Superficial Blisters Research Articles

A role for chromosomal protein HMGN1 in corneal maturation

Corneal differentiation and maturation are associated with major changes in the expression levels of numerous genes, including those coding for the chromatin-binding high-mobility group (HMG) proteins. Here we report that HMGN1, a nucleosome-binding protein that alters the structure and activity of chromatin, affects the development of the corneal epithelium in mice. The corneal epithelium of Hmgn1 −/− mice is thin, has a reduced number of cells, is poorly stratified, is depleted of suprabasal wing cells, and its most superficial cell layer blisters. In mature Hmgn1 −/− mice, the basal cells retain the ovoid shape of immature cells, and rest directly on the basal membrane which is disorganized. Gene expression was modified in Hmgn1 −/− corneas: glutathione-S-transferase (GST)α 4and GST ω 1, epithelial layer-specific markers, were selectively reduced while E-cadherin and α-, β-, and γ-catenin, components of adherens junctions, were increased. Immunofluorescence analysis reveals a complete co-localization of HMGN1 and p63 in small clusters of basal corneal epithelial cells of wild-type mice, and an absence of p63 expressing cells in the central region of the Hmgn1 −/− cornea. We suggest that interaction of HMGN1 with chromatin modulates the fidelity of gene expression and affects corneal development and maturation.

Ichthyosis bullosa of Siemens: Response to topical tazarotene

In 1937, Siemens described a Dutch family with superficial blistering, flexural hyperkeratosis, and characteristic mauserung appearance. Since then, less than 20 kindreds with this condition have been described in the English dermatologic literature. A 14-year-old boy presented with history of recurrent blistering and peeling of skin since the age of 1 month, predominantly seen over limbs and trunk, often associated with secondary infection. His mother also had similar symptoms from childhood. On examination, the child had typical mauserung peeling of the skin and dirty gray hyperkeratosis in a rippled pattern over flexures. Skin biopsy from the boy showed intracorneal blistering with epidermolytic hyperkeratosis in the upper spinous layers. The typical history and clinical features along with characteristic histological findings confirmed our diagnosis of ichthyosis bullosa of Siemens. It must be differentiated from other conditions with epidermolytic hyperkeratosis and skin peeling, such as bullous ichthyosiform erythroderma of Brocq and peeling skin syndrome. Our patient responded well to 0.05% topical tazarotene gel over four weeks.

Staphylococcus hyicus exfoliative toxins selectively digest porcine desmoglein 1

Virulent strains of Staphylococcus hyicus can cause exudative epidermitis in pigs. The major symptom of this disease is exfoliation of the skin in the upper stratum spinosum. Exfoliation of the skin is strongly associated with exfoliative toxin including ExhA, ExhB, ExhC, ExhD, SHETA, and SHETB. Recently, genes for ExhA, ExhB, ExhC and ExhD were cloned. Exfoliative toxins produced by S. aureus have been shown to selectively cleave human or mouse desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study, we attempted to identify the molecular target of Exhs in porcine skin. Each of recombinant Exhs injected in the skin of pigs caused superficial epidermal blisters or crust formation. Cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal porcine skin were incubated with one of Exhs suggesting that Exh selectively degrade porcine desmoglein 1. In vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 of human, mouse or canine origin demonstrated that only mouse desmogleins 1α and 1β were cleaved by ExhA and ExhC at high concentration. Furthermore, injection of ExhA and ExhC at high concentration caused superficial blisters in neonatal mice. These findings strongly suggest that Exhs cause blister formation of porcine skin by digesting porcine desmoglein 1 in a similar fashion to exfoliative toxins from S. aureus.

Beinschwellung mit Blasenbildung

We report the case of a 84-year-old woman suffering from strong pain in her right leg initially resembling thrombosis of deep veins. Eight hours after admission a superficial blister developed at the calf with following hemorrhagic aspect and spontanous eruption of clear yellowish fluid. Later on a new blister appeared at the thigh. The patient died 33 hours after admission of streptococcal toxic shock syndrome. The latter was based on a necrotizing fasciitis. Streptoccus pyogenes (group A) could be cultivated from the blood and fluid of the blister. We discuss the clinical presentation of necrotizing fasciitis with "pain out of proportion" as characteristic complaint and the appropriate management.

Temperature threshold for burn injury: an oximeter safety study.

