bromochloroacetic-acid and Alopecia

The diagnosis of inherited skin diseases has been traditionally been based on clinical findings and occasionally on dermatopathology. Recent developments in molecular genetics have increased tremendously the diagnostic accuracy of genetic skin diseases, but also expanded the role of dermatopathology in the diagnosis and understanding of the pathogenesis of inherited skin diseases. The following is a review of some of the recent discoveries and how they interact with dermatopathology.

Topics: Alopecia; Dermatology; Humans; Keratins; Molecular Biology; Pathology; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous

The last ten years has revealed some of the key players in the development and differentiation of the hair follicle and the epidermis in general. In this review, we discuss how our current understanding of these processes has been made possible by the elucidation of the molecular basis of human inherited diseases and mouse mutants which display defects in the hair and epidermis. For examples, the study of ectodermal dysplasias and the basal cell carcinoma predisposition disease Gorlin syndrome have allowed the determination of signalling hierarchies critical in the formation of the hair follicle. Epidermolytic diseases and hyperkeratoses have focussed attention on the importance of the programs of keratin expression, while ichthyoses provide insight in the final stage of epidermal development, cornification. Finally, the increasing range of diseases and mouse models exhibiting alopecias are revealing the critical pathways in control of the hair follicle cycle.

Topics: Alopecia; Animals; Basal Cell Nevus Syndrome; Cell Differentiation; Epidermis; Forecasting; Genetic Predisposition to Disease; Humans; Keratins; Keratosis; Mice; Mice, Transgenic; Models, Biological; Mutation; Skin; Skin Diseases; Skin Neoplasms

The mature hair follicle undergoes a unique developmental cycle, in which phases of growth are interspersed with phases of involution and rest. The main effectors of this cycle are skin epithelial stem cells that reside in a specialized compartment of the follicle. Defects in this cycle, or in the structure of the hair produced, often result in alopecia (partial or complete hair loss), a condition that affects a significant fraction of the population. Here we discuss transgenic mouse models that exhibit alopecia as a primary phenotype, resulting from the inactivation of genes encoding structural proteins.

Topics: Alopecia; Animals; Cathepsins; Cell Adhesion Molecules; DNA-Binding Proteins; Forkhead Transcription Factors; Hair Follicle; Homeodomain Proteins; Keratins; Mice; Mice, Knockout; Mice, Transgenic; Models, Animal; Transcription Factors

Topics: 4-Aminobenzoic Acid; Administration, Oral; Alopecia; Clinical Trials as Topic; Cysteine; Dermatologic Agents; Drug Combinations; Hair; Hair Preparations; Humans; Keratins; Nail Diseases; Pantothenic Acid; Thiamine; Treatment Outcome; Yeast, Dried

Recent advances have challenged the prevailing view that keratins are merely passive bystanders of keratinocyte biology. With the exciting discovery that three autosomal dominant genetic skin disorders, epidermolysis bullosa simplex (EBS), epidermolytic hyperkeratosis (EHK) and palmoplantar keratoderma (PPK), are in fact disorders of keratins comes the realization that the integrity of the keratin filament network is crucial to the structural integrity of the skin. Since it has been recently established that mutations in keratins K5/K14, K1/K10 and K9 are causative for these keratinocyte disorders, it is very likely that mutations in K6 or in its obligate partner, K16 will result in disease. In order to test this we have produced transgenic mice that express a mutant K6 gene. These mice develop a progressive scarring alopecia at about 6 months of age. Later, the denuded areas developed a keratosis which was prone to infection. Ultrastructural analysis suggests that hair loss is due to the destruction of the outer root sheath. We believe that these mice are models of another keratin disorder.

Topics: Alopecia; Animals; Disease Models, Animal; Epidermis; Humans; Keratinocytes; Keratins; Mice; Mice, Transgenic; Molecular Structure; Multigene Family; Mutation

In 1984, Zaun described a new type of pilary dysplasia characterized by easily pluckable hair. We were able to observe three patients with this anomaly, and this paper is an attempt at reviewing the subject on the basis of these new cases compared with those previously published. Clinical features. The major sign of the anomaly is that hairs can be pulled off in tufts easily and painlessly, and promptly grow again (our cases). In all cases reported so far the hair was blond or dark-blond; in some patients it is described as scintillating (our cases). The hair shaft is usually thin (one of our cases), but it may be of normal caliber (two of our patients). In the occipital region the hairs are entangled, dry and short (our cases). They are implanted wide apart or at normal intervals (our patients); areas of alopecia are sometimes encountered (our cases). Hair growth may be slow (one of our cases) or of normal speed (two of our cases). The eyelashes and eyebrows, as well as other body hairs, are normal in all patients (fig. 1). Microscopy. The trichogram is exclusively composed of anagenic and dystrophic roots (our cases). Pathological examination by biopsy of the scalp is characteristic: transverse and oblique sections of the follicles show that the hairs are oval, triangular or trapezoidal in shape (fig. 7). Alterations of the inner epithelial sheath are also present, including keratinization and early decomposition (fig. 8), lack of complementation (fig. 7) and fissures between the cuticle of the inner epithelial sheath and of the hair, in the keratogenic area (fig. 9). (ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alopecia; Child; Child, Preschool; Epithelium; Female; Hair; Hair Diseases; Humans; Keratins; Male; Microscopy, Electron, Scanning; Microscopy, Polarization

Topics: Adolescent; Adult; Alopecia; Alopecia Areata; Anemia, Sickle Cell; Animals; Autoradiography; Child; Child, Preschool; Down Syndrome; Female; Hair; Humans; Infant; Infant, Newborn; Keratins; Male; Pregnancy; Puerperal Disorders; Rats; Stress, Physiological; Zinc

Topics: Alopecia; Amines; Antioxidants; Cosmetics; Fatty Acids, Unsaturated; Hair; Keratins; Lipids; Methionine; Oxidation-Reduction

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Alopecia; Androstenedione; Animals; Cyclic AMP; Disease Models, Animal; Energy Metabolism; Fumarate Hydratase; Glucose; Glucosephosphate Dehydrogenase; Glucosyltransferases; Glycolysis; Hair; Haplorhini; Hexokinase; Humans; Keratins; L-Lactate Dehydrogenase; Macaca; Nucleotidyltransferases; Protein Kinases; Testosterone; Transferases

Topics: Adrenal Cortex Hormones; Alopecia; Androgens; Animals; Antineoplastic Agents; Diet; Embryology; Female; Hair; Hirsutism; Humans; Keratins; Male; Mitosis; Nutritional Physiological Phenomena; Scalp; Skin; Thyroid Hormones; Vitamins

Several pharmaceutical products have been formulated over the past decades for the treatment of male and female alopecia, and pattern baldness, but relatively few metadata on their efficacy have been published. For these reasons, the pharmaceutical and medical attention has recently focused on the discovery of new and safer remedies. Particularly, great interest has been attracted by oligomeric procyanidin bioactivity, able to promote hair epithelial cell growth as well as to induce the anagen phase. Specifically, the procyanidin B2, a dimeric derivative extracted from apples, has demonstrated to be one of the most effective and safest natural compounds in promoting hair growth, both in vitro and in humans by topical applications. By evaluating the polyphenolic content of different apple varieties, we have recently found in the apple fruits of cv Annurca (AFA), native to Southern Italy, one of the highest contents of oligomeric procyanidins, and, specifically, of procyanidin B2. Thus, in the present work we explored the in vitro bioactivity of AFA polyphenolic extract as a nutraceutical formulation, named AppleMets (AMS), highlighting its effects on the cellular keratin expression in a human experimental model of adult skin. Successively, testing the effects of AMS on hair growth and tropism in healthy subjects, we observed significant results in terms of increased hair growth, density, and keratin content, already after 2 months. This study proves for the first time the impact of apple procyanidin B2 on keratin biosynthesis in vitro, and highlights its effect as a nutraceutical on human hair growth and tropism.

