A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa is a severe mutilating genodermatosis. Previous ultrastructural demonstrations of altered anchoring fibrils, and recent genetic linkage analyses have suggested that type VII collagen, the major component of anchoring fibrils, is a candidate gene. We have identified a homozygous methionine-to-lysine mutation in two affected siblings, while their unaffected mother and half-brother are heterozygous carriers. The mutation resides in a highly conserved region of the C-terminus of type VII collagen, strongly suggesting that it is the cause of the disease in this family.

Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.

In vitro studies in patients with hepatitis B virus (HBV) infection have suggested that hepatocytolysis induced by CD8+ cytotoxic T lymphocytes (CTLs) is the most important effector pathway in eliminating infected cells. The recognition is implicated in the endogenously processed HBV antigens in the context of HLA class I molecules presented on the liver cell membrane. However, the naturally occurring HBV peptide antigens have not yet been demonstrated. We report here that a naturally processed peptide antigen P2 was isolated from HLA class I molecules of HBV-infected liver cell membrane. The P2 peptide exhibited the activity of sensitizing target cells for lysis by CD8+ CTLs. The P2 sequence (YVNVNMGLK) purified from liver tissue was in concordance with that encoded by the viral genome for the HBV nucleocapsid antigen or HBcAg 88-96. P2 peptide could also be isolated from the EBV-transformed B cells that were transfected by HBcAg-expressing vector. The P2 epitope, sharing the HLA-A11 binding motifs, was recognized by HLA-A11-restricted CD8+ CTLs. The data provided direct evidence that, in hepatitis B patients, antigenic peptides of HBV were processed by hepatocytes, presented with the class I MHC molecules, and recognized by CD8+ CTLs.

Junctional epidermolysis bullosa keratinocytes in culture display adhesive, structural, and functional abnormalities.

An unusual, elongated, refractile cell morphology was observed in keratinocytes cultured from three patients with non-lethalis forms of junctional epidermolysis bullosa (JEB). To determine whether these changes might be related to altered cell adhesion, keratinocyte strains established from one patient were examined for adhesive, structural, and functional characteristics. JEB keratinocytes expressed keratin tonofilaments, as determined by staining with AE1 monoclonal antibodies and direct observation of tonofilaments by electron microscopy. JEB keratinocytes showed diminished cell-substratum adhesions, judged by interference reflection microscopy. Areas of diminished cell-substratum adhesion corresponded to F-actin-rich cell adhesions (focal adhesions) and not to cellular areas that abundantly express hemidesmosomal antigens. Analysis of cell-substratum adhesion by electron microscopy revealed extensive areas of cell-substratum separation in JEB keratinocytes that were not present in normal keratinocytes maintained in serum-free medium. Normal keratinocytes displayed numerous regions of focal contact between the ventral plasma membrane and the culture substratum, but these structures were not seen in JEB keratinocytes. Bundled actin filaments (stress fibers) were greatly diminished in expected regions of cell-substratum adhesion in JEB keratinocytes and, instead, displayed disorganized individual filaments. The growth rate of JEB keratinocytes was quite slow in culture, with a population doubling time of 2.7 d versus 1.5 d for normal keratinocytes under identical conditions. JEB keratinocytes also displayed a reduced ability to aggregate into colonies upon exposure to medium with increased extracellular calcium. JEB keratinocytes thus display adhesive, structural, and functional abnormalities that suggest this cell type may be central to the pathogenesis of junctional epidermolysis bullosa. Study of affected keratinocytes could be important to characterize associated molecular pathologies.

Abnormalities of plasma and erythrocyte essential fatty acid composition in epidermolysis bullosa: influence of treatment with diphenylhydantoin.

The fatty acid composition of plasma and erythrocyte phospholipids was determined in children with various subtypes of epidermolysis bullosa (EB) and in their parents. Patients with recessive dystrophic, dominant dystrophic, simplex, or junctional forms of EB had a higher percentage composition of arachidonic acid in plasma and/or erythrocyte phospholipids compared to age-matched controls. Epidermolysis bullosa patients treated with diphenylhydantoin had lower levels of arachidonic acid in plasma and erythrocyte phospholipids than did untreated EB patients. Parents of children with the recessive dystrophic or junctional EB subtypes had higher linoleic and arachidonic acids in plasma and erythrocyte phospholipids than did controls. Plasma and erythrocyte total lipids were within the normal range in children with EB. Plasma zinc was also normal but plasma copper was elevated in children with recessive dystrophic EB. We conclude that higher arachidonic acid in plasma and erythrocytes may be related to the pathology of EB.

Gastrointestinal manifestations of epidermolysis bullosa. A study of 101 patients.

One hundred one patients with EB were evaluated by a combination of prospective and retrospective review, and analyzed regarding the nature, incidence, and prevalence of their gastrointestinal (GI) manifestations. Involvement of the GI tract is a well-known extracutaneous manifestation of dystrophic EB, but it also occurred in more than one-half and one-third, respectively, of those with junctional and simplex EB. Most of the serious consequences, such as esophageal strictures and microstomia, occurred in recessive dystrophic EB but were also seen, although infrequently, in the junctional and simplex forms. The majority of patients with dysphagia had an esophageal stricture, and the cervical esophagus was the most common location. The onset of dysphagia generally occurred in the first decade of life, in patients much younger than previously recognized. Diagnostic endoscopy did not reveal lesions which could not have been detected radiographically. Lower GI complaints were common, especially constipation and perianal blistering, and affected all types of EB. These complaints contributed substantially to management problems but they did not correlate with colonic pathology and appeared to reflect anal or perianal disease.

Wound healing and epidermolysis bullosa.

Wound healing is reviewed in the context of the unique problems of the chronic ulcerating skin lesions associated with epidermolysis bullosa. Management approaches, including treatment of erosions with epidermal autografts, are considered.

Management of patients with epidermolysis bullosa.

Epidermolysis bullosa is a group of systemic disorders whose management requires familiarity with its many extracutaneous complications. These include gastrointestinal, ophthalmologic, laryngeal, dental, and hematologic problems. This article reviews wound care and management of systemic complications seen in patients with epidermolysis bullosa.

Skin cancer in the elderly.

This article discusses the relation between aging and development of nonmelanoma skin cancer. Possible age-related risk factors for development of such cancers are cumulative exposure to ultraviolet irradiation from the sun, decreased DNA repair capacity, decreased immunosurveillance, reduced melanocyte density, and altered dermal matrix. Clinical features of basal-cell carcinoma, squamous-cell carcinoma, and keratoacanthoma are discussed.

Nonmelanoma skin cancers in the elderly.

This article discusses the relationship between aging and development of nonmelanoma skin cancer. Possible age-related risk factors for development of such cancers are cumulative exposure to ultraviolet irradiation from the sun, decreased DNA repair capacity, decreased immunosurveillance, reduced melanocyte density, and altered dermal matrix. Clinical features of basal-cell carcinoma, squamous-cell carcinoma, and keratoacanthoma are discussed.

Junctional epidermolysis bullosa of the larynx. Report of a case and literature review.

Epidermolysis bullosa (EB) is a group of rare inherited disorders in which minor trauma causes blister formation in the skin and mucosa, including the esophagus. Morbidity varies with the type of disease and ranges from occasional trivial skin blisters to death in infancy. Laryngeal involvement presenting as hoarseness and respiratory distress has been reported in nine patients, five of whom had junctional EB. We present the sixth case of junctional EB with laryngeal involvement, and offer guidelines for otolaryngologists and anesthesiologists caring for these fragile patients.

Familial lichen planus.