Pulse oximeters have become essential devices for evaluating and monitoring patient oxygenation. The probe emits a small amount of heat into the skin in the process of signal detection. Regulations set by the Food and Drug Administration currently limit the maximum allowable temperature of an oximeter probe to 41 degrees C. As a result of the prolonged exposure of extremities to these devices, we sought to determine the actual temperature threshold for burn injury in patients. Eighteen patients undergoing surgery for removal of redundant skin (abdominoplasty, breast reduction) consented to the application of a temperature-controlled custom probe with four light-emitting diodes that had temperatures set randomly at the expected threshold for burn injury (42.5 degrees C, 43 degrees C, 43.5 degrees C, and 44 degrees C). The probe was left in place for 8 hours (or less if significant pain was noted). The sites covered by the probes were then checked for signs of injury. On the next day, the redundant skin was removed as a scheduled procedure, and histopathology was performed to detect the extent of burn injury. The study was approved by the local institutional research board. Two patients were excluded because of technical problems with the probe, one of whom had the probe turned off because of pain. The only observed sign of injury was either erythema or a superficial blister that was usually unobservable or slightly red at operation. These subtle signs of a burn were noted in one patient at 43 degrees C, four at 43.5 degrees C, and nine at 44 degrees C. No burns were noted in two patients. Minimal or no signs of injury frequently were noted by histopathology. Pulse oximeter probes are safe up to a temperature of 43 degrees C for at least 8 hours in well-perfused skin. Above that temperature, there is a risk of burn injury. Performing temperature threshold tests in redundant skin that is planned for excision is a potential method for testing the safety of devices or materials.

Understanding the mechanism of action of the exfoliative toxins of Staphylococcus aureus

The exfoliative toxins of Staphylococcus aureus are responsible for the staphylococcal scalded skin syndrome, a blistering skin disorder that particularly affects infants and young children, as well as adults with underlying disease. Their three-dimensional structure is similar to other glutamate-specific trypsin-like serine proteases with two substrate-binding domains and a serine-histidine-aspartate catalytic triad that forms the active site. However, unlike other serine proteases, the exfoliative toxins possess a highly charged N-terminal α-helix and a unique orientation of a critical peptide bond, which blocks the active site of the toxins so that, in their native state, they do not possess any significant enzymatic activity. The target for the toxins has recently been identified as desmoglein-1, a desmosomal glycoprotein which plays an important role in maintaining cell-to-cell adhesion in the superficial epidermis. It is speculated that binding of the N-terminal α-helix to desmoglein-1 results in a conformation change that opens the active site of the toxin to cleave the extracellular domain of desmoglein-1 between the third and fourth domains, resulting in disruption of intercellular adhesion and formation of superficial blisters. Elucidating the mechanism of action of the toxins and identifying desmoglein-1 as their specific epidermal substrate has not only given us an insight into the pathogenesis of the staphylococcal scalded skin syndrome, but also provided us with useful information on normal skin physiology and the pathogenesis of other toxin-mediated diseases. It is hoped that this knowledge will lead to development of rapid screening and diagnostic tests, and new antitoxin strategies for the treatment and prevention of the staphylococcal scalded skin syndrome in the near future.

The Clinical Spectrum of Congenital Ichthyosis in Sweden: A Review of 127 Cases

Congenital ichthyosis comprises a rare group of usually monogenetic diseases that present at birth as a collodion phenotype or as variable degrees of ichthyosiform erythroderma, with or without superficial blisters. Depending on which gene mutation causes the disease, the skin problems later in life may range from a severe lamellar or bullous ichthyosis to mild or only focally expressed hyperkeratotic lesions. It is obviously important, but sometimes painstakingly difficult, to make a correct diagnosis already in infancy. Fortunately, recent advances in our understanding of the molecular genetics of ichthyosis have led to several new diagnostic tools that are continuously being updated. Based on this development, and on our own 5 years of experience in a national genodermatosis centre, we describe 127 cases of congenital ichthyosis examined in childhood or adulthood. Applying a combination of phenotypic and genotypic criteria, the patients were classified into three main groups: 1) Bullous ichthyosis (epidermolytic hyperkeratosis) and related disorders due to keratin mutations (n=21); 2) Non-bullous ichthyosiform erythroderma and lamellar ichthyosis mainly due to transglutaminase 1 mutations (n=80); 3) Syndromic ichthyosis, i.e. systemic (multi-organ) diseases due to many different causes (n=26). Each group could be further stratified into 4–11 entities using mutation analysis, electron microscopy of epidermis and various other techniques. Our findings are discussed in relation to recent data in the literature emphasizing the clinical usefulness of various diagnostic procedures for ichthyosis.