Topics: Adult; Aged; Aged, 80 and over; Alopecia; Dietary Supplements; Drug Compounding; Female; Hair; Humans; Italy; Keratinocytes; Keratins; Male; Malus; Middle Aged; Plant Extracts; Proanthocyanidins; Skin; Tropism

Growth and quality of hair was studied after treatment with Pantogar, another prescription (Verum-2) and placebo for four months in 60 patients with diffuse effluvium capillorum and agnogenic structural alternations of hair. Efficacy was assessed by measurements of swelling, dye-binding and thickness for hair-quality and evaluation of hair-density and trichograms for hair-growth. Statistical analysis of swelling properties and trichogram data indicated that Pantogar was effective, the second preparation improved quality of hair and retarded hair loss. Placebo was ineffective judged by the used parameters. Tolerance of the treatment was good and adverse effects could not be substantiated.

Topics: 4-Aminobenzoic Acid; Alopecia; Aminobenzoates; Calcium; Cysteine; Cystine; Double-Blind Method; Drug Combinations; Female; Hair Diseases; Humans; Keratins; Male; Pantothenic Acid; Thiamine; Yeast, Dried

Bald thigh syndrome is a common hair loss disorder in sighthounds. Numerous possible causes, including environmental conditions, trauma, stress, endocrinopathies and genetic components have been proposed, but only endocrinopathies have been ruled out scientifically. The overall goal of our study was to identify the cause of bald thigh syndrome and the pathological changes associated with it. We approached this aim by comparing skin biopsies and hair shafts of affected and control dogs microscopically as well as by applying high-throughput technologies such as genomics, transcriptomics and proteomics. While the histology is rather unspecific in most cases, trichogram analysis and scanning electron microscopy revealed severe structural abnormalities in hair shafts of affected dogs. This finding is supported by the results of the transcriptomic and proteomic profiling where genes and proteins important for differentiation of the inner root sheath and the assembly of a proper hair shaft were downregulated. Transcriptome profiling revealed a downregulation of genes encoding 23 hair shaft keratins and 51 keratin associated proteins, as well as desmosomal cadherins and several actors of the BMP signaling pathway which is important for hair shaft differentiation. The lower expression of keratin 71 and desmocollin 2 on the mRNA level in skin biopsies corresponded with a decreased protein expression in the hair shafts of affected dogs. The genetic analysis revealed a missense variant in the IGFBP5 gene homozygous in all available Greyhounds and other sighthounds. Further research is required to clarify whether the IGFBP5 variant represents a predisposing genetic risk factor. We conclude from our results that structural defects in the hair shafts are the cause for this well-known disease and these defects are associated with a downregulation of genes and proteins essential for hair shaft formation. Our data add important knowledge to further understand the molecular mechanisms of HF morphogenesis and alopecia in dogs.

Topics: Alopecia; Animals; Dog Diseases; Dogs; Female; Gene Expression Regulation; Hair; Insulin-Like Growth Factor Binding Protein 5; Keratins; Male; Skin

Patterned hair loss (PHL) affects around 50% of the adult population worldwide. The negative impact that this condition exerts on people's life quality has boosted the appearance of over-the-counter products endowed with hair-promoting activity. Nutraceuticals enriched in polyphenols have been recently shown to promote hair growth and counteract PHL.

Topics: Alopecia; Amino Acids; Animals; Biflavonoids; Catechin; Hair Follicle; Humans; Italy; Keratins; Malus; Mass Spectrometry; Metabolomics; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Pentose Phosphate Pathway; Phytotherapy; Plant Extracts; Polyphenols; Proanthocyanidins

Chemotherapy-induced alopecia (CIA) is a common side effect of conventional chemotherapy and represents a major problem in clinical oncology. Even months after the end of chemotherapy, many cancer patients complain of hair loss, a condition that is psychologically difficult to manage. CIA disturbs social and sexual interactions and causes anxiety and depression. Synthetic drugs protecting from CIA and endowed with hair growth stimulatory properties are prescribed with caution by oncologists. Hormones, growth factors, morphogens could unwontedly protect tumour cells or induce cancer cell proliferation and are thus considered incompatible with many chemotherapy regimens. Nutraceuticals, on the contrary, have been shown to be safe and effective treatment options for hair loss. We here show that polyphenols from

Topics: Administration, Topical; Alopecia; Animals; Antineoplastic Agents; Bridged-Ring Compounds; Dietary Supplements; Dinoprost; Fatty Acids, Unsaturated; Hair Follicle; Keratins; Male; Malus; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Plant Extracts; Polyphenols; Taxoids

Non-invasive sample collection methods could facilitate clinical research on hair diseases. In an exploratory experimental study on six male volunteers with untreated androgenetic alopecia (AGA), Hamilton-Norwood stage IIIv-IV, skin surface and infundibular protein as well as RNA extracts from plucked hair follicles were analyzed from frontal skin, vertex and clinically unaffected occiput. Slightly increased levels of inflammatory markers were only found in AGA-affected scalp skin and infundibulum, not in RNA from plucked hair follicles. RNA expression profiles point towards differential expression of genes involved in hair cycle regulation, hair keratin production, but also RNA methylation and ion channel regulation.

Topics: Alopecia; Biomarkers; Disease Progression; DNA Methylation; Gene Expression Profiling; Gene Expression Regulation; Hair; Hair Follicle; Humans; Inflammation; Keratins; Male; Methylation; Pilot Projects; RNA; Scalp; Skin

Cytokeratins are a major component of colloid bodies that are essentially diagnostic of lichen planopilaris (LPP). Here, the authors assess the ability of the cytokeratin 903 antibody (CK-903) to stain colloid bodies and differentiate LPP from other histologically similar appearing primary cicatricial alopecias. A retrospective review of all specimens submitted to the dermatopathology department over a 2-year window identified 18 cases of LPP and 20 cases of histologically similar appearing entities (discoid lupus erythematosus or central centrifugal cicatricial alopecia) through a combination of H&E, elastic van gieson, and periodic acid-schiff stains. All 38 samples were then prospectively stained with CK-903. Colloid bodies were identifiable in 3 of the 18 LPP cases based on H&E alone but were seen in 9 of 18 cases when CK-903 was used. There were no cases where colloid bodies were seen on H&E but not subsequently identified with CK-903. Additionally, there was no CK-903 staining in any of the 20 cases of similar appearing entities except 1 case of discoid lupus erythematosus, which is known to occasionally show colloid bodies. The authors conclude that CK-903 is a useful adjunctive tool that will allow for a quicker, less costly, and more accurate diagnosis of LPP given its ability identify colloid bodies even in the setting of significant inflammation and fibrosis and its advantages over direct immunofluorescence of low cost, short preparation time, and lack of need for a specialized fluorescent microscope.

Topics: Adult; Aged; Aged, 80 and over; Alopecia; Antibodies; Antibodies, Monoclonal, Murine-Derived; Biomarkers; Biopsy; Diagnosis, Differential; Female; Hair Follicle; Humans; Immunohistochemistry; Keratins; Lichen Planus; Male; Middle Aged; New York City; Predictive Value of Tests; Retrospective Studies; Scalp; Scalp Dermatoses; Workflow; Young Adult

Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth.

