisciplinary management of cases with severe course is required.     

白色丘疹样大疱性表皮松解症—附6例报告

报告６例白色丘疹样大疱性表皮松解症，临床上均具有典型的象牙白色丘疹，部位以小腿最多，一般无自觉症状。取水疱作组织病理显示表皮下疱或裂隙，真皮浅层轻度纤维母细胞增生；丘疹的病理表现为真皮浅层结缔组织轻度增生；取１例患者外观正常皮肤作透射电镜发现锚状纤维明显减少。我们认为本病的确诊需同时具有ＥＢ典型表现和特征性的白色丘疹，治疗以对症处理为主，预后较好。     

Dermal eosinophilic infiltrate in junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is a rare genodermatosis characterized by a split in the lamina lucida usually because of mutations in LAMA3, LAMB3 and LAMC2 resulting in absence or reduction of laminin‐332. Rare subtypes of JEB have mutations in COL17A1, ITGB4, ITGA6 and ITGA3 leading to reduction or dysfunction of collagen XVII, integrin α6β4 and integrin α3. The classic finding under light microscopy is a paucicellular, subepidermal split. We describe the unusual presence of an eosinophilic infiltrate in the bullae and subjacent dermis in a neonate with JEB, generalized intermediate (formerly known as non‐Herlitz‐type JEB), discuss the histologic differential diagnosis for a subepidermal blister in a neonate, review the literature regarding cases of epidermolysis bullosa (EB) presenting with inflammatory infiltrates, and discuss mechanisms to explain these findings. This case highlights that eosinophils can rarely be seen in EB and should not mislead the dermatopathologist into diagnosing an autoimmune blistering disorder.     

A specific defect in glycosylation of epidermal cell membranes. Definition in skin from patients with epidermolysis bullosa simplex

Why blister formation occurs within the epidermis in epidermolysis bullosa (EB) simplex is not known. One possibility is that there are diminished amounts, absence, or biochemical alterations of one or more structural components of epidermal cell membranes, thereby leading to increased skin fragility. In order to test this hypothesis, biopsy specimens were obtained from clinically normal-appearing skin of patients with simplex, junctional, and dystrophic forms of EB and normal adult volunteers. Immunofluorescence studies were performed on each specimen using eight fluorescein-labeled affinity-purified lectins shown to bind uniformly to epidermal cell membranes of normal human adult skin and neonatal foreskin. To examine the epidermal cytoskeleton, each tissue specimen was also examined using two antikeratin monoclonal antibodies. Irregular and focally granular epidermal membrane staining was noted in each EB simplex specimen examined with the lectin-peanut agglutinin. In contrast, uniformly crisp membrane staining was seen in each specimen from patients with junctional or dystrophic EB and from normal volunteers. This epidermal cell membrane glycosylation defect appears to have the restricted carbohydrate specificity of peanut agglutinin since staining of EB simplex skin with each of the remaining seven lectins was indistinguishable from that seen in skin from patients with the other forms of EB and normal adult skin. Furthermore, the epidermis in EB simplex skin appears to be selectively abnormal since the same tissue specimens demonstrated normal keratin cytoskeleton staining.     

Defective in vivo expression and apparently normal in vitro expression of a newly identified 105-kDa lower lamina lucida protein in dystrophic epidermolysis bullosa