Staphylococcal Exfoliative Toxin B Specifically Cleaves Desmoglein 1

Staphylococcal scalded skin syndrome and its localized form, bullous impetigo, show superficial epidermal blister formation caused by exfoliative toxin A or B produced by Staphylococcus aureus. Recently we have demonstrated that exfoliative toxin A specifically cleaves desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study we determine the target molecule for exfoliative toxin B. Exfoliative toxin B injected in neonatal mice caused superficial epidermal blisters, abolished cell surface staining of desmoglein 1, and degraded desmoglein 1 without affecting desmoglein 3 or E-cadherin. When adenovirus-transduced cultured keratinocytes expressing exogenous mouse desmoglein 1 or desmoglein 3 were incubated with exfoliative toxin B, desmoglein 1, but not desmoglein 3, was cleaved. Furthermore, cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal human skin were incubated with exfoliative toxin B, suggesting that living cells were not necessary for exfoliative toxin B cleavage of desmoglein 1. Finally, in vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 with exfoliative toxin B demonstrated that both mouse and human desmoglein 1, but not desmoglein 3, were directly cleaved by exfoliative toxin B in a dose-dependent fashion. These findings demonstrate that exfoliative toxin A and exfoliative toxin B cause blister formation in staphylococcal scalded skin syndrome and bullous impetigo by identical molecular pathophysiologic mechanisms.

Treatment of port-wine stains with a noncoherent pulsed light source: a retrospective study.

We investigated whether a noncoherent intense pulsed light source (IPLS) would be effective in therapy of port-wine stains (PWSs). To evaluate the efficacy in treatment of PWSs with IPLS, a retrospective study was initiated. The data were collected by physicians working in private practices and departments of university hospitals and medical centers, respectively. A total of 37 randomly selected patients with a total of 40 PWSs were included in the study. Clinical PWS characteristics recorded were color and location of the PWS. All patients were treated with IPLS. Data collected included treatment parameter (filters, pulse duration, fluence, and pulse sequencing), percentage of clearance, and side effects (purpura, blisters, crusting, altered pigmentation, and scarring). Good and complete (70%-100%) clearance was achieved in 28 of 40 PWSs treated with IPLS. The average number of treatment sessions in PWSs reaching 100% clearance included 4.0 for pink PWSs and 1.5 for red PWSs. The average number of sessions for purple PWSs reaching good clearance (70%-99%) was 4.2 sessions. Parameters used most frequently were 515- and 550-nm cut-off filters, pulse duration of 2.5 to 5.0 milliseconds, and fluences of 24 to 60 J/cm2. Side effects included purpura in 133 (76%), superficial blisters in 14 (8%), and crusting in 35 (20%). Transient pigmentation changes were seen in 10.8% of patients (hypopigmentation in 3 [8.1%], hyperpigmentation in 1 [2.7%]). No scarring was observed. Intense pulsed light source presents an effective and safe method for treating PWSs, especially purple PWSs.

In this Issue

In this Issue

Spinal Anesthesia for Cesarean Section in a Case of Pemphigus Foliaceous

Spinal Anesthesia for Cesarean Section in a Case of Pemphigus Foliaceous

Ichthyosiform dermatosis with superficial blister formation and peeling: Evidence for a desmosomal anomaly and altered epidermal vitamin A metabolism

We describe a man with generalized congenital ichthyosiform dermatosis, severe cheilitis, and palmar and plantar hyperkeratosis with superficial blistering. Low-dose acitretin therapy induced areas of peeling skin, similar to that seen in the peeling skin syndrome. Histologically, the skin was moderately hyperkeratotic and the palmar blisters were subcorneal. Electron microscopy revealed that the splitting occurred within the desmosomal plaque. Ultrastructural and biochemical investigations indicated epidermal hypervitaminosis A, probably related to alteration of epidermal retinoic acid metabolism. This disease is proposed as a hitherto unreported variant of the peeling skin syndrome.

Staphylococcus aureus-induced blistering distal dactylitis in an adult immunosuppressed patient

Blistering distal dactylitis (BDD) is a superficial infection of the anterior fat pad of the distal portion of the finger. [-4 BDD has the distinctive clinical appearance of large tense superficial blisters on a tender, erythematous base. The blister may involve the distal and medial phalanges, extend to the dorsal nailfolds, and involve more than one finger. Two cases have been reported involving toes.f 5 BDD occurs most commonly between 2 and 16 years of age. Only three cases have been reported in adults. I, 6, 7 BDD is generally caused by group A ,a-hemolytic streptococci. However, in one instance group B streptococci caused BDD.6 In one study of 13 children with BDD, f3-hemolytic streptococci were cultured from the lesions of all children; in addition, three cultures grew hemolytic staphylococci. We report the first case of BDD in an adult immunocompromised patient from whom hemolytic Staphylococcus aureus was the only organism isolated.

Immunopathology of pemphigus

The term pemphigus refers to a group of cutaneous diseases that are characterized by the development of intra-epidermal blisters and, sometimes, mucosal erosions [l] (Table 1). All forms of pemphigus are characterized by epidermal cell-cell detachment (acantholysis) which leads to (intra-epidermal) vesicle formation, and by the presence of IgG autoantibodies directed against antigenic determinants present on the cell surfaces of differentiating keratinocytes [2]. The most severe form of pemphigus is pemphigus vulgaris (PV) (Figure l), which may occur at any age, although its most common onset is in the fourth, fifth and sixth decades. PV is characterized by the presence of flaccid, exceedingly fragiIe noninflammatory bullae which usually arise on normal appearing skin. These bullae have a tendency to coalesce and rupture easily resulting in large denuded areas which are, in fact, the predominant clinical feature of this type of pemphigus. PV involves both the skin and mucous membranes and, in virtually all cases, the initial lesion affects the oral mucosa. Prior to the introduction of corticosteroids in the 195Os, PV was considered almost uniformly fatal mainly due to protein, fluid and electrolyte losses and/ or uncontrollable sepsis. Acantholysis, the histological hallmark of PV, starts with the development of epidermal intercellular edema leading to dissolution of intercellular ‘bridges’ and widening of intercellular spaces (ICS), finally ending in cell to cell detachment. These microscopic changes occur in the suprabasilar area, i.e. between the basal and spinous cell layers. Basal cells remain attached to the dermis, but are laterally detached, resembling a ‘row of tombstones’ [ 11. Endemic pemphigus foliaceus (PF) or fogo selvagem (FS) (Figure 2) is clinically and immunopathologically similar to the non-endemic form seen in other parts of the world. Clinically, PF is characterized by superficial blistering and erosive lesions that affect the skin and rarely involve mucosal surfaces [3-61. Histologically, PF is characterized by acantholysis involving the subcorneal layers of the epidermis. In

Chapter 16 Immunologic skin diseases

Several immunologic skin disorders are of known importance to the clinical immunologist. Pemphigus vulgaris (PV) is a chronic bullous disease having flaccid vesicles and bullae with ulcerations that is associated with low mortality (5% to 10%). Pemphigus foliaceus (PF) has more superficial blisters rarely associated with slow desquamating ulcerating lesions. A subcategory, fogo selvagem (FS), is spread by an arthropod vector and is endemic to Brazil. Antigens to PV, PF, and FS are all unique. Bullous pemphigoid (BP) can present with tense bullae on the abdomen, groin, and flexural aspects of the extremities with rare mucous membrane involvement; these patients are usually elderly (>60 years). Remission occurs with therapy in most cases and no correlation is noted with antibody titers or immunofluorescent (IF) studies and severity of the disease. Brunsting-Perry pemphigoid is a very mild form of BP. Dermatitis herpetiformis (DH) has intensely pruritic lesions and symmetric vesicles located primarily on extensor surfaces, interscapular areas, and sacral areas, with subepidermal vesicles and adjacent abscesses in dermal papillae. DH is often associated with an HLA-B8/DRW3(DQ) haplotype and asymptomatic bowel disease, especially gluten-sensitive enteropathy. Chronic bullous dermatosis of childhood (CBD-CH) is a rare vesiculobullous disease of young children, with tense bullae in intertriginous and flexural areas causing extensive skin involvement and denudation with minimal symptoms. Epidermolysis bullosa aquisita (EBA) is clinically similar to BP and porphyria cutanea tarda, with lesions over the hands, feet, ears, and elbows induced by trauma. No therapy is known to be effective. Herpes gestationalis (HG) is a vesicular, bullous eruption of pregnancy occurring in approximately 1 / 10.000 to l/50,000 white births. The illness may recur, with an earlier onset with each subsequent pregnancy. Lesions are pruritic, urticarial (containing lymphocytes, histiocytes, and eosinophils), and bullous. Offspring may develop the disease. localization of the lesions, all of which contain imrnunoglobulin depositions, is important in distinguishing between them. lntraepidermal lesions are associated with PV, PF, and FS. Those exhibiting dermoepidermal junctional deposition include BP, DH, and CBD-CH. Subepidermal deposition (dermal side) is seen in EBA and HG. Antibodies to tissue components are noted in PV (antiepithelial antibodies) and PF. In the latter, antibody levels are not a useful guide to regulate therapy or as to prognosis. Autoimmune diseases are reported in association with PV (systemic lupus erythematosus and myasthenia gravis), PF (Senear-Usher syndrome), and EBA. Causative factors are not known, although drugs have been associated with PV (phenylbutazone, penicillamine, and rifampin) and BP. In DH, antireticulin, antithyroglobulin, and antimicrosomal and antinuclear antibodies are found. As noted, the vesiculobullous diseases primarily involve the skin, with the exception of cicatricial pemphigoid (CP), a clinical variation of BP that has primarily mucous membrane involvement. CP is not benign, as scarring of the oral cavity and conjunctival sac may occur. The immunopathology is the same in CP and BP. EBA may also have both skin and mucous membrane involvement. The pathophysiology of the vesiculobullous diseases consists of the deposition of immunoglobulins and complement in the skin. DH is associated primarily with activation of the alternate complement pathway. In CBD-CH, positive IF is associated with clearance of the clinical syndrome and indirect IF results are negative. In HG, HG factor is an IgG that deposits on the basement membrane zone (BMZ) fixing complement and giving positive indirect IF studies. The primary type of immunoglobulin involved in complement activation is important. IgG is associated with PV, PF, and BP; IgA is associated with PF, BP, DH (granular deposition), and CBD-CH (linear deposition), whereas IgM is also seen in PF and BP. Multiple immunoglobulins are involved in some. Therapy for all except EBA involves either systemic or topical steroids. No consistently effective therapy has been found for EBA. In HG, sulfones are used in early pregnancy, whereas systemic steroids and antihistamines are used in late pregnancy. In PV, immunosuppressants, such as azothiazine. methotrexate,

Superficial chest wall recurrences of breast cancer: prognostic treatment factors for combined radiation therapy and hyperthermia.

Forty-nine patients with chest wall recurrences of breast carcinoma received radiation therapy and 915-MHz microwave hyperthermia for 95 lesions. Follow-up ranged from 3 to 39 months, with five patients dying before 6 months follow-up. At 1 month follow-up, 49 (52%) of 95 lesions showed complete response; 28 (29%), partial response; and 18 (19%), no change. At 6 or more months follow-up, 54 (67%) of 81 lesions demonstrated local control; 10 (12%), partial response; six (7%), no change; and 11 (14%), local-regional recurrences. Superficial blisters occurred in 24 (25%) of 95 lesions, whereas long-term complications (deep necrosis, subcutaneous burns) occurred in seven (7%) lesions. Relapse occurred in 16 (17%) lesions, seven after initial complete response and nine after partial response. Several prognostic treatment factors were identified: applied radiation dose (greater than 30 Gy, P less than .01), size of tumor (less than 6 cm diameter, P less than .001), minimum tumor temperature (greater than 41 degrees C, P less than .001), and status of disease (M0 or M1 vs M2, P less than .001). Treatment complications were correlated with maximum temperatures (greater than 45 degrees C, P less than .001). In summary the palliative treatment concept proved to be safe and effective.

Ultrasound-induced hyperthermia for the treatment of human superficial tumors

Ultrasonic systems were developed for the treatment of superficial human tumors, generating local tumor hyperthermia at tumor center temperatures ranging from 43°to 50°. Twenty-eight patients with disease of varying histology were evaluable for response, and demonstrated an overall response rate of 57 % with a complete response rate of 18 %. In 11 patients who had received definitive radiation therapy to the heat treated area, the response rate was 81 %; there were no toxicities other than those noted for the overall study. As temperature was escalated a marked increase was observed both in response rates (from 53% (43–44°C) to 83% (48–50°C) and in duration of response (from 29 to 250 days for the same temperatures). Toxicities were minimal, consisting of superficial blistering in four patients and pain in six patients. Pain was usually associated with tumor involvement in the periostium.