bromochloroacetic-acid and Ichthyosis--Lamellar

Molecular genetic analyses during the past half-decade have brought unexpected insights into the molecular defects underlying a wide variety of abnormal skin phenotypes. Highlights of the efforts in the past year include the identification of mutations in an epidermal transglutaminase gene in lamellar ichthyosis as well as mutations in an additional five keratin genes causing four different abnormal phenotypes, and mutations in beta 4 integrin and bullous pemphigoid antigen 2 genes in junctional epidermolysis bullosa and in the p16NK-4a gene in 50% of kindreds with familial melanoma.

Topics: Epidermolysis Bullosa, Junctional; Humans; Ichthyosis, Lamellar; Keratins; Melanoma; Skin Diseases; Skin Neoplasms

Topics: Animals; Cell Differentiation; Cell Membrane; Humans; Ichthyosis; Ichthyosis, Lamellar; Intermediate Filaments; Keratinocytes; Keratins; Lipid Metabolism; Mutation; Transglutaminases

Harlequin ichthyosis is an inherited skin disorder that usually results in death shortly after birth. Although the clinical features of this disorder are well described, the underlying molecular basis is not understood. In this article, we discuss the results of the latest histologic, immunochemical, and Western immunoblotting studies done in our laboratory and propose a hypothesis for molecular basis of this disorder.. Previous experiments done in our laboratory show suggestive evidence for defective lipid synthesis and protein dephosphorylation in harlequin ichthyosis. Our latest study shows that the catalytic subunit of one of the most prevalent protein phosphatase, type 2A protein phosphatase, appears to be altered in some cases of type 2 harlequin ichthyosis.. Based on these observations and the known functions of protein phosphatase in keratinocytes, we hypothesize that the underlying molecular basis of harlequin ichthyosis may be related to mutations affecting protein dephosphorylation. We further describe approaches by which this hypothesis can be tested.

Topics: Cells, Cultured; Humans; Ichthyosis; Ichthyosis, Lamellar; Infant, Newborn; Keratinocytes; Keratins; Keratosis; Molecular Biology; Mutation; Phosphoprotein Phosphatases; Skin

In a bilaterally paired double-blind comparison study, a cream containing 0.1% 13-cis-retinoic acid (13-cis-RA) and cream base only were applied over 4 weeks in seven patients with non-erythrodermic lamellar ichthyosis (NELI), two patients with Darier's disease and one patient with autosomal dominant ichthyosis vulgaris (ADIV). In two patients with NELI and two patients with Darier's disease a half-side effect was observed in favour of the side treated with 13-cis-RA. In three patients an induction of cytokeratin-4, and in one of these patients expression of cytokeratin-13, were observed after therapy. Topical 13-cis-RA appears to be a promising approach in the treatment of disorders of keratinization. The selective modulation of the cytokeratin pattern may provide an immunohistochemical tool to investigate the mode of action of retinoids.

Topics: Administration, Cutaneous; Adolescent; Adult; Antibodies, Monoclonal; Darier Disease; Double-Blind Method; Female; Humans; Ichthyosis, Lamellar; Immunoenzyme Techniques; Isotretinoin; Keratins; Male

Epidermolytic ichthyosis (EI) is a major form of nonsyndromic inherited ichthyosis, characterized by erythroderma, marked hyperkeratosis and scale, bulla and erosion at birth, associated with KRT1/KRT10 mutations. The cytokine and chemokine profiles in EI are poorly understood, and specific treatment options have not been established.. To explore novel biomarkers and therapeutic targets in patients with EI.. We analysed cytokine levels in serum and skin samples from 10 patients with inherited ichthyosis, including seven patients with EI. Wild-type and mutant KRT1 constructs were established and transfected into HaCaT cells, an immortalized keratinocyte cell line, for in vitro immunoblotting and immunocytochemistry analyses.. Multiplex cytokine/chemokine analysis revealed that 10 cytokines/chemokines [interleukin (IL)-1β, IL-4, IL-17A, IL-16, IL-18, IL-1 receptor-α, macrophage colony-stimulating factor, interferon-α2, basic fibroblast growth factor and monocyte chemotactic protein-3] were significantly increased in patients with EI. Furthermore, IL-18 levels were significantly higher in patients with EI [n = 7; 2714.1 (1438.0) pg mL-1] than in healthy controls [n = 11; 218.4 (28.4) pg mL-1, P < 0.01]. Immunohistochemical analyses showed that IL-18 expression was elevated in skin samples from patients with EI. Serum IL-18 levels correlated with the severity of ichthyosis, as measured by the Ichthyosis Scoring System. Immunoblotting analysis revealed that mature IL-18 levels were increased in the supernatant of mutant KRT1 expressing HaCaT cells. Additionally, these cells showed NLRP3 aggregation in the cytoplasm and ASC clustered around mutant keratin aggregations. These findings suggest that mutant keratin might promote the activation of the NLRP3 inflammasome and its downstream caspase-1-mediated IL-18 release in keratinocytes from patients with EI.. Our results suggest that serum IL-18 is a severity marker released from the skin of patients with EI. Blockade of IL-18 may be a useful novel therapeutic option for patients with EI.

