bromochloroacetic-acid and Keratoderma--Palmoplantar--Diffuse

Topics: Cations; Connexin 26; Connexins; Deafness; Genes, Recessive; Humans; Ichthyosis; Ion Transport; Keratinocytes; Keratins; Keratitis; Keratoderma, Palmoplantar; Keratoderma, Palmoplantar, Diffuse; Mosaicism; Nevus; Porokeratosis; Skin Diseases, Genetic; Sweat Gland Neoplasms; TRPV Cation Channels

A clinically and genetically heterogeneous group of disorders, known collectively as the palmoplantar keratodermas, are unified by the phenotypic characteristic of a thickening of the skin over the palms and soles. Although spectacular progress has been made in understanding the basis of many genodermatoses, the genetic defects causing many of the keratodermas are still largely unknown. These unusual phenotypes are beginning to capture the attention of investigators in epidermal biology, and several compelling lines of evidence point to the cornified cell envelope and structural components of the desmosome as potential underlying targets of disease. It is anticipated that understanding the molecular basis of the keratodermas will underscore the importance of the integrity of the cell envelope and the desmosome, and provide new insights into the mechanisms of epidermal differentiation and related disorders.

Topics: Animals; Autoantibodies; Cell Differentiation; Cell Membrane; Desmosomes; Epidermal Cells; Esophageal Neoplasms; Genetic Linkage; Humans; Keratins; Keratoderma, Palmoplantar; Keratoderma, Palmoplantar, Diffuse; Keratosis; Membrane Proteins; Mice; Mice, Transgenic; Pemphigus; Protein Precursors

The inherited palmoplantar keratodermas (PPK) constitute a complex heterogeneous group of genodermatoses, which are difficult to classify clinically. The application of modern molecular biology techniques are leading to an increased understanding of the genetic bases of these disorders and are paving the way towards a classification based upon molecular pathology. We review the recent research advances in this field and the implications for development of novel approaches to disease management.

Topics: Humans; Keratins; Keratoderma, Palmoplantar; Keratoderma, Palmoplantar, Diffuse; Mutation

Topics: Animals; Epidermolysis Bullosa; Gene Expression; Humans; Hyperkeratosis, Epidermolytic; Intermediate Filaments; Keratins; Keratoderma, Palmoplantar, Diffuse; Mice; Mice, Transgenic; Point Mutation; Skin Diseases

Topics: China; Humans; Keratin-16; Keratin-9; Keratins; Keratoderma, Palmoplantar; Keratoderma, Palmoplantar, Diffuse; Mutation; Papilloma; Pedigree

Keratin gene mutations affecting nonhelical head and tail domains are not usually associated with prominent skin blistering and keratin filament clumping. Instead, they have been associated with several distinct clinical phenotypes, such as epidermolysis bullosa simplex with mottled pigmentation (mutation P25L in the V1 domain of keratin 5), epidermolysis bullosa simplex with migratory circinate erythema (frameshift mutation c1649delG in the V2 domain of keratin 5), striate palmoplantar keratoderma (PPK), and ichthyosis hystrix Curth-Macklin (different frameshift mutations in the V2 domain of keratin 1 (K1)). We have studied a family with severe, diffuse, nonepidermolytic PPK and verrucous hyperkeratotic plaques over the joints and in flexures and identified a new KRT1 gene mutation that is predicted to completely alter the K1 tail domain. In addition, a new K1 size polymorphism has been detected, which is especially prevalent among the African-American population. These results further emphasize the functional importance of the nonhelical tail domain in keratin molecules despite the obvious variability in the number of glycine loop motifs and underscore the broad phenotypic spectrum of disorders due to dominant keratin tail mutations.

Topics: Adolescent; Adult; Amino Acid Sequence; Base Sequence; Black or African American; Female; Glycine; Humans; Keratin-1; Keratins; Keratoderma, Palmoplantar, Diffuse; Male; Molecular Sequence Data; Mutation; Polymorphism, Genetic; Protein Structure, Tertiary; Sequence Deletion

Topics: Adolescent; Base Sequence; DNA Mutational Analysis; Follow-Up Studies; Foot Dermatoses; Genetic Predisposition to Disease; Hand Dermatoses; Humans; Japan; Keratins; Keratoderma, Palmoplantar, Diffuse; Keratosis; Male; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Risk Assessment; Severity of Illness Index

To identify the gene causing diffuse palmoplantar keratoderma in a Chinese pedigree.. Four normal individuals and 3 patients in a diffuse palmoplantar keratoderma family and 10 unrelated control samples were recruited. The hotspot of the mutations of keratin 9 gene was analyzed by polymerase chain reaction and direct sequencing.. We found a G485A transition in ke ratin 9 gene, resulting in the substitution of glutamine for arginine at codon 162 in this diffuse palmoplantar keratoderma family. The mutation was not found in the 10 unrelated control samples and 4 normal individuals.. The mutation G485A found in keratin 9 gene is the disease-causing mutation in the diffuse palmoplantar keratoderma family.