We have previously identified a novel 105-kDa lower lamina lucida protein detected by the autoantibodies from a group of patients who developed a unique immune-mediated subepidermal bullous dermatosis. We sought to determine if this novel basement membrane zone (BMZ) protein is normally expressed in the skin of patients with various subsets of epidermolysis bullosa (EB). Indirect immunofluorescence microscopy performed on non-lesional skin sections from patients with three major EB subsets revealed absence or significantly reduced expression of this novel BMZ protein in 20 out of 23 skin sections from patients with generalized dominant and recessive dystrophic EB. However, immunoblot analyses with the autoantibodies on Western-blotted proteins revealed that a comigrating 105-kDa protein is present in both cytosol extracts (n=6) and conditioned media (n=3) of cultured dermal fibroblasts derived from patients with dystrophic EB, as well as those cultured from two healthy individuals. Although the reason for such disparate findings is not known, the defective in vivo expression of this novel 105-kDa protein in dystrophic EB is presumably not due to a failure of fibroblasts to synthesize or secrete the protein. It is possible, however, that the 105-kDa protein may be unable to incorporate into the BMZ because it is produced in a dysfunctional form, or its BMZ binding site is missing. It is also possible that other structural alterations in skin BMZ, which occur in dystrophic EB, result in masking of the antigenic binding by the autoantibody when intact BMZ is probed. In any case, the reduced in vivo expression of the 105-kDa protein represents additional evidence for a defect in BMZ composition in dystrophic EB which extends to a number of molecular components.     

Hereditary blistering disorders

Epidermolysis bullosa (EB) is a group of genetic skin disorders whose common feature is the formation of blisters following minor trauma. They present with a wide clinical spectrum of manifestations because of a variety of molecular defects. In patients with mild phenotypes, only skin is affected. The most severe EB forms are multiorgan disorders with a poor prognosis. EB arises from abnormalities in proteins of the dermal-epidermal junction. These specialized protein components aggregate to form anchoring complexes, which attach the epidermis to the dermis. Three major EB-forms can be distinguished on the basis of ultrastructural blistering level: EB simplex--epidermolytic, junctional EB--in the lamina lucida and dystrophic EB--dermolytic. To establish a provisional diagnosis for an EB patient, clinical data, family history and morphologic examination of the skin, e.g. by antigen-mapping, are needed. Complete knowledge of the genetic defect provides the basis to a rational genetic counseling and prenatal testing. Treatment of EB is based on wound care; multidisciplinary management of cases with severe course is required.     

Recently Identified Forms of Epidermolysis Bullosa

Epidermolysis bullosa (EB) comprises a collection of clinically diverse inherited blistering diseases that affect the skin and, in some subtypes, mucous membranes and other organs. Currently classified into four main subtypes (EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, mainly based on the level of skin cleavage), the spectrum of EB extends to more than 30 clinical subtypes with pathogenic mutations in at least 18 distinct genes. This review focuses on three recent additions to variants of EB: all are autosomal recessive, and result from mutations in either DST-e (coding for epidermal dystonin, also known as the 230 kDa bullous pemphigoid antigen, BP230), EXPH5 (coding for exophilin-5, also known as Slac2-b), or ITGA3 (coding for the integrin alpha-3 subunit). Each of these new forms of EB is reviewed with respect to the initial gene discovery, clinical features, the current mutation database, and skin pathology. Awareness of these recently described forms of EB is helpful in the clinical evaluation of patients with EB and in defining genotype-phenotype correlation for inherited blistering skin diseases.     

Localized subepidermal bullae after intravenous phenobarbital

The occurrence of subepidermal bullae and sweat gland necrosis in barbiturate-induced coma is well recognized. We report the case of a patient who received intravenous phenobarbital for refractory seizures and subsequently sustained subepidermal bullae without sweat gland necrosis in the skin around and proximal to the intravenous site. Although this may have been secondary to extravasation, a different mechanism of barbiturate-induced bulla formation may exist.     

Low‐Dose Cyclosporine A in the Treatment of Severe Atopic Dermatitis Complicated by Chronic Hepatitis C Virus Infection

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disorder in children and is usually accompanied by genetic and environmental factors. Effective management and treatment of AD is challenging and often requires systemic immunosuppressive therapy when refractory to topical treatments. We report a rare association between chronic hepatitis C virus (HCV) and severe AD, management of which required systemic cyclosporine because of its favorable effects on inflammatory and viral‐related clinical outcomes.     