Topics: Cytokines; Humans; Hyperkeratosis, Epidermolytic; Ichthyosis, Lamellar; Infant, Newborn; Interleukin-18; Keratins; NLR Family, Pyrin Domain-Containing 3 Protein

Defects in keratinocyte transglutaminase (TGM1), resulting in an improper protein scaffold for deposition of the lipid barrier, comprise a major source of autosomal recessive congenital ichthyosis. For that reason, the composition and formation of the cornified (cross-linked) protein envelope of the epidermis have been of considerable interest. Since the isopeptide cross-linked protein components are not individually isolable once incorporated, purified envelopes were analysed by mass spectrometry after trypsin digestion. Quantitative estimates of the identified components revealed some 170 proteins, each comprising at least 0.001% of the total, of which keratins were major constituents accounting for ≈74% of the total. Some prevalent non-keratin constituents such as keratinocyte proline-rich protein, loricrin and late envelope protein-7 were preferentially incorporated into envelopes. The results suggest a model where, as previously observed in hair shaft and nail plate, a diversity of cellular proteins are incorporated. They also help rationalize the minimal effect on epidermis of ablating genes for specific single envelope structural components. The quantitative profile of constituent proteins provides a foundation for future exploration of envelope perturbations that may occur in pathological conditions.

Topics: Cell Membrane; Cytoskeletal Proteins; Epidermis; Female; Hair; Humans; Ichthyosis, Lamellar; Keratinocytes; Keratins; Lipids; Male; Membrane Proteins; Nails; Proline; Proteins; Proteome; Proteomics; Skin; Transglutaminases

Topics: Child; Humans; Ichthyosis, Lamellar; Keratins; Male; Phenotype; Temperature

Harlequin icthyosis is a very rare inborn error of epidermal keratinization with autosomal recessive inheritance. Abnormal lipid metabolism in mitochondria with defective lamellar body formation is the main defect leading to hyperkeratosis. Prenatal diagnosis can be done by invasive procedures such as fetal skin biopsy and also by ultrasonography.

Topics: Fatal Outcome; Female; Humans; Ichthyosis, Lamellar; Infant; Keratinocytes; Keratins; Metabolism, Inborn Errors; Skin

Harlequin ichthyosis (HI) is an extremely severe and usually fatal congenital keratinization disorder whose responsible genes have not yet been identified. For prenatal diagnosis, the fetal skin biopsy is the only available method and has been usually performed at 21 to 22 weeks' estimated gestational age (wEGA). Hair canal keratinization is thought to occur around 15 wEGA prior to the interfollicular keratinization, and characteristic abnormalities of HI are known to be expressed more strongly in the hair canal. Thus, we expected the fetal skin specimen at 19 wEGA to have sufficient information for prenatal diagnosis. Fetal skin biopsy was undertaken from a fetus at risk at 19 wEGA. Electron microscopy demonstrated abnormal vacuoles in keratinized cells and malformation of lamellar granules in the hair canal. Clumps of aberrantly keratinized cells containing lipid droplets were seen in the amniotic fluid. The fetus was diagnosed as affected. The abortus at 21 wEGA demonstrated HI phenotype clinically. The present results indicate that the prenatal diagnosis of HI is possible at 19 wEGA, an earlier stage of gestation than previously reported, by the ultrastructural observation of the hair canal and the amniotic fluid cells, but not the interfollicular epidermis, of fetuses at risk.