Topics: Alopecia; Apoptosis; Cell Differentiation; Cell Proliferation; Female; Gene Expression Regulation, Developmental; Hair Follicle; Humans; Keratinocytes; Keratins; MicroRNAs; Signal Transduction; Stem Cells; Transcription Factors

The sebaceous gland and the follicular bulge region have important role in biology of the hair. They initiate destruction of the hair follicle both in human and animal models in certain conditions. The morphometric feature of the sebaceous gland is not well understood so as the distribution of the bulge stem cells in pathological conditions of male pattern hair loss or androgenic alopecia (AGA).. The authors perform morphometric analysis of the sebaceous gland in AGA patients and also study distribution of the follicular stem cells in the bulge region in these populations.. Two hundred and fifty cases of glass slide specimen from Japanese patients with male pattern hair loss were reviewed. Among these, 23 cases of the longitudinal (vertical) sections of the scalp skin with diagnosis of AGA were found and analyzed for the morphometric characteristics. Each sebaceous gland area was measured using NIH imagej system and statistically analyzed. For the identification of the follicular bulge region, an immunohistochemistry using anticytokeratin 15 (C8/144B clone) was carried out in the cases of AGA.. The sebaceous gland area of the AGA group was noticeably increased, while the size of each sebaceous gland remains unchanged. It has more lobules in the hair follicular unit in the AGA population. In the immunohistochemistry, the follicular stem cells are present in the bulge regions in cases of AGA.. The overgrowth (multilobulation) of the sebaceous gland and relative preservation of the follicular stem cells suggest that the changes in the sebaceous gland could be an important factor in the pathology of AGA.

Topics: Adult; Alopecia; Hair Follicle; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Retrospective Studies; Sebaceous Glands; Stem Cells; Young Adult

Histone deacetylases (HDACs) are present in the epidermal layer of the skin, outer root sheath, and hair matrix. To investigate how histone acetylation affects skin morphogenesis and homeostasis, mice were generated with a K14 promoter-mediated reduction of Hdac1 or Hdac2. The skin of HDAC1 null (K14-Cre Hdac1(cKO/cKO)) mice exhibited a spectrum of lesions, including irregularly thickened interfollicular epidermis, alopecia, hair follicle dystrophy, claw dystrophy, and abnormal pigmentation. Hairs are sparse, short, and intermittently coiled. The distinct pelage hair types are lost. During the first hair cycle, hairs are lost and replaced by dystrophic hair follicles with dilated infundibulae. The dystrophic hair follicle epithelium is stratified and is positive for K14, involucrin, and TRP63, but negative for keratin 10. Some dystrophic follicles are K15 positive, but mature hair fiber keratins are absent. The digits form extra hyperpigmented claws on the lateral sides. Hyperpigmentation is observed in the interfollicular epithelium, the tail, and the feet. Hdac1 and Hdac2 dual transgenic mice (K14-Cre Hdac1(cKO/cKO) Hdac2(+/cKO)) have similar but more obvious abnormalities. These results show that suppression of epidermal HDAC activity leads to improper ectodermal organ morphogenesis and disrupted hair follicle regeneration and homeostasis, as well as indirect effects on pigmentation.

Topics: Abnormalities, Multiple; Alopecia; Animals; Ectoderm; Epidermis; Hair Follicle; Histone Deacetylase 1; Histone Deacetylase 2; Homeostasis; Keratins; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Nails, Malformed; Sequence Deletion; Skin Pigmentation

Epidermolysis bullosa (EB) was diagnosed in eight calves from four farms in the United Kingdom on the basis of clinical, histological and ultrastructural findings. In three affected herds, pedigree Simmental bulls had been mated with Simmental-cross cows. In a fourth herd two Holstein-Friesian calves were affected. Lesions included multifocal erosion and ulceration of the hard and soft palates, tongue, nares and gingiva, with onychomadesis (dysungulation). There was alopecia, erosion and crusting of the coronets, pasterns, fetlocks, carpi, hocks, flanks and axillae. Histopathological findings included segmental separation of full thickness epidermis from the dermis, with formation of large clefts containing eosinophilic fluid, extravasated red blood cells and small numbers of neutrophils. Follicular and interfollicular areas of skin were affected, with clefts extending around hair follicles and sometimes involving whole follicles. Ultrastructurally, there was evidence of vacuolar change within basal keratinocytes, corresponding to areas of histological clefting. Preliminary genetic screening of the candidate keratin genes (bKRT5 and bKRT14) has excluded mutations of these as the cause of this condition.

Topics: Alopecia; Animals; Cattle; Epidermis; Epidermolysis Bullosa; Female; Keratinocytes; Keratins; Mutation; Nail Diseases; Pedigree; Pregnancy; Skin; United Kingdom

Hair is maintained through a cyclic process that includes periodic regeneration of hair follicles in a stem cell-dependent manner. Little is known, however, about the cellular and molecular mechanisms that regulate the layered differentiation of the hair follicle. We have established a mutant mouse with a cyclic alopecia phenotype resulting from the targeted disruption of Sox21, a gene that encodes a HMG-box protein. These mice exhibit progressive hair loss after morphogenesis of the first hair follicle and become completely nude in appearance, but then show hair regrowth. Sox21 is expressed in the cuticle layer and the progenitor cells of the hair shaft in both mouse and human. The lack of this gene results in a loss of the interlocking structures required for anchoring the hair shaft in the hair follicle. Furthermore, the expression of genes encoding the keratins and keratin binding proteins in the hair shaft cuticle are also specifically down-regulated in the Sox21-null mouse. These results indicate that Sox21 is a master regulator of hair shaft cuticle differentiation and shed light on the possible causes of human hair disorders.

Topics: Alopecia; Animals; Cell Differentiation; Hair; Hair Follicle; Keratins; Mice; Mice, Knockout; SOXB2 Transcription Factors; Stem Cells

Humans with selected mutations in the vitamin D receptor (VDR) and mouse models lacking VDR develop alopecia. Mice null for the Vdr gene are born with a normal coat of hair, but fail to initiate normal hair follicle cycling. In this study, we examined the morphology of the hair follicle of the Vdr null mouse during days 13-22 when the hair follicle normally initiates and completes the first catagen. We then explored the possibility that the abnormality in hair follicle cycling was associated with abnormal expression of hairless (Hr), a putative transcriptional regulator known to regulate hair follicle cycling and recently shown to regulate VDR transcriptional activity. Our results demonstrate the progressive deterioration of the hair follicle through catagen. Comparable to VDR, Hr was found in the basal cells of the epidermis and ORS of the hair follicle. However, Hr was also found in the IRS and matrix of the follicle, regions with little or no VDR. Hr levels increased during catagen, reaching a peak by day 19. Levels of Hr were greater in the Vdr null mice compared to wildtype controls, results confirmed by quantitative RT-PCR. We conclude that lack of VDR causes disruption of hair follicle structure during the first catagen resulting in failure of subsequent hair follicle cycling. These changes are associated with increased expression of Hr, suggesting a role for VDR in regulating Hr expression. Both Hr and VDR are required for normal hair follicle cycling.