Toxische Kontaktdermatitis auf Poison Ivy in einem Privatgarten in Deutschland

A couple suffered for 5 years from recurrent eruptions with vesicles and bullae after contact with an unknown "climbing weed" in their private garden in Germany. After this plant was identified as poison ivy and eradicated, their skin problems were solved. This is the first report of poison ivy in this setting. Urushiols in poison ivy are not only strong allergens but also potent irritants. Negative patch tests in the husband suggest that the bullous dermatitis was a toxic reaction.     

KF-1 monoclonal antibody defines a specific basement membrane antigen defect in dystrophic forms of epidermolysis bullosa

The monoclonal antibody, KF-1, identifies a noncollagenous constituent of the lamina densa of the basement membrane zone (BMZ) of skin. In order to determine whether this BMZ constituent is affected in epidermolysis bullosa (EB), a mechanobullous skin disease often resulting in marked disfigurement, we have examined skin from patients with various forms of this disease for binding by KF-1 as well as for binding by polyclonal antibodies to laminin, type IV collagen, and bullous pemphigoid antigen, three other known BMZ components of normal skin. In all specimens from patients with simplex and junctional forms of EB, all four antibodies bound normally. In contrast, absent or diminished KF-1 binding was noted in all skin specimens from patients with dystrophic EB; antibodies directed against the other BMZ constituents, however, bound normally. This suggests that KF-1 may play a role in the structural integrity of normal skin and its absence or diminution may be important in the pathogenesis of lesion formation in dystrophic EB.     

A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis

Atopic dermatitis (AD, atopic eczema) is a very common skin condition affecting 10-20% of children. It affects children of all skin colours and seems to occur more often in Asian children and children with dark skin types. However, most research is performed on children with light skin types. This study, performed in Amsterdam, the Netherlands, aimed to investigate differences between AD in children with dark and light skin types. To study this, the investigators took tape strips from 53 AD children aged 0-12 years and 50 healthy children as control (comparison). Tape stripping is a painless procedure which is ideal to perform in children, in which a small round sticker is attached to the skin. When removing this special sticker, a thin layer of skin cells remains attached to the sticker, allowing the investigators to study several aspects of skin inflammation and skin barrier. The authors found that AD skin from children with light and dark skin have similar levels and types of skin inflammation. However, they found differences in skin barrier markers between these two groups. In light skinned children, markers of good skin barrier were lower in AD skin when compared to healthy children's skin, while in dark AD skin these skin barrier markers were not significantly different from healthy dark skin. This study showed that dark-skinned and light-skinned AD children are similar when it concerns skin inflammation, but in light skinned AD children the skin barrier dysfunction may play an additional role in the development of AD. This suggests that AD in light and dark skin has different mechanisms of development.     

Pretibial epidermolysis bullosa and hypothyroidism

BACKGROUND: We report a case of primary non-autoimmune hypothyroidism causing pretibial epidermolysis bullosa. CASE REPORT: A 70-year-old man with primary non-autoimmune hypothyroidism developed blisters of different ages on the lateral aspect of both legs. Pathology reported blisters with subepidermal cleavage. Direct immunofluorescence was negative. Electron microscope examination showed a variable cleavage level and diffuse infiltration of a granulous and amorphous microfibrillar substance. After hormone replacement therapy, euthyroidism was associated with a reduction in the number of bullae and finally complete remission. After 12 months follow-up, the patient has not experienced recurrence. DISCUSSION: Recurrence-free clinical improvement after hormone replacement therapy suggests the diagnosis of hypothyroidism pretibial epidermolysis bullosae. Mochizuki et al. described a similar case which rapidly regressed after hormone therapy but where the electron microscope showed a different cleavage level. These bullae appear to result from a mechanical mechanism due to their localization in areas exposed to friction and also to the presence of bullae of different ages. This hypothesis is confirmed by the presence of a variable level of cleavage and a substance dense to electrons at electron microscopy as well as by the skin weakness. Our case confirms the reality of hypothyroidism pretibial epidermolysis bullosa. Thyroid hormones should be assayed in patients presenting pretibial bullae.