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Biomedical subjects

K A Holbrook

Publications and source records attributed to K A Holbrook.

At least 19 recordsLinked to original sources
PubMed1992

Restrictive dermopathy. Report of two affected siblings and a review of the literature.

BACKGROUND: Restrictive dermopathy is a lethal genetic disorder consisting of abnormally tight skin, generalized joint contractures, distinctive facies, and pulmonary hypoplasia. Autosomal recessive inheritance has been suggested based on multiply affected siblings and some reports of parental consanguinity. This article describes two siblings with the restrictive dermopathy syndrome and reviews previously reported cases. OBSERVATIONS: Eight other cases have been reported in the literature as restrictive dermopathy. These cases have shared striking similarities in their clinical histories and phenotypes. The skin in these infants has been described as rigid and tense, with skin biopsy specimens showing a thick epidermis, thin dermis, abnormally arranged collagen bundles, and poorly developed appendages. Other prominent features are flexion contractures and craniofacial and pulmonary abnormalities. The genetic and/or developmental defects leading to the restrictive dermopathy syndrome are presently not known. CONCLUSIONS: The restrictive dermopathy syndrome is distinct and is easily differentiated from other congenital diseases such as the icthyoses and also from the clinical conditions of sclerema neonatorum and subcutaneous fat necrosis of the newborn. Recognition of this syndrome is important for determining the prognosis of affected infants and for recommending genetic counseling to affected families.

Contracture↗
PubMed1992

Diagnosis and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling-Meara) in a mother, two affected children, and an affected fetus.

In utero skin biopsy was performed on a fetus at risk of an uncertain form of epidermolysis bullosa (EB). The mother had produced two affected offspring diagnosed variously as having junctional or dystrophic EB. The two offspring and the fetus were products of different fathers. The mother claimed to have no disease and on clinical examination was without blisters. Examination of the fetal skin biopsy by light and electron microscopy revealed separation of the epidermal sheet from the majority of the biopsy sample, although occasional remnants of basal cells remained associated with the basement membrane. Aggregations of keratin filaments were observed within basal cells of the detached epidermis and in the attached basal cell remnants. The diagnosis was thus suggested to be epidermolysis bullosa Dowling-Meara. Re-review of the clinical and laboratory data from the affected infants revealed a clinical and histological pattern consistent with this diagnosis. Further discussion with the mother revealed that her skin had blistered as a child and that she presently had hyperkeratotic palms and soles. This history is consistent with the autosomal dominantly inherited epidermolysis bullosa herpetiformis (Dowling-Meara). This is the first reported prenatal diagnosis of EB Dowling-Meara. The morphological criteria of intraepidermal blistering and clumped keratin filaments within basal and immediately suprabasal cells characteristic of an affected individual postnatally also identified an affected fetus. There is, however, insufficient experience to be certain that these findings will hold from region to region in the body or among all affected fetuses, and thus prenatal diagnosis on a morphological basis should still be made with caution.

Adult↗
PubMed1992

CHILD syndrome: lack of expression of epidermal differentiation markers in lesional ichthyotic skin.

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare genetic disorder. The epidermal abnormalities associated with the unilateral ichthyosis have previously been examined only by morphology. In order to describe these abnormalities more completely we analyzed the expression of markers of epidermal differentiation (keratins and filaggrin), grew keratinocytes in culture, and correlated the results with ultrastructural features. Expression of all differentiation markers was significantly reduced or absent, whereas keratins K5 and K14 and keratins K6 and K16 were strongly expressed in lesional epidermis, suggesting that basal cell keratin expression was not down-regulated as in normal epidermis and that lesional keratinocytes mature via an abnormal pathway. When removed from the tissue and grown in culture, keratinocytes from lesional and non-lesional biopsies had similar phase microscopic morphology as well as keratin and profilaggrin expression, in contrast to the extreme differences in vivo. Lesional keratinocytes also had similar contents of keratin filaments and keratohyalin, but showed abnormal accumulation of intercellular vesicles and debris and altered cell-cell and cell-substratum interaction. Comparison of the results in tissue and in culture suggests that systemic or dermal factors influence the abnormal structural protein expression and ichthyosiform epidermal differentiation seen in CHILD syndrome, but that lesional keratinocytes maintain abnormalities in the secretion and accumulation of extracellular material in vitro similar to the lesional tissue in vivo.