Topics: Alkaline Phosphatase; Alopecia; Animals; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Progression; Epidermis; Fibroblasts; Gene Expression; Hair Follicle; Hyperplasia; Keratin-15; Keratin-5; Keratinocytes; Keratins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Scanning; Proliferating Cell Nuclear Antigen; Receptors, Calcitriol; Skin; Transcription Factors

Topics: Alopecia; Animals; Cicatrix; Disease Models, Animal; Hair Follicle; Humans; Keratins; Stem Cells

Mammalian hair follicles cycle between stages of rapid growth (anagen) and metabolic quiescence (telogen) throughout life. Transition from anagen to telogen involves an intermediate stage, catagen, consisting of a swift, apoptosis-driven involution of the lower half of the follicle. How catagen is coordinated, and spares the progenitor cells needed for anagen re-entry, is poorly understood. Keratin 17 (K17)-null mice develop alopecia in the first week post-birth, correlating with hair shaft fragility and untimely apoptosis in the hair bulb. Here we show that this abnormal apoptosis reflects premature entry into catagen. Of the proapoptotic challenges tested, K17-null skin keratinocytes in primary culture are selectively more sensitive to TNFalpha. K17 interacts with TNF receptor 1 (TNFR1)-associated death domain protein (TRADD), a death adaptor essential for TNFR1-dependent signal relay, suggesting a functional link between this keratin and TNFalpha signaling. The activity of NF-kappaB, a downstream target of TNFalpha, is increased in K17-null skin. We also find that TNFalpha is required for a timely anagen-catagen transition in mouse pelage follicles, and that its ablation partially rescues the hair cycling defect of K17-null mice. These findings identify K17 and TNFalpha as two novel and interdependent regulators of hair cycling.

Topics: Alopecia; Animals; Apoptosis; Cell Cycle; Hair Follicle; Keratinocytes; Keratins; Mice; Mice, Mutant Strains; NF-kappa B; Signal Transduction; TNF Receptor-Associated Death Domain Protein; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Tumor Necrosis Factor-alpha

Topics: Adolescent; Alopecia; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Testing; Genotype; Heterozygote; Humans; Keratins; Keratins, Hair-Specific; Keratins, Type II; Mutation, Missense; Polymorphism, Genetic

Hypohidrotic ectodermal dysplasia is a human syndrome defined by maldevelopment of one or more ectodermal-derived tissues, including the epidermis and cutaneous appendices, teeth, and exocrine glands. The molecular bases of this pathology converge in a dysfunction of the transcription factor nuclear factor of the kappa-enhancer in B cells (NF-kappaB), which is essential to epithelial homeostasis and development. A number of mouse models bearing disruptions in NF-kappaB signaling have been reported to manifest defects in ectodermal derivatives. In ectoderm-targeted transgenic mice overexpressing the glucocorticoid receptor (GR) [keratin 5 (K5)-GR mice], the NF-kappaB activity is greatly decreased due to functional antagonism between GR and NF-kappaB. Here, we report that K5-GR mice exhibit multiple epithelial defects in hair follicle, tooth, and palate development. Additionally, these mice lack Meibomian glands and display underdeveloped sweat and preputial glands. These phenotypic features appear to be mediated specifically by ligand-activated GR because the synthetic analog dexamethasone induced similar defects in epithelial morphogenesis, including odontogenesis, in wild-type mice. We have focused on tooth development in K5-GR mice and found that an inhibitor of steroid synthesis partially reversed the abnormal phenotype. Immunostaining revealed reduced expression of the inhibitor of kappaB kinase subunits, IKKalpha and IKKgamma, and diminished p65 protein levels in K5-GR embryonic tooth, resulting in a significantly reduced kappaB-binding activity. Remarkably, altered NF-kappaB activity elicited by GR overexpression correlated with a dramatic decrease in the protein levels of DeltaNp63 in tooth epithelia without affecting Akt, BMP4, or Foxo3a. Given that many of the 170 clinically distinct ectodermal dysplasia syndromes still remain without cognate genes, deciphering the molecular mechanisms of this mouse model with epithelial NF-kappaB and p63 dysfunction may provide important clues to understanding the basis of other ectodermal dysplasia syndromes.

Topics: Abnormalities, Multiple; Alopecia; Animals; Disease Models, Animal; Ectodermal Dysplasia; Female; Gene Expression Regulation, Developmental; Hair Follicle; Keratin-15; Keratin-5; Keratins; Male; Mice; Mice, Transgenic; Pregnancy; Receptors, Glucocorticoid; Tooth Abnormalities

Monilethrix is a rare hereditary disorder that affects the hair and is characterized by shaft anomaly. There is no known treatment that successfully cures the condition. In this report we present a case of monilethrix in a 7-year-old girl treated with oral acitretin. A very good clinical and cosmetic result was obtained while treatment was continued. However, clinical symptoms recurred after discontinuation of acitretin therapy.

Topics: Acitretin; Administration, Oral; Alopecia; Child; Female; Hair; Humans; Keratins; Keratolytic Agents; Mutation; Recurrence; Treatment Outcome

We report a congenital follicular dysplasia in five coatis from four different litters of the same parents born between 1996 and 2001. These coatis were born apparently alopecic with the entire body covered by very short dark hairs, with secondary lichenification of the skin, crusting and scaling. The main histopathological feature consisted of premature cornification of the cortical cells of the hair shaft. Cells were already fully cornified below the Adamson's fringe, leading to a disorganized, fragmented and constricted hair shaft. Based on the history of the animals and the nature of the lesions, a genetic defect in hair shaft keratinization was suspected.

Topics: Alopecia; Animals; Animals, Zoo; Female; Hair Diseases; Hair Follicle; Immunohistochemistry; Keratins; Male; Procyonidae

Viral-associated trichodysplasia of immunosuppression is a newly described clinicopathologic entity found in patients who are undergoing drug-induced immunosuppression to prevent organ transplant rejection. Patients have numerous erythematous papules concentrated in the central portion of the face and variable degrees of hair loss, most severely affecting facial hair. Histologic findings of facial papules are highly distinctive and unique, and suggest that the entire machinery of the follicular bulb is devoted to the manufacture of inner root sheath-type keratin. Electron microscopy reveals intranuclear viral particles, but precise viral identification has not yet been achieved.

Topics: Adolescent; Alopecia; Erythema; Facial Dermatoses; Female; Hair Follicle; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Keratins; Kidney Transplantation; Microscopy, Electron

Androgenic alopecia (AGA) is the most common type of baldness in men. Although etiological studies have proved that androgen is one of the causes of this symptom, the defined molecular mechanism underlying androgen-related actions remains largely unknown.. To clarify the difference in the gene expression profile of dermal papilla cells (DPCs) in skin affected by baldness.. DNA macroarray study was carried out on cultured DPCs from AGA skin comparing with DPCs from skin that is not affected by baldness.. From DNA macroarray analysis, we observed that 107 of the 1185 analyzed genes had differing expression levels. A marked difference was observed in the decreased gene expression of BMP2 and ephrin A3 and up-regulated in NT-4 gene. In order to clarify the roles of BMP2 and ephrin A3 in the hair follicles, we examined the proliferation of hair follicle keratinocyte and expression of a hair acidic keratin gene. Both BMP2 and ephrin A3 raised the proliferation rate of the outer root sheath cells (ORSCs) and induced gene expression in acidic hair keratin 3-II.. These results lead us to the hypothesis that both BMP2 and ephrin A3 function as hair growth promoting factors in the hair cycle.

Topics: Alopecia; Androgens; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cell Proliferation; Dermis; Dose-Response Relationship, Drug; Down-Regulation; Ephrin-A3; Gene Expression Regulation; Hair Follicle; Humans; Keratins; Male; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Skin; Transforming Growth Factor beta; Up-Regulation

Gain-of-function mutations in SMO have been implicated in constitutive activation of the hedgehog signaling pathway in human basal cell carcinomas (BCCs). We used a truncated keratin 5 (DeltaK5) promoter to assess the potential role of the human M2SMO mutant in BCC development in adult transgenic mice. DeltaK5-M2SMO mouse epidermis is hyperproliferative, ex presses BCC protein markers and gives rise to numerous epithelial downgrowths invading the underlying dermis. Lesions strikingly similar to human basaloid follicular hamartomas develop, but BCCs do not arise even in elderly mice. Hedgehog target gene transcripts were only modestly upregulated in mouse and human follicular hamartomas, in contrast to the high levels detected in BCCs. Cyclins D1 and D2 were selectively upregulated in mouse BCCs. Our data suggest that the levels of hedgehog pathway activation and G(1) cyclins are major determinants of tumor phenotype in skin, and strongly implicate deregulated hedgehog signaling in the genesis of human basaloid follicular hamartomas. Expression of an activated SMO mutant in keratinocytes appears to be insufficient for the development and/or maintenance of full-blown BCCs.

Topics: Alopecia; Animals; Carcinoma, Basal Cell; Cell Differentiation; Hamartoma; Hedgehog Proteins; Humans; Hyperplasia; Keratin-15; Keratin-5; Keratinocytes; Keratins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phenotype; Promoter Regions, Genetic; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Trans-Activators

Reduced coat 3 (Rco3) is a new spontaneous autosomal recessive mutation with defects in hair structure and progressive alopecia. Here we describe chromosomal mapping and molecular identification of the Rco3 mutation. The murine Rco3 locus maps to a 2-Mb interval on chromosome 15 encompassing the keratin type II gene cluster. Recently, mK6irs1 was described as a type II keratin expressed in Henle's and Huxley's layer of the murine inner root sheath. Genomic sequencing revealed a 10-bp deletion in exon 1 of mK6irs1 resulting in a frameshift after 58 amino acid residues and, therefore, the absence of 422 carboxy-terminal amino acid residues containing the complete alpha-helical rod domain. Henle's and Huxley's layers show no immunoreactivity with mK6irs1-specific antibodies and the absence of intermediate filament formation in electron microscopic images. These results indicate that the expression of functional mK6irs1 is indispensable for intermediate filament formation in the inner root sheath and highlights the importance of the keratinization of the inner root sheath in the normal formation of the hair shaft.

Topics: Alopecia; Amino Acid Sequence; Animals; Base Sequence; Chromosomes, Mammalian; Cloning, Molecular; Disease Models, Animal; Frameshift Mutation; Keratins; Mice; Mice, Inbred AKR; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Sequence Data; Phenotype

The active form of vitamin D3 can regulate epidermal keratinization by inducing terminal differentiation; and mice lacking the vitamin D receptor display defects leading to postnatal alopecia. These observations implicate the vitamin D3 pathway in regulation of hair growth. We tested the ability of 1,25 dihydroxyvitamin D3 and its synthetic analogs to stimulate hair growth in biege/nude/xid (BNX) nu/nu (nude) mice exhibiting congenital alopecia. Nude mice were treated with different vitamin D3 analogs at doses that we had previously found to be the highest dose without inducing toxicity (hypercalcemia). The mice were monitored for hair growth and were scored according to a defined scale. Skin samples were taken for histological observation of hair follicles and for extraction of RNA and protein. Vitamin D3 analogs dramatically stimulated the hair growth of nude mice, although parental 1,25 dihydroxyvitamin D3 had no effect. Hair growth occurred in a cyclical pattern, accompanied by formation of normal hair follicles and increased expression of certain keratins (Ha7, Ha8, and Hb3). Vitamin D3 analogs seem to act on keratinocytes to initiate hair follicle cycling and stimulate hair growth in mice that otherwise do not grow hair.

Topics: Alopecia; Animals; Calcitriol; Cholecalciferol; Female; Hair; Hair Follicle; Keratinocytes; Keratins; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Skin

Alopecia is a predominant feature of vitamin D receptor inactivation in mice and humans. To determine the role of vitamin D receptor in the regulation of hair growth directly, we used the human keratin 14 promoter to target human vitamin D receptor expression to the skin of transgenic mice, and generated vitamin D receptor null mice that express the human vitamin D receptor transgene. Parallel studies were carried out in littermates of wild-type, vitamin D receptor null, transgenic, and human vitamin D receptor-expressing null mice in two transgenic lines. The transgenic mice were grossly normal. The vitamin D receptor null and vitamin D receptor null/human vitamin D receptor mice were growth retarded and developed hypocalcemia, secondary hyperparathyroidism, and rickets. In contrast to the vitamin D receptor null mice that developed alopecia, however, the vitamin D receptor null/human vitamin D receptor mice displayed a normal hair coat, and their hair shaft and skin histology were indistinguishable from those of the wild-type mice. Immunohistochemical analyses revealed that the human vitamin D receptor was highly expressed in the basal layer of the epidermis and outer root sheath of the hair follicle. During follicular morphogenesis, no major histologic differences were seen in the skin of wild-type, vitamin D receptor null, transgenic, and vitamin D receptor null/human vitamin D receptor littermates. When anagen was induced by hair depilation at day 20 after birth, the vitamin D receptor null mice failed to initiate the hair cycle, whereas the vitamin D receptor null/human vitamin D receptor mice displayed the same pattern of anagen follicle formation as the wild-type mice. Interestingly, the transgenic mice initiated the follicular cycle earlier than the wild-type and vitamin D receptor null/human vitamin D receptor mice in a gene concentration-dependent manner. Taken together, these data provide direct evidence that vitamin D receptor is required for the initiation of the postnatal hair follicular cycle in mice.

Topics: Alopecia; Animals; Calcium; Gene Expression; Hair Follicle; Homeostasis; Humans; Keratin-14; Keratins; Mice; Mice, Knockout; Promoter Regions, Genetic; Receptors, Calcitriol; Transgenes

Onset of type I keratin 17 (K17) synthesis marks the adoption of an appendageal fate within embryonic ectoderm, and its expression persists in specific cell types within mature hair, glands, and nail. We report that K17 null mice develop severe alopecia during the first week postbirth, correlating with hair fragility, alterations in follicular histology, and apoptosis in matrix cells. These alterations are incompletely penetrant and normalize starting with the first postnatal cycle. Absence of a hair phenotype correlates with a genetic strain-dependent compensation by related keratins, including K16. These findings reveal a crucial role for K17 in the structural integrity of the first hair produced and the survival of hair-producing cells. Given that identical inherited mutations in this gene can cause either pachyonychia congenita or steatocystoma multiplex, the features of this mouse model suggest that this clinical heterogeneity arises from a cell type-specific, genetically determined compensation by related keratins.

Topics: Age Factors; Alopecia; Animals; Apoptosis; Blotting, Western; Crosses, Genetic; Disease Models, Animal; Genetic Techniques; Genotype; In Situ Nick-End Labeling; Keratins; Mice; Mice, Inbred C57BL; Models, Genetic; Phenotype; Recombination, Genetic; Skin; Species Specificity; Time Factors

RXR-alpha is the most abundant of the three retinoid X receptors (RXRs) in the epidermis. In this study, we have used Cre-mediated recombination to selectively disrupt the mouse gene for RXR-alpha in epidermal and hair follicle keratinocytes. We show that RXR-alpha is apparently dispensable for prenatal epidermal development, while it is involved in postnatal skin maturation. After the first hair pelage, mutant mice develop a progressive alopecia, histologically characterised by the destruction of hair follicle architecture and the formation of utriculi and dermal cysts in adult mice. Our results demonstrate that RXR-alpha plays a key role in anagen initiation during the hair follicle cycle. In addition, RXR-alpha ablation results in epidermal interfollicular hyperplasia with keratinocyte hyperproliferation and aberrant terminal differentiation, accompanied by an inflammatory reaction of the skin. Our data not only provide genetic evidence that RXR-alpha/VDR heterodimers play a major role in controlling hair cycling, but also suggest that additional signalling pathways mediated by RXR-alpha heterodimerised with other nuclear receptors are involved in postnatal hair follicle growth, and homeostasis of proliferation/differentiation of epidermal keratinocytes and of the skin's immune system.

Topics: Alopecia; Animals; beta-Galactosidase; Blotting, Southern; Cell Differentiation; Cloning, Molecular; Cysts; DNA; Epidermis; Female; Genes, Reporter; Hair Follicle; Immunohistochemistry; Integrases; Intercellular Adhesion Molecule-1; Keratinocytes; Keratins; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Plasmids; Receptors, Retinoic Acid; Recombination, Genetic; Retinoid X Receptors; T-Lymphocyte Subsets; Transcription Factors; Transgenes; Viral Proteins

Studying the roles of Hox genes in normal and pathological development of skin and hair requires identification of downstream target genes in genetically defined animal models. We show that transgenic mice overexpressing Hoxc13 in differentiating keratinocytes of hair follicles develop alopecia, accompanied by a progressive pathological skin condition that resembles ichthyosis. Large-scale analysis of differential gene expression in postnatal skin of these mice identified 16 previously unknown and 13 known genes as presumptive Hoxc13 targets. The majority of these targets are downregulated and belong to a subgroup of genes that encode hair-specific keratin-associated proteins (KAPs). Genomic mapping using a mouse hamster radiation hybrid panel showed these genes to reside in a novel KAP gene cluster on mouse chromosome 16 in a region of conserved linkage with human chromosome 21q22.11. Furthermore, data obtained by Hoxc13/lacZ reporter gene analysis in mice that overexpress Hoxc13 suggest negative autoregulatory feedback control of Hoxc13 expression levels, thus providing an entry point for elucidating currently unknown mechanisms that are required for regulating quantitative levels of Hox gene expression. Combined, these results provide a framework for understanding molecular mechanisms of Hoxc13 function in hair growth and development.

Topics: Alopecia; Amino Acid Sequence; Animals; Cell Differentiation; Down-Regulation; Evolution, Molecular; Feedback; Homeodomain Proteins; Keratinocytes; Keratins; Mice; Mice, Transgenic; Molecular Sequence Data; Multigene Family; Phylogeny; Sequence Homology, Amino Acid

Atrichia with papular lesions is a rare inherited skin disorder characterized by congenital atrichia with numerous papules. We describe a 27-year-old woman with atrichia, who had numerous papules on her scalp, nape, and axillae. Histologically, many keratinous cysts were seen in the middermis of a skin specimen from the nape. Electron microscopy showed that the developing keratinocytes in the walls of some cysts were rich in glycogen granules and had epidermoid keratinization with formation of keratohyaline granules and that laminated bodies were formed before keratinization. Langerhans cells were often seen in the walls of the cysts. In addition, a broad glassy vitreous layer surrounded the cyst wall. From these findings, it was suggested that the cystic lesions might have originated from immature or incomplete hair follicles. In particular, the structure of the cyst wall corresponded well to infundibular and/or isthmal portions of the outer root sheath of the hair follicle.

Topics: Adult; Alopecia; Cysts; Female; Humans; Keratinocytes; Keratins; Microscopy, Electron; Skin; Skin Diseases

Olmsted syndrome is an uncommon inherited disorder of keratinization that presents mutilating palmoplantar keratoderma, perioral hyperkeratosis, leukokeratosis and alopecia. We report a case of this rare syndrome diagnosed in a 48-year-old woman and confirms the existence of a generalized abnormality in keratin expression. Immunoreactivity in our case suggests an abnormal expression of keratins 5 and 14 similar to the observed in other hyperproliferative disorders.

Topics: Abnormalities, Multiple; Alopecia; Antibodies, Monoclonal; Female; Humans; Immunoenzyme Techniques; Keratins; Keratoderma, Palmoplantar; Leukoplakia, Oral; Middle Aged; Skin; Syndrome

The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate epidermal barrier defect. The epidermis is fragile, and acantholysis in the granular layer generates localized lesions, compromising skin barrier function. Neutrophils accumulate in the lesions and further degrade the tissue, causing sloughing (flaking) of lesional epidermis, but rapid wound healing prevents the formation of overt lesions. Null epidermis is hyperproliferative and overexpresses keratins 6 and 16, indicating abnormal differentiation. From 6 wk, null mice develop ulcerating lesions resembling chronic dermatitis. We speculate that ulceration occurs after acantholysis in the fragile epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human blistering diseases is discussed. These results show that Dsc1 is required for strong adhesion and barrier maintenance in epidermis and contributes to epidermal differentiation.

Topics: Aging; Alopecia; Animals; Antigens, CD; Cadherins; Cell Differentiation; Cell Division; Dermatitis; Desmocollins; Desmosomes; Epidermis; Eyelids; Gene Targeting; Immunohistochemistry; Integrin beta4; Keratins; Ki-67 Antigen; Membrane Glycoproteins; Mice; Mice, Transgenic; Phenotype; Protein Isoforms; Recombination, Genetic; Skin Diseases

Hair follicle (HF) growth and regression is an exquisitely regulated process of cell proliferation followed by massive cell death and is accompanied by cyclical expression of the apoptosis regulatory gene pair, Bcl-2 and Bax. To further investigate the role of Bcl-2 expression in the control of hair growth and keratinocyte apoptosis, we have used transgenic mice that overexpress human Bcl-2 in basal epidermis and in the outer root sheath under the control of the human keratin-14 promoter (K14/Bcl-2). When irradiated with ultraviolet B (UVB) light, K14/Bcl-2 mice developed about 5-10-fold fewer sunburn cells (ie, apoptotic keratinocytes) in the basal layer of the epidermis, compared to wild-type mice, whereas cultures of primary keratinocytes from transgenic mice were completely resistant to UVB-induced histone formation, at doses that readily induced histone release from wild-type cells. K14/Bcl-2 mice show no alteration of neonatal hair follicle morphogenesis or of the onset of the first wave of HF regression (catagen). However, compared to wild-type controls, K14/Bcl-2 mice subsequently displayed a significant acceleration of spontaneous catagen progression. During chemotherapy-induced alopecia, follicular dystrophy was promoted in K14/Bcl-2 mice. Thus, although K14-driven overexpression of Bcl-2 protected murine epidermal keratinocytes from UVB-induced apoptosis, it surprisingly promoted catagen- and chemotherapy-associated keratinocyte apoptosis.

