Dermatologic birth defects and congenital skin disease.
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Alopecia Areata↗
Biomedical subjects
L A Goldsmith
Publications and source records attributed to L A Goldsmith.
Steatocystoma multiplex suppurativum: treatment with isotretinoin.
A patient with steatocystoma multiplex with multiple ruptured draining cysts and abscesses was treated with a twenty-week course of isotretinoin. Abscesses involuted and inflamed cysts shrank. The remission persisted for ten weeks after discontinuing therapy; subsequently cysts and abscesses occurred in multiple sites.
Adult↗
Recent advances in epidermal biology: relevance to epidermal malignancies.
Recent advances in the biology of the epidermis increase our understanding of skin cancer. Epidermal tissue culture demonstrates that cells from epidermal malignancies retain their malignant characteristics. Some epidermal tumors contain a low molecular weight keratin as a major structural protein; a low molecular weight keratin is a characteristic of fetal epidermis as well. Certain epidermal cell-surface antigens, such as the pemphigus antigen, may be absent in skin cancers. A population of long-lived skin cells may be the site for genetic alterations that eventually produces skin cancers. A population of basal "dark" cells is increased after treatment with tumor promoting agents such as phorbol esters. Two-stage (initiation, promotion) epidermal carcinogenesis can now be studied in tissue culture. Several components of the complex multilayered basement membrane zone are produced by epidermal cells. Malignancies of epidermal cells may extend beyond the basement membrane zone by disordered synthesis of the zone or by producing enzymes including collagenases that alter the zone.
Animals↗
Monoclonal antibodies to anchoring fibrils for the diagnosis of epidermolysis bullosa.
Murine monoclonal antibodies to human anchoring fibrils reacted with human and monkey cervix, tongue, esophagus, and vagina. Rat, mouse, and guinea pig tissues were negative. In 11 patients with dystrophic recessive epidermolysis bullosa there was no reaction by immunofluorescence and immunoelectron microscopy. Other forms of epidermolysis bullosa had normal reactivity.
Animals↗
Antizyme release is an early event in ornithine decarboxylase induction by hair plucking.
Plucking of hair from the dorsal skin of rats resulted in a rapid decrease in ornithine decarboxylase (ODC) activity. A significant loss of activity did not occur in other skin enzymes under the same conditions and in vivo incorporation of [3H]-leucine in skin was not significantly decreased 60 min immediately following hair plucking. Treatment of ODC enzyme preparations with 10% (NH4)2SO4 resulted in recovery of approximately 75% greater ODC activity than in untreated samples, suggesting the presence of an inhibitor (antizyme). ODC inhibitor was detected in plucked skin; inhibitor levels increased after treatment of plucked skin extracts with 10% (NH4)2SO4.
Animals↗
Tyrosinemia II: lessons in molecular pathophysiology.
Tyrosinemia II is caused by a deficiency of hepatic tyrosine aminotransferase. With the deficiency of this key enzyme of tyrosine catabolism there is an increase in plasma tyrosine and then an increase in tyrosine metabolites in the urine. The increased plasma tyrosine causes tyrosine to crystallize in the cornea, producing corneal ulcerations and sometimes proliferation of corneal epithelium. In the epidermis of the palms and soles, tyrosine leads to erosions, crusting, and then hyperkeratosis. The human disease is due to an autosomal recessive gene, and similar genetic diseases have been found in mink and in dogs. A nutritional model for the disease, in which a high-tyrosine low-protein diet is fed to rats, produces almost identical features. The features of this disorder and some of the implications of this disease for the study of other genetic diseases is discussed in this review.
Adolescent↗
Monoclonal antibodies to normal and abnormal epithelial antigens.
Mouse monoclonal antibodies to various human epidermal and basement membrane components were formed by immunizing Balb/c mice with ME-180, a line of human cervical carcinoma cells. The spleen cells from hyperimmunized mice were fused with a nonsecreting mouse myeloma cell line using polyethylene glycol. The resulting hybrids were selected by growth in media containing 20% fetal calf serum, hypoxanthine, thymidine, and methotrexate in RPMI-1640 in 24-well Linbro plates. Wells producing antibodies of interest were grown and eventually cloned over an HGPRT- rat fibroblast feeder layer. These cultures were expanded and recloned. Two cloned antibodies of interest are DUX 5.2 and DUX 1.1.3. DUX 5.2 is the mouse IgG1 subclass and reacts with the membranes of ME-180 cells and the human skin epidermal basement membrane zone as shown by direct immunofluorescent microscopy. Ultrastructural localization using electron microscopic immunoperoxidase techniques showed localization of the DUX 5.2 antigen to be beneath the lamina densa; the reaction product may include the anchoring fibrils. Although DUX 5.2 reacts with the normal human basement membrane zone and the basement membrane zone in several diseases, there is no reactivity in the normal, never-blistered skin of patients with dystrophic epidermolysis bullosa (DEB). This suggests that the increased collagenase in the disease may be destroying antigenicity of the antigen recognized by DUX 5.2 or that the antigen may not be present in DEB. This antibody will thus allow early neonatal and prenatal diagnosis in DEB and allow isolation of the structural moiety which is deficient in DEB. DUX 1.1 is an IgM mouse immunoglobulin specific for the cytoplasm of human basal cells. Its reactivity with upper epidermis is significantly less than that seen in the basal layer. All cells of the basal layer stain uniformly. The slight amount of staining in upper cells probably represents dilution of antigen which is not synthesized beyond the basal layer. Basal cells of hair follicles and sweat glands are stained to some degree.