Abnormalities, Multiple↗
PubMed1992

Abnormal lamellar granules in harlequin ichthyosis.

Lamellar granules are specialized lipid-rich organelles present in epidermal granular cells. They fuse with the apical cell surface and discharge their contents into the intercellular space forming lamellar sheets. It was previously shown by electron microscopy that lamellar granules in biopsies of infants affected with harlequin ichthyosis are either absent or abnormal and no intercellular lamellae could be detected. A monoclonal antibody (AE17) directed against a protein component of lamellar granules was used for immunoblotting and immunohistochemical studies as an indication of both the presence and function of lamellar granules. Epidermal extracts from all harlequin and normal specimens tested showed an immunoreactive protein of 25-28 kD. Immunohistochemical staining of normal skin using AE17 showed apical cytoplasmic staining in the granular layer and intercellular staining between the granular and stratum corneum cells. Harlequin samples showed variable degrees of staining ranging from little to heavy apical cytoplasmic staining of granular cells. No intercellular staining was detected. The immunohistochemical staining pattern correlated with the electron microscopic localization of abnormal vesicles and the absence of intercellular lamellae in the affected samples. We conclude that the vesicles represent lamellar granules that contain the AE17 antigen but are structurally abnormal and defective in their ability to discharge both their lipid and protein contents into the intercellular space. We suggest that this defect in the lamellar granules represents the underlying basis for stratum corneum cell retention and subsequent accumulation of scale in harlequin ichthyosis.

Adult↗
PubMed1992

Separation of noncutaneous epithelia in a fetus diagnosed in utero with junctional epidermolysis bullosa.

This study was undertaken to identify the extent of involvement of cutaneous and noncutaneous epithelia during expression in utero of junctional epidermolysis bullosa. Skin and other organs from a 19-wk estimated gestational age fetus affected with junctional epidermolysis bullosa and from age-matched controls were examined by light and transmission electron microscopy. In the affected fetus, skin samples from different body regions including trunk, leg, arm, and finger all showed some separation at the dermal-epidermal junction in the plane of the lamina lucida. Hemidesmosomes were absent or hypoplastic, whereas anchoring fibrils appeared normal in structure and number. Interfollicular epidermis appeared to have separated easily, whereas some follicles remained anchored in the dermis. Areas of epithelium in the trachea and bronchi had separated, but within the lung parenchyma the epithelium of smaller bronchioles and alveoli remained attached to supporting connective tissue. The transitional epithelium of the urinary bladder showed small areas of separation compared with the gall bladder epithelium, which showed extensive separation. Gall bladder epithelium in several control fetuses also was consistently separated. In the affected fetus as well as in controls, gall bladder had multiple layers of basal lamina, a previously unrecognized structural feature of human fetal gall bladder. Epithelia that remained intact included the linings of the stomach and small and large intestines and endothelium of large and small vessels in all organs. Kidney, spleen, liver, and lymph nodes appeared normal in all aspects. In control samples, neither skin nor most of the noncutaneous epithelia had separated from the underlying connective tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Prenatal diagnosis of severe dermatologic diseases.

It is obvious that the nature of prenatal diagnosis of severe or lethal skin conditions is rapidly evolving. New molecular, enzymatic, and ultrastructural markers will become available. The biochemical base of many of these disorders will become known and the accuracy and utility of in utero diagnosis will improve. We wish to make one point again. The field is rapidly outpacing the ability of review articles to keep current. We urge you to refer to a genetic center for information when you are dealing with a situation in which prenatal diagnosis may be an issue.

Amniocentesis↗
PubMed1991

Alpha-fetoprotein and acetylcholinesterase are not predictive of fetal junctional epidermolysis bullosa, Herlitz variant.