Topics: Alopecia; Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Cyclophosphamide; Epidermis; Gene Expression; Hair Follicle; Humans; Keratin-14; Keratinocytes; Keratins; Mice; Mice, Inbred Strains; Mice, Transgenic; Phenotype; Proto-Oncogene Proteins c-bcl-2; Reference Values; Skin; Sunburn; Transgenes; Ultraviolet Rays

The biological effects of 1,25-dihydroxyvitamin D3 are mediated by a nuclear receptor, the vitamin D receptor (VDR). Targeted ablation of the VDR in mice results in hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, osteomalacia, and alopecia. Normalization of mineral ion homeostasis prevents these abnormalities with the exception of the alopecia. Because 1,25(OH)2D3 has been shown to play a role in keratinocyte proliferation and differentiation, we undertook studies in primary keratinocytes and skin isolated from VDR null mice to determine if a keratinocyte abnormality could explain the alopecia observed. The basal proliferation rate of the VDR null and wild-type keratinocytes was identical both under proliferating and differentiating conditions. Assessment of in vivo keratinocyte proliferation at 4 days of age confirmed that VDR ablation did not have a significant effect. There was no difference in the basal expression of markers of keratinocyte differentiation (keratin 1, involucrin, and loricrin) in the keratinocytes isolated from VDR-ablated mice when compared with those isolated from control littermates. Similarly, in vivo expression of these genes was not altered at 4 days of age. When anagen was induced by depilation at 18 days of age, the VDR null mice had a profound impairment in initiation of the hair cycle. These data suggest that the alopecia in the VDR null mice is not attributable to an intrinsic defect in keratinocyte proliferation or differentiation, but rather to an abnormality in initiation of the hair cycle.

Topics: Alopecia; Animals; Calcitriol; Calcium; Cell Differentiation; Cell Division; Cells, Cultured; Keratinocytes; Keratins; Membrane Proteins; Mice; Mice, Hairless; Mice, Knockout; Mutation; Protein Precursors; Receptors, Calcitriol

Topics: Alopecia; Hair; Humans; Keratins; Point Mutation

The type I epidermal keratins K14 and K16 are remarkably similar at the primary sequence level. While a structural function has been clearly defined for K14, we have proposed that a function of K16 may be to play a role in the process of keratinocyte activation that occurs after acute injury to stratified epithelia. To compare directly the functions of the two keratins we have targeted the expression of the human K16 cDNA to the progenitor basal layer of the epidermis of K14 null mice. Mice null for K14 blister extensively and die approximately 2 d after birth (Lloyd, C., Q.C. Yu, J. Cheng, K. Turksen, L. Degenstein, E. Hutton, and E. Fuchs. 1995. J. Cell Biol. 129:1329-1344). The skin of mice expressing K16 in the absence of K14 developed normally without evidence of blistering. However, as the mice aged they featured extensive alopecia, chronic epidermal ulcers in areas of frequent physical contact, and alterations in other stratified epithelia. Mice expressing a control K16-C14 cDNA also rescue the blistering phenotype of the K14 null mice with only a small percentage exhibiting minor alopecia. While K16 is capable of rescuing the blistering, phenotypic complementation in the resulting skin is incomplete due to the multiple age dependent anomalies. Despite their high sequence similarity, K16 and K14 are not functionally equivalent in the epidermis and other stratified epithelia and it is primarily the carboxy-terminal approximately 105 amino acids of K16 that define these differences.

Topics: Aging; Alopecia; Animals; Animals, Newborn; Blister; Cells, Cultured; Epidermis; Female; Gene Deletion; Genetic Complementation Test; Hair Follicle; Humans; Keratinocytes; Keratins; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Recombinant Fusion Proteins; Regeneration; RNA, Messenger; Skin; Solubility; Transgenes

Mouse keratin 6a (MK6a) is constitutively expressed in a single cell layer of the outer root sheath (ORS) of hair follicles, but its synthesis can be induced in interfollicular epidermis including the basal cell layer in response to perturbing stimuli. A basally inducible human K6 (HK6) isoform has not been described, and it is not clear which of the known HK6 isoforms is expressed in the ORS. In this study we show that expression of a dominant-negative MK6a construct (Delta2B-P) in the interfollicular epidermis caused severe blistering and neonatal lethality, suggesting that mutations in a yet to be identified basally expressed HK6 isoform might result in a severe blistering phenotype. Surviving Delta2B-P animals showed transgene expression only in isolated epidermal cells and not in all cells of the ORS, but nevertheless developed severe alopecia. Expression of two different C-terminal mutant transgenes also caused alopecia while a third C-terminal mutant had no phenotypic conse- quences. Electron microscopy revealed that Delta2B-P expression resulted in the collapse of keratin filaments, while destruction of hair follicles in the two phenotypic C-terminal mutant lines occurred in the absence of filament abnormalities. The latter finding indicates that the innermost ORS cells are uniquely sensitive to expression of even slightly altered K6 proteins, suggesting that mutations affecting an HK6 isoform expressed in this cell layer could result in alopecia in humans as well.

Topics: Age of Onset; Alopecia; Amino Acid Sequence; Animals; Animals, Newborn; Epidermis; Gene Expression; Genes, Dominant; Hair Follicle; Keratins; Mice; Mice, Inbred BALB C; Mice, Transgenic; Microscopy, Electron; Molecular Sequence Data; Mutagenesis, Site-Directed; Phenotype; Protein Isoforms; Skin Diseases; Time Factors; Transgenes

Monilethrix is an autosomal dominant hair disorder characterized by a beaded appearance of the hair due to periodic thinning of the shaft. The phenotype shows variable penetrance and results in hair fragility and patchy dystrophic alopecia. Mutations of the helix-encoding region in two hair-specific keratins (hHb1 and hHb6) have been identified. We have now investigated two unrelated monilethrix patients and identified two different novel heterozygous point mutations of the same codon in exon 7 of the hHb6 gene. Dystrophic hair samples obtained from both patients showed the typical beaded appearance by scanning electron microscopy. Both mutations affected the first base of codon 402 (glutamic acid). In patient A, a G to C transition occurred causing a glutamine substitution (GAG to CAG: E402Q) whereas in patient B, the transition was G to A yielding a lysine substitution (GAG to AAG: E402K). The sequence of the 1A helical regions of hHb1 and hHb6 as well as the 2B helical region of hHb1, were normal. Unaffected relatives did not have the hHb6 mutation and this codon was found to be highly conserved showing no alteration in the normal population (100 alleles examined). Both mutations disrupted a Taq I restriction site and restriction fragment length polymorphism analysis showed that a diagnostic 361 bp fragment could confirm the mutation. Thus, two new point mutations of the hair-specific keratin gene hHb6 have been identified in this genetic disease.

Topics: Alopecia; Codon; Hair; Humans; Keratins; Mutation; Polymorphism, Restriction Fragment Length

Several clinical syndromes are characterized by ectodermal dysplasia (ED) in association with clefting of the lip and/or palate. In these syndromes, alopecia is primarily due to abnormalities of the hair shaft associated with increased hair fragility. Scalp dermatitis is yet another peculiar finding, primarily seen in the ankyloblepharon-ED-clefting (AEC) syndrome. We report on a 16-year-old patient with ectrodactyly-ED-clefting (EEC) syndrome, who exhibited a scarring alopecia due to deep folliculitis. On scanning electron microscopy, irregular torsion and longitudinal grooving of the hair shaft (pili torti et canaliculi) were observed. Quantitative determinations of the elastic and viscous parameters of hair demonstrated a normal viscosity but a significantly reduced hair elasticity, indicating either an abnormal composition or a disordered arrangement of microfibrils within the apparently normal keratin matrix. In contrast to the erosive scalp dermatitis of early onset in the AEC syndrome, alopecia in this case of EEC syndrome demonstrated follicular scarring with onset during puberty. We question a possible role of the anatomical hair abnormality in the pathogenesis of chronic deep folliculitis in this and clinically related syndromes.