Topics: Adult; Amniotic Fluid; Female; Fetal Diseases; Gestational Age; Hair; Humans; Ichthyosis, Lamellar; Keratins; Pregnancy; Prenatal Diagnosis

The pathogenesis of 'collodion baby' has not been clarified yet, and this descriptive term is thought to include several heterogeneous conditions. We report a collodion baby whose clinical features had changed to those of lamellar ichthyosis (LI) as the patient got older. By electron microscopy, skin specimens at 3 days of age revealed the presence of lipid inclusions within the cornified cells, abnormal lamellar granules in the granular layer keratinocytes and a lack of extracellular lamellar structure between the first cornified cell and the granular cell though the cornified cell envelope appeared to be normally formed. Immunohistochemical labeling showed normal distribution of keratins 1, 5, 10, 14, filaggrin/profilaggrin and cornified cell envelope proteins (involucrin, small proline-rich proteins and loricrin). These observations suggested that a collodion baby might have a normal cornified cell envelope and show morphologic changes similar to those of harlequin ichthyosis at birth, even though its underlying disorder is LI.

Topics: Abnormalities, Multiple; Ear; Filaggrin Proteins; Follow-Up Studies; Humans; Ichthyosis, Lamellar; Infant, Newborn; Intermediate Filament Proteins; Keratins; Male; Membrane Proteins; Microscopy, Electron; Skin; Syndrome

Modern pharmacological and dermatological research requires the use of appropriate in vitro models which permit a faithful reproduction of various aspects of the in situ situation. The air-exposed culture of keratinocytes on dead de-epidermized dermis is one of the best models of in vitro epidermal differentiation known at the moment. In this study, we verified the model's validity for the reproduction of a hyperproliferative genodermatosis: non-bullous congenital ichthyosiform erythroderma. We used subcultured epidermal keratinocytes originating from normal and ichthyotic patients. Light and electron microscopy of pathological cultures disclosed, on day 14, a terminally differentiated epidermis with a marked granular layer and hyperkeratosis which, however, was not dramatically different from the normal controls. On day 25, the normal cultures displayed an even more pronounced hyperkeratosis and hypergranulosis, whereas the reconstructed epidermis of pathological origin presented a considerable reduction of the viable non-keratinized compartment and a focal parakeratosis. Indirect immunofluorescence revealed the expression of several differentiation markers which were not observed in the immersed culture models (e.g. the desmosome- and differentiation-related antigens KM48 and G36-19). Abundant keratohyalin granules were stained with AKH1 antibody and observed even in the deep epidermal layers, but no profilaggrin-filaggrin conversion could be detected biochemically.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antibodies, Monoclonal; Biomarkers; Cell Division; Cells, Cultured; Child; Culture Media; Female; Filaggrin Proteins; Humans; Hyalin; Ichthyosis, Lamellar; Keratinocytes; Keratins; Male; Skin

Two patients suffering from ichthyosis with unusual ultrastructural features were examined. One was a 14-year-old boy with ichthyotic skin since birth. The ichthyosis was initially erythrodermic and later presented as follicular hyperkeratosis. The other patient was an ichthyotic child who died 2 days after birth of respiratory distress syndrome. Although apparently not consanguineous, both families came from the same relatively isolated rural area and autosomal recessive inheritance seems likely. Light microscopy did not yield diagnostic features, but the ultrastructural findings in the granular and horny cells showed diagnostic lamellar membrane packages. Identical ultrastructural features have previously been published in one prematurely born baby who died soon after birth and once in a prenatal diagnosis in the same family; the disease was termed "ichthyosis congenita type IV".

Topics: Adolescent; Cell Nucleus; Cytoplasm; Epidermis; Genes, Recessive; Hair; Humans; Hyalin; Ichthyosis, Lamellar; Infant, Newborn; Keratins; Keratosis; Langerhans Cells; Male; Microtubules; Scalp; Skin

A case of harlequin ichthyosis was studied with electron microscopy. From the basal cell to granular cell layers, keratinocytes contained giant mitochondria (860 nm) which exhibited vesicular cristae. Typical lamellar granules were absent; instead, numerous dense cored granules (DCG) and particles containing cored granules (PCG) were produced. Some of these were discharged into the intercellular spaces of granular cells, but the majority failed to be released from the cytoplasm. These retained DCG and PCG coalesced to form large vacuoles and cavities in the stratum corneum. In the hair follicle, keratinized cells failed to loosen and desquamate into the hair canal; instead, they formed concentric keratin rings surrounding hair, a diagnostic feature of this disease. It is suggested that the abnormal lamellar granule underlies the pathogenesis of this disease and that giant mitochondria may be related to an abnormal lipid metabolism of keratinocytes which may affect lipid composition of lamellar granules.

Topics: Adult; Cytoplasmic Granules; Female; Fetus; Hair; Humans; Ichthyosis, Lamellar; Infant, Newborn; Keratinocytes; Keratins; Male; Microscopy, Electron; Mitochondria; Pregnancy

Topics: Humans; Ichthyosis; Ichthyosis, Lamellar; Keratins