Junctional epidermolysis bullosa, Herlitz variant (junctional EB-Herlitz) is a lethal autosomal recessive skin disorder currently amenable to prenatal diagnosis only by direct analysis of fetal skin. However, elevated levels of alpha-fetoprotein, as well as the presence of acetylcholinesterase in amniotic fluid, have been associated with other severe fetal genodermatoses. Fetal skin samplings were performed in ten pregnancies at risk for fetal junctional EB-Herlitz, with three fetuses affected on the basis of electron microscopic detection of blisters within the lamina lucida and abnormal hemidesmosomes. In neither affected nor unaffected pregnancies were maternal serum or amniotic fluid alpha-fetoprotein levels elevated. Moreover, alpha-fetoprotein levels in both maternal serum and amniotic fluid were not statistically different comparing affected and unaffected fetuses. Acetylcholinesterase was not present in the amniotic fluid samples of the three affected pregnancies. Unlike other severe fetal genodermatoses, neither alpha-fetoprotein nor acetylcholinesterase was predictive of junctional EB-Herlitz.

Acetylcholinesterase↗
PubMed1991

Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry.

Inherited epidermolysis bullosa encompasses a number of diseases, with the common finding of blister formation after minor mechanical trauma to the skin. In some forms significant, if not eventually fatal, extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently, many new phenotypes have been recognized, in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately, this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.

Epidermolysis Bullosa↗
PubMed1990

Applicability of 19-DEJ-1 monoclonal antibody for the prenatal diagnosis or exclusion of junctional epidermolysis bullosa.

Recently a monoclonal antibody (19-DEJ-1) was produced with binding specificity for the mid-lamina lucida of the skin dermo-epidermal junction, in very close association with overlying hemidesmosomes. Since skin cleavage occurs within the lamina lucida in the inherited blistering disorder, junctional epidermolysis bullosa (EB), and is associated with aberrations in the morphology and/or number of hemidesmosomes in such tissue, we have sought to determine whether this monoclonal antibody could be used for prenatal diagnosis. Fetoscopy-directed skin biopsies were obtained from two fetuses at risk for junctional EB and post-mortem samples from two other fetuses with the Herlitz type of junctional EB, the latter after prenatal diagnosis by electron microscopy and termination of each pregnancy. Specimens were examined in part by light and electron microscopy for evidence of skin cleavage or other alterations in morphology, and in part by indirect immunofluorescence for altered basement membrane antigenicity. Three of four fetuses were shown to have intra-lamina lucida blister formation indicative of, and hemidesmosome hypoplasia proving, junctional EB. Each was also shown to lack expression of GB3 and 19-DEJ-1 antigens, consistent with findings noted postnatally in junctional EB; diagnosis was confirmed in each at the time of therapeutic abortion. A fourth fetus had no abnormalities detected; lack of disease involvement was confirmed at the time of delivery, and subsequently over 8 months of careful serial evaluation. We conclude that 19-DEJ-1 monoclonal antibody is an accurate and sensitive immunohistochemical probe for junctional EB, and may be employed in the prenatal diagnostic evaluation of fetuses at risk for this disorder.

Antibodies, Monoclonal↗
PubMed1990

Postinflammatory elastolysis and cutis laxa. A case report.

One of the rarest forms of cutis laxa is postinflammatory elastolysis and cutis laxa, a disease previously reported only in children in Africa and South America. This disease is characterized by an urticarial or papular eruption followed by acute destruction of elastic tissue that results in atrophy and severe disfigurement. It is distinguished from anetoderma and acquired cutis laxa by its clinical features, its occurrence in young children, and its relatively benign course. This article describes the first case of postinflammatory elastolysis and cutis laxa reported in a white child from North America.

Atrophy↗
PubMed1990

Heterogeneity in harlequin ichthyosis, an inborn error of epidermal keratinization: variable morphology and structural protein expression and a defect in lamellar granules.