Animals↗
Human epidermal transglutaminase.
Epidermal transglutaminase and its structural consequences were first described by studies of the Massachusetts General Hospital dermatology research laboratories in the early 1970s. The enzyme catalyzes an irreversible and necessary step in epidermal terminal differentiation. These features of the process catalyzed by the enzyme have generated great interest in the control mechanisms for enzyme activity. Like all transglutaminases, the human epidermal enzyme has strict requirements for calcium (or strontium) and for a free sulfhydryl group. It is similar to liver transglutaminase in not requiring proteolytic activation; plasma transglutaminase (factor XIII) requires proteolytic activation. Antibodies produced to human epidermal transglutaminases showed high species specificity and no cross-reaction with the human hair follicle transglutaminase. Purified human epidermal transglutaminase has several-fold increases in its activity after treatment with organic solvents, including dimethylsulfoxide, heating in the presence of calcium, and treatment with chaotropic reagents, such as NaSCN or NaI. The enzyme with enhanced activity has altered gel-filtration characteristics, although it exhibits no major molecular weight changes by SDS-electrophoresis or major immunologic differences with the conventional antibodies for human epidermal transglutaminases. A series of monoclonal antibodies to human epidermal transglutaminase is being prepared to allow detailed analysis of its structural activation and detection of common antigenic sites among transglutaminase that may be masked or not present in conventional antibodies to the enzyme. The ability of solvents, simple chemicals, and drugs to alter the function of transglutaminase allows one to consider safe methods for in vivo modulation of the enzyme and consequent modulation of altered function in human epidermal diseases.
Acyltransferases↗
Congenital cystic microphthalmia and consequent anophthalmia in the rat: a study in abnormal ocular morphogenesis.
An otherwise normal adult Charles River rat (CD strain) was observed to have no recognizable eyes. Breeding and morphological studies were undertaken to determine the nature of the ocular defect, as well as its cause and pathogenesis. The anomaly was found to be inherited as an autosomal recessive trait with variable expressivity. It was characterized by unilateral or bilateral congenital microphthalmia with multiple associated ocular abnormalities including a neuroepithelial cyst, optic nerve aplasia, and cataract. In several elderly rats, no eye was found histologically in the orbit, suggesting reabsorption of malformed tissues as the basis of the anophthalmia. Study of the prenatal morphogenesis of the microphthalmia suggested that the primary disorder reflects a disturbance of the neuroepithelium of the retinal anlage and results in defective early formation of the optic cup. The abnormalities in other ocular structures, particularly in the lens, are considered secondary. This ocular malformation emphasizes the early interactions and interdependence of the lens and retina in normal morphogenesis and provides an animal model for study of lens-retinal relationships in abnormal morphogenesis. It is particularly relevant in understanding the pathogenesis of microphthalmia with cysts in the human eye.
Animals↗
Pityriasis rubra pilaris response to 13-cis-retinoic acid (isotretinoin).
Forty-five patients with pityriasis rubra pilaris were treated with oral 13-cis-retinoic acid (isotretinoin). There was marked improvement in the degree of erythema, in duration, and scaling noted within 4 weeks. Remission or maintained improvement persisted after stopping therapy in many of the patients. The drug is a significant addition to the therapeutic armamentarium in this difficult-to-treat disease.
Adolescent↗
The peeling skin syndrome.
A unique form of congenital ichthyosis in two unrelated patients is described and characterized histologically by separation of the epidermis between the stratum corneum and the stratum granulosum. The clinical history, genetics, serially performed skin biopsies, and biochemical studies are reviewed. This form of ichthyosis is different from previously described entities. Lifelong peeling of the general body epidermis, pruritus, short stature, easily removed anagen hairs, and the ability to easily mechanically separate stratum corneum from the rest of the epidermis characterize the syndrome. In two families with this disorder, autosomal recessive inheritance is suggested. A low plasma tryptophan level as present in two patients with this disease. This inherited disorder of the epidermis was first described in 1924 before the genetics and histology of ichthyosis were extensively studied and is a distinct genetic and clinical entity to be considered in unusual cases of ichthyosis.
Adult↗
Tyrosine aminotransferase deficiency in mink (Mustela vision): a model for human tyrosinemia II.
Mink pseudodistemper, a recessive disease associated with high blood tyrosine levels, is an animal analogue of the human inborn error of metabolism, tyrosinemia II. Affected mink and man have eye and skin lesions. Affected mink have no hepatic tyrosine aminotransferase (TAT) activity, as measured immunologically and biochemically. Hepatic mitochondrial aspartate aminotransferase is increased to 188% of control. This new genetic animal model of TAT deficiency should allow new studies of tyrosine metabolism.