Topics: Adolescent; Alopecia; Biophysical Phenomena; Biophysics; Cicatrix; Cleft Lip; Cleft Palate; Dermatomycoses; Ectodermal Dysplasia; Elasticity; Fingers; Folliculitis; Hair; Humans; Keratins; Malassezia; Male; Microscopy, Electron, Scanning; Puberty; Scalp Dermatoses; Staphylococcal Skin Infections; Syndrome; Viscosity

Monilethrix is an autosomal dominant disorder chiefly affecting hair. The degree of hair dystrophy is highly variable, as is the presence of additional features, such as follicular keratoses. In three British families of monilethrix, linkage has recently been reported to the type II keratin gene cluster at chromosome 12q13, and it has been suggested that the disease is due to a defect in the hard keratins of hair and nail. If monilethrix is a keratin disorder, we would predict that some pedigrees might map to the type I keratin gene cluster on 17q where hard keratin genes are also found. We have now studied clinically and by linkage analysis three new and unrelated pedigrees from England, Scotland and Spain, the first of which showed a variant phenotype. In this family the disease was expressed in four of 12 cases only as a follicular-keratosis of the neck, elbows and knees, and without clinical or historical evidence of hair anomalies; non-penetrance in an obligate carrier was also observed. In all three families, we have established linkage to a series of microsatellite markers at the type II locus at 12q13 (Zmax = 6.34 at theta = 0.00 for D12S368) and have excluded linkage from the type I keratin gene cluster on 17q. It remains probable that monilethrix is a disorder of hard keratins, but at present there is no evidence that it is due to defects in type I keratins.

Topics: Alopecia; Chromosome Mapping; Chromosomes, Human, Pair 12; Female; Hair Diseases; Humans; Keratins; Lod Score; Male; Microsatellite Repeats; Pedigree; Phenotype

Trichorhinophalangeal syndrome (TRPS) comprises a distinctive combination of hair, facial and bony abnormalities with variable expression. A 20-year-old man with TRPS was seen because of marked androgenetic alopecia. Scanning electron-microscopic studies of the hair revealed flattened hair with an elliptoid transverse section pattern. Mechanical behavior of the hair was abnormal with a significant increase in the viscous parameter, indicating a decreased intermolecular bridging within the keratin matrix. The dermatologist confronted with premature or marked alopecia in young adults should always consider the possibility of an underlying congenital syndrome involving the hair and prompt further investigation.

Topics: Adult; Alopecia; Elasticity; Finger Joint; Fingers; Hair; Humans; Keratins; Male; Microscopy, Electron, Scanning; Nose; Syndrome; Viscosity

A vector, derived from the human K1 keratin gene, has been employed to target v-fos expression exclusively in the epidermis of transgenic mice. Adult transgenic mice expressors (3-4 months) displayed hyperplasia and hyperkeratosis, initially in wounded (tagged) ears, which later became bilateral. This phenotype appeared at other epidermal sites, most notably in the axilla and inguinal areas. This indicates that a second promoting event, such as wounding or friction, is required to elicit these pathological changes. Highly keratotic benign ear lesions and benign squamous papillomas appeared after long latency at sites of phenotypic epidermis. These data suggest that v-fos may be interfering with c-fos function in normal keratinocyte differentiation, but by itself is insufficient to elicit overt benign lesions.

Topics: Alopecia; Animals; Base Sequence; Cell Differentiation; Epidermis; Gene Expression Regulation, Neoplastic; Genes, fos; Hyperplasia; Keratins; Keratosis; Mice; Mice, Transgenic; Molecular Sequence Data; Oncogene Proteins v-fos; Proto-Oncogene Proteins c-fos; Skin Neoplasms

The clinicopathological features of the scarring alopecia of discoid lupus erythematosus (DLE) were studied. Scarring alopecia was present in 34% of 89 patients with DLE and was associated with a prolonged disease course. More than half these patients had scalp involvement at the onset of the disease. There was a significant reduction in size of sebaceous glands in affected scalp. Perifollicular lymphocytic inflammation was maximal around the mid-follicle at the level of the sebaceous gland, which seems to be an important functional level in the follicle. There are changes in the expression of the matrix molecules, the proteoglycans, in the connective tissue sheath and the keratin intermediate filaments in the outer root sheath cells at this level in normal scalp and in diseased scalp. Loss of a population of mid-follicular stem cells may be important in the pathogenesis of scarring alopecia in DLE.

Topics: Adolescent; Adult; Aged; Alopecia; Chronic Disease; Female; Humans; Immunohistochemistry; Keratins; Lupus Erythematosus, Discoid; Male; Middle Aged; Scalp; Sebaceous Glands; Skin Diseases

A 37-year-old woman developed ichthyosiform desquamation of the skin and a severe diffuse alopoecia 3 weeks after taking the antidepressant maprotilin. No signs of inflammation were present. Histology revealed acanthosis with preserved stratum granulosum, follicular hyperkeratosis and dystrophic changes of the hair follicle. Electron microscopy revealed rarefication of tonofilaments and necrobiotic changes of epidermal keratinocytes with vacuolar degeneration of the cytoplasm and disorganization of the organelles. Pathogenetically this disease represents a drug-induced transitory disorder to keratinization, which had resulted in desquamation of the stratum corneum and alopecia. The authors propose the designation corneolysis for this pathogenetic principle.

Topics: Adjustment Disorders; Adult; Alopecia; Female; Humans; Huntington Disease; Ichthyosis; Keratins; Maprotiline; Microscopy, Electron; Skin

Ichthyosis follicularis (IF) is a rare disorder of keratinization that has been described primarily in males and proposed as a possible X-linked disorder. We report two black girls with nonscarring alopecia; photophobia; follicular hyperkeratoses; hyperkeratosis of the extensor aspects of the hands, knees, and elbows; fixed, erythematous, perineal plaques; and angular cheilitis who seem to fit the clinical criteria for IF. One girl also had gingival hypertrophy and a hearing deficit. One child's father had identical symptoms. We propose that these girls may have a variant of IF that is inherited as an autosomal dominant trait.

Topics: Alopecia; Child, Preschool; Female; Humans; Ichthyosis, X-Linked; Keratins; Nail Diseases

Topics: Alopecia; Female; Hair; Humans; Keratins; Male

Topics: Alopecia; Brain Neoplasms; Cobalt Radioisotopes; Facial Dermatoses; Forehead; Glioma; Hair Diseases; Humans; Keratins; Male; Middle Aged; Scalp Dermatoses; Skin Pigmentation

Topics: Alopecia; Animals; Cell Membrane; Cytoplasm; Glutaral; Histological Techniques; Keratins; Mice; Mice, Inbred Strains; Microscopy, Electron; Osmium; Rodent Diseases; Skin; Species Specificity; Staining and Labeling

Topics: Alopecia; Biomechanical Phenomena; Elasticity; Female; Genetic Diseases, Inborn; Hair; Homocystinuria; Humans; Hyperthyroidism; Hypothyroidism; Ichthyosis; Keratins; Keratosis; Male; Oxidation-Reduction; Skin Diseases; Ultrasonography; X-Ray Diffraction

Topics: Alopecia; Antineoplastic Agents; Cantharidin; Culture Techniques; Hair; Humans; Keratins; Mitosis

Topics: Alopecia; Alopecia Areata; Dermatitis; Dermatitis, Atopic; Dermatitis, Seborrheic; Dermatology; Humans; Keratins; Mercury; Nails; Ointments; Pigmentation; Psoriasis