Skin biopsies and scale samples from nine infants and one fetus affected with harlequin ichthyosis (HI) were obtained from eight families. Epidermal differentiation was examined by morphologic and biochemical criteria and cell culture studies. Two striking abnormalities were identified; first, keratin and filaggrin expression were abnormal and varied between cases, and, second, in all cases lamellar granules were absent or abnormal, and intercellular lamellae within the stratum corneum were absent. Three HI phenotypes were distinguished by variable expression of epidermal structural proteins. Cases were classified by the absence (type 1) or presence (types 2 and 3) of keratins K6 and K16 ("hyperproliferative" keratins) and by the presence of profilaggrin in the interfollicular epidermis (types 1 and 2 only). Profilaggrin is apparently not converted to filaggrin, but it is retained in the scale. The block in profilaggrin processing may be due to an inactive phosphatase. Siblings in two families (presenting with types 1 and 2) showed the same type classification suggesting that expression of the phenotype is consistent within families but differs between families. Cultured HI keratinocytes were normal by phase microscopy, but abnormal by electron microscopy with no lamellar granules and extensive stacking of the upper layers. We conclude that harlequin ichthyosis is a genetically heterogeneous group of disorders with altered lamellar granules, intercellular lipids, and variation in expression and/or processing of structural protein markers of normal epidermal keratinization. Furthermore, the lamellar granule and structural protein defects may be indirectly related via a mechanism involving phosphorylation/dephosphorylation.

Biopsy↗
PubMed1990

Immunolocalization of epidermal growth factor receptors in normal developing human skin.

The embryogenesis of normal human skin is a complex process involving multiple cell types and developmentally regulated growth factors. The immunohistochemical localization of epidermal growth factor receptors (EGF-R) was studied in human fetal skin because this receptor modulates all known actions of EGF and TGF-alpha. EGF-R are present in developing skin as early as the 42nd day of gestation. Immunoreactive EGF-R are present in keratinocytes, endothelial, and skeletal muscle cells. In contrast to normal adult human skin in which the EGF-R are primarily restricted to the basal and immediately suprabasal keratinocytes, the fetal epidermis showed a persistent expression of EGF-R in all cell layers. The absence of EGF-R on the outer, apical surface of periderm cells that are exposed to amniotic fluid was unexpected and may reflect down-regulation of EGF-R by EGF/TGF-alpha or related fetal growth factors present in amniotic fluid. The complex regulation of EGF-R in embryonic hair follicles and sebaceous glands indicates an active and perhaps regulatory role for EGF/TGF-alpha in the development and function of pilosebaceous glands as well as mammalian skin in general.

Embryo, Mammalian↗
PubMed1989

Ontogeny of Langerhans cells in human embryonic and fetal skin: cell densities and phenotypic expression relative to epidermal growth.

Langerhans cells (LCs) positive for HLA-DR antigens were present in developing human epidermis by at least 7 weeks estimated gestational age (EGA). Most were negative for CD1 (T6) until 12-13 weeks EGA when they underwent a dramatic increase in CD1 reactivity. To gain insight into the density of LCs during ontogeny and to assess whether their distribution was coordinated with epidermal growth, the number of cells positive for both HLA-DR and CD1 antigens was determined relative to surface area and to volume of developing, interfollicular epidermis. LCs differed in their phenotype, distribution (follicular vs. interfollicular), size, and shape between 7 and 21 weeks EGA; however, during this period they maintained a statistically equivalent (P greater than .25) density (65 cells/mm2 and 1,750/mm3) even though the epidermis increased in thickness and the fetus rapidly expanded its surface area. While LCs were evenly distributed within the epidermal sheets at all gestational ages, those in embryonic skin were much smaller and less dendritic than the older cells. The density, size, and shape of LCs in developing skin seemed to be independent of epidermal status (e.g., thickness of keratinization, and number of cell layers) but rather were correlated with gestational age. The number of fetal LCs, through at least 23 weeks EGA, was only 10-20% of the adult LC density. Thus, we can conclude that the increase in LC density to adult levels must occur either during the third trimester or after birth.

Cell Aggregation↗
PubMed1989

Skin is a window on heritable disorders of connective tissue.

A skin biopsy contains the macromolecules present in most connective tissues: collagens, elastin, glycoproteins, and proteoglycans. The specific combination and assembly of these matrix components and their interactions with other structures (e.g., epidermal appendages, nerve and vascular networks) and cells are responsible for the distinction among specific regions of the dermis. The matrix components are interactive and interdependent and modification of one of them, by extrinsic (environmental) and/or intrinsic (systemic, genetic, age-related) factors, may have consequences on the tissue as a whole. The skin, therefore, provides a window through which it is possible to examine how mutations in one connective tissue macromolecule can change the interactions among matrix components and affect tissue structure and organization. Light and electron microscopic studies of skin from patients with inherited connective tissue disorders (e.g., Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, cutis laxa) have led us to the following generalizations about what components change, how individual collagen or elastic fibers are altered and how individual alterations affect overall dermal organization: 1) There is a limited change in the repertoire of collagen fibrils in the skin; 2) there appears to be a greater range of abnormal structure in dermal elastic fibers than in the collagen fibrils; 3) the morphology of the fibroblastic cells may provide clues to the defect in matrix components; 4) similar structural abnormalities result from different molecular defect; 5) a molecular defect in one connective tissue molecule has consequences for the structural properties of other connective tissue components; and 6) although structural alterations in connective tissue fibers are rarely specific for a given disease, there are characteristic patterns of structural change in the matrix that may be used to confirm a diagnosis. These generalizations show that mutations rarely affect only a single aspect of macromolecular function and because of the interactions of matrix components in this complex organ (skin) often disturb the organization of the entire dermis. Genotype-phenotype relationships are important to understand if effective therapies are to be designed. The structure of skin should provide the next level of integration in our efforts to determine how mutations produce disease.

Collagen↗
PubMed1989

Embedding prolene for the development of fiducial markers.

A simple, inexpensive method is described for embedding Prolene with tissue samples to provide landmarks for fiducial points to align serial sections in tissue reconstructions. Prolene is a monofilament suture material that can be easily sectioned with diamond knives to provide circular markers in each section. The sections are photographed, the negatives are projected through an enlarger and the contours, Prolene circles, and scratches from the diamond knife are traced onto paper. These landmarks establish a framework for assigning fiducial points that are necessary for the correct alignment of the contours. No special equipment is needed for embedding the Prolene and the method is adaptable for both automated and nonautomated computer systems. An example of this method for tissue alignment is given using embryonic limb tissue to determine the spatial organization of developing blood vessels as demonstrated by computer reconstruction.

Blood Vessels↗
PubMed1989

The appearance, density and distribution of melanocytes in human embryonic and fetal skin revealed by the anti-melanoma monoclonal antibody, HMB-45.

The presence, densities, and patterns of distribution of melanocytes in the epidermis of human embryos and fetuses, ranging in age from 40 d to 140 d estimated gestational age (EGA), were studied using the HMB-45 monoclonal antibody that recognizes an antigen in melanoma cells and fetal melanocytes. Immunostained sections of skin and epidermal sheets revealed dendritic melanocytes within the basal or intermediate layers of 50 d EGA and older skin. Melanocytes could not be identified by immunostaining or electron microscopy in younger (40-50 d EGA) epidermis or in cultured epidermal cells from these specimens. However, skin from a 45 d EGA embryo grown in organ culture for 11 d stained positively with HMB-45, suggesting that melanocytes are present at the age either in the epidermis or dermis of the explant. Double-labeling experiments using ATPase and HMB-45 confirmed the specificity of HMB-45 for melanocytes and demonstrated that melanocytes and Langerhans cells are nonoverlapping populations. Melanocytes were present in the embryonic epidermis in relatively high numbers (mean value of approximately 1050 cells/mm2); they increased in density to approximately 2300 cells/mm2 during the late first trimester and early second trimester, then declined during later stages of development to a density of approximately 800 cells/mm2, within the range of values for the newborn child and young adult. Equivalent numbers of melanocytes were recognized by silver staining and with the HMB-45 antibody in an 87 d EGA test sample, indicating that HMB-45 reacted with the total melanocytic population. Melanocytes appeared to be distributed in epidermal sheets in a regular pattern. Statistical tests used to evaluate the randomness of a population revealed a tendency toward a non-random distribution in specimens younger than 80 d EGA, just prior to appendage formation and epidermal stratification into multiple layers, however there was variability in the degree of randomness for any given age. The results of this study have closed the gap in timing between the conclusion of neural crest formation and migration (around 6 weeks) and the appearance of melanocytes in the skin between 40-50 d EGA.

Antibodies, Monoclonal↗