Amino Acid Metabolism, Inborn Errors↗
Principles of genetics as applied to dermatologic diseases.
Skin diseases are frequently genetic in origin; knowing basic genetic principles allows the clinician to understand hundreds of diverse conditions. The structural basis of genetic disease is related to the multiple steps in DNA replication, messenger RNA (m-RNA) production and modification, protein synthesis, and the posttranslational modification of proteins. The multiple steps in these processes are reviewed. Metabolic processes are connected and interconnected by pathways and networks. The general principles of their control are discussed. The modes of inheritance and their distinguishing characteristics are emphasized, as are factors causing variability among those with the same genetic disease. Tables categorizing many genetic diseases are presented, as is a detailed guide to the literature relevant to modern dermatologic genetics.
DNA↗
Dilantin digital defects.
Diphenylhydantoin (phenytoin) is a widely used drug with multiple adverse effects, several of them cutaneous. Prenatal exposure to hydantoins may result in a spectrum of structural, developmental, and behavioral changes known as the fetal hydantoin syndrome (FHS). A patient with the dysmorphic characteristics of FHS had unusual hyperpigmentation of several fingernails, a finding which has not been described in other patients with FHS. We propose a mechanism for the dysmorphic action of phenytoin on the developing fetus, consonant with the known effects of hydantoins on collagen metabolism.
Abnormalities, Drug-Induced↗
Epidermal protein synthesis in newborn rat skin.
Protein synthesis in newborn rat epidermis was assessed by in vivo labeling of epidermal proteins with radioactive glycine and the isolation of neutral buffer, sodium-dodecylsulfates (SDS) dithiothreitol soluble proteins, and 0.1 M NaOH soluble protein fractions of the epidermis. There was an increase in the labeling of proteins in the buffer and SDS fractions for 5 h after injection and then no further increase at 19 h after injection. In the 0.1 M NaOH soluble proteins and the final pellet after these extractions there was a progressive increase in glycine incorporation up to 19 h after injection. SDS gel electrophoresis of the labeled proteins showed early synthesis and continued synthesis of proteins of 56,000 and 65,000 daltons corresponding to the main fibrous proteins (alpha-keratins) of the epidermis. At 19 h a new protein band of 45,000 daltons first appeared and was associated with a decrease in the labeling of very high molecular weight (or highly aggregated) proteins. This later protein is presumptively identified as keratohyalin. Free amino acid pools were associated with both the neutral buffer and SDS extractable fractions.
Amino Acids↗
Skin sulfhydryl oxidase. Purification and some properties.
A sulfhydryl-oxidizing enzyme has been found in skin of young rats and a method for purifying the enzyme over 600-fold has been developed. Enzymatic activity was assayed either by its ability to oxidize dithiothreitol of by measuring its ability to renature reductively denatured ribonuclease A. Skin sulfhydryl oxidase catalyzed the oxidation of various thiols: dithiothreitol, dithioerythritol, D-penicillamine, and L-cysteine. Glutathione and 2-mercaptoethanol were very poor substrates for the enzyme. The enzyme also reactivated reductively denatured ribonuclease A, with neither the presence of a thiol nor prior reduction of the enzyme being necessary. The molecular weight of the enzyme was estimated to be 66 000 +/- 2000, and the isoelectric point was determined to be at pH 4.65. Alkylating reagents alone had some inhibiting effect on skin sulfhydryl oxidase; when the enzyme was preincubated with thiols which were substrates, inhibition by alkylating reagents was greatly increased. After preincubation with dithiothreitol, treatment of the enzyme with alkylating reagents or N-ethylmaleimide caused significant inhibition; preincubation with a poor substrate, reduced glutathione, did not enhance inhibition by alkylating reagents or N-ethylmaleimide.
Animals↗
The effect of 13-cis retinoic acid on epidermal lysosomal hydrolase activity in Darier's disease and pityriasis rubra pilaris.
Five patients with Darier's disease and 6 patients with pityriasis rubra pilaris were treated with 13-cis-retinoic acid. Extracts of separated epidermis were assayed for extractable protein, lactic dehydrogenase, Cathepsin D, beta glucuronidase and neutral proteinase before beginning therapy and 2, 4 and 8 weeks after therapy had begun. The epidermal extracts from patients with pityriasis rubra pilaris before beginning therapy were similar to extracts from normal control patients. During the course of therapy with 13-cis-retinoic acid, protein extractability, lactic dehydrogenase and neutral proteinase did not change; there was a highly significant decrease in the specific activity of the lysosomal hydrolases Cathepsin D and beta glucuronidase. A similar but less dramatic fall was noted in the Darier's patients taking 13-cis-retinoic acid. Darier's patients also had a decrease in neutral proteinase activity before beginning therapy; the specific activity of this enzyme increased during the course of therapy. 13-cis-retinoic acid does not induce clinical remission by increasing the intracellular concentration of lysosomal enzymes in epidermis in vivo.
Darier Disease↗