We observed the simultaneous occurrence of generalized lichen planus in a woman and her mother. Both patients improved after therapy with topical steroid and salicylic acid ointment. Of the eighty-one cases of familial lichen planus previously reported, the vast majority (89 percent) occurred in blood relatives. The intervals of onset between familial cases were long, ranging from six weeks to thirty years (mean 73.4 months). These observations suggest that familial lichen planus may result from genetic predisposition, rather than from an infectious cause.

Wound management in patients with epidermolysis bullosa.

An examination of the treatment options available - including dressings and antimicrobial therapy - for patients with this condition.

Epidermolysis bullosa: practical management and clinical update.

Epidermolysis bullosa (EB) is a heterogeneous group of rare, heritable disorders characterized by marked fragility of the skin and mucosa. Patients require a specialized program of wound care and timely intervention to treat the many systemic complications, some of which are potentially life-threatening.

Epidermolysis bullosa.

Epidermolysis bullosa is a group of genetically determined diseases characterized by abnormal fragility of the skin and mucosa. In this chapter, we review current thinking about classification, pathogenesis, and molecular genetics, and we discuss management guidelines.

Onycholysis and thyroid disease: report of three cases.

BACKGROUND: Onycholysis is a common disorder with many causes. It is known to be associated with thyroid disease (especially hyperthyroidism), but physicians probably do not routinely screen for underlying thyroid disease. OBJECTIVE: To study the association of onycholysis and thyroid disease. METHODS: We report three patients with onycholysis who were investigated for thyroid disease. RESULTS: In two patients, onycholysis was the presenting sign of previously undiagnosed hypothyroidism, whereas the third developed onycholysis while undergoing therapy for hypothyroidism. CONCLUSIONS: These three cases appear to suggest that patients with unexplained onycholysis should be screened for asymptomatic thyroid disease.

Location of the redox-active thiols of ribonucleotide reductase: sequence similarity between the Escherichia coli and Lactobacillus leichmannii enzymes.

The redox-active thiols of Escherichia coli ribonucleoside diphosphate reductase and of Lactobacillus leichmannii ribonucleoside triphosphate reductase have been located by a procedure involving (1) prereduction of enzyme with dithiothreitol, (2) specific oxidation of the redox-active thiols by treatment with substrate in the absence of exogenous reductant, (3) alkylation of other thiols with iodoacetamide, and (4) reduction of the disulfides with dithiothreitol and alkylation with [1-14C]iodoacetamide. The dithiothreitol-reduced E. coli B1 subunit is able to convert 3 equiv of CDP to dCDP and is labeled with 5.4 equiv of 14C. Sequencing of tryptic peptides shows that 2.8 equiv of 14C is on cysteines-752 and -757 at the C-terminus of B1, while 1.0-1.5 equiv of 14C is on cysteines-222 and -227. It thus appears that two sets of redox-active dithiols are involved in substrate reduction. The L. leichmannii reductase is able to convert 1.1 equiv of CTP to dCTP and is labeled with 2.1 equiv of 14C. Sequencing of tryptic peptides shows that 1.4 equiv of 14C is located on the two cysteines of C-E-G-G-A-C-P-I-K. This peptide shows remarkable and unexpected similarity to the thiol-containing region of the C-terminal peptide of E. coli B1, C-E-S-G-A-C-K-I.

Sulfur revisited.

Sulfur is a time-honored therapeutic agent useful in a variety of dermatologic disorders. Its keratolytic action is due to formation of hydrogen sulfide through a reaction that depends upon direct interaction between sulfur particles and keratinocytes. The smaller the particle size, the greater the degree of such interaction and the greater the therapeutic efficacy. When applied topically, sulfur induces various histologic changes, including hyperkeratosis, acanthosis, and dilatation of dermal vasculature. One study showed that sulfur was comedogenic when applied onto human and rabbit skin, findings that were not reproduced in other studies. About 1% of topically applied sulfur is systemically absorbed. Adverse effects from topically applied sulfur are uncommon and are mainly limited to the skin. In infants, however, fatal outcome after extensive application has been reported.