Topics: Base Sequence; DNA Mutational Analysis; Female; Heterozygote; Humans; Keratins; Keratoderma, Palmoplantar, Diffuse; Male; Molecular Sequence Data; Mutation; Pedigree

Topics: Amino Acid Substitution; Female; Humans; Infant; Keratins; Keratoderma, Palmoplantar, Diffuse; Point Mutation; Skin

We described a 5-year-old Japanese girl with epidermolytic palmoplantar keratoderma and examined her for a keratin 9 gene mutation. Physical examination disclosed diffuse yellowish hyperkeratosis with an erythematous border limited strictly to the palms and soles. Histological examination revealed hyperkeratosis with vacuolar degeneration in the spinous and granular layers of the epidermis. Sequence analysis demonstrated an A to G transition at the middle position of codon 160 in the 1A domain of the keratin 9 gene. The amino acid at codon 160 was deduced to have changed from asparagine (Asn) to serine (Ser). This is the first case with an Asn160Ser mutation in a Japanese. The substitution of Ser for Asn at codon 160 of the keratin 9 gene is assumed to be fatal for keratin filament assembly regardless of race or ethnicity.

Topics: Asian People; Biopsy, Needle; Child, Preschool; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Japan; Keratins; Keratoderma, Palmoplantar, Diffuse; Mutation; Point Mutation; Polymerase Chain Reaction

Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) belongs to the heterogeneous group of skin diseases characterized by thickening of the stratum corneum of the palms and soles (1). This autosomal dominant PPK is characterized by a diffuse pattern of palmar and plantar hyperkeratosis giving the affected areas a thickened yellowish appearance with a marked erythematous edge. Linkage of diffuse NEPPK to chromosome 12q11-q13 has been demonstrated in two independent reports (2, 3). In this study, we describe detailed haplotyping with microsatellite markers mapping to this chromosomal region in three diffuse NEPPK pedigrees from the south of England. Fine mapping of a previously identified recombination event and the identification of a common disease haplotype segregating in the three pedigrees places the diffuse NEPPK locus proximal to the type II keratin gene cluster.

Topics: Chromosome Mapping; Chromosomes, Human, Pair 12; Female; Genetic Linkage; Haplotypes; Humans; Keratins; Keratoderma, Palmoplantar, Diffuse; Male; Microsatellite Repeats; Multigene Family; Pedigree

An increasing number of syndromes with palmoplantar keratoderma (PPK) with associated diseases are being identified, representing a wide spectrum of distinct entities. At present only one case report has described the combination of marked anogenital leukokeratosis with diffuse PPK evolving in a collodion baby. We report a patient with a diffuse, nonprogressive PPK in combination with an intermittently pruritic, slowly progressive anogenital leukokeratosis. Hyperkeratosis of the perineal area was most pronounced and extended to the distal portion of the anal mucosa. The opalescent lesion was also visualized at the margin of the major labia. Vulvar structures were not otherwise involved or dystrophic. There were no signs or symptoms of ectodermal dysplasia. Specifically, the nails were normal and showed no signs of pachyonychia congenita. Other differential diagnoses included dyskeratosis congenita and white sponge nevus, which may be associated with anogenital leukokeratosis, but a keratoderma is not associated with these entities. Keratin immunocytochemistry showed marked expression of suprabasal K17 and absence of K6 and K16. Further examination of the initial case described by Itin and Rufli demonstrated the same expression pattern and supports the contention that these two cases represent the same entity.

Topics: Adult; Anal Canal; Female; Genital Neoplasms, Female; Hand Dermatoses; Humans; Immunohistochemistry; Keratins; Keratoderma, Palmoplantar, Diffuse; Leukoplakia; Skin

Some hereditary palmoplantar keratodermas (PPK) have been defined at the molecular level.. Our purpose was to establish the cause of a hereditary PPK with unique histopathologic findings in the epidermis.. Investigative studies included light and electron microscopy and determination of genomic DNA sequence.. Six patients with PPK were found to have unique changes in the epidermis characterized by orthokeratosis, parakeratosis, perinuclear vacuolization, and keratohyalin granules that varied in size and shape and were located in the cell periphery. Electron microscopy showed the perinuclear region contained many ribosomes and vacuoles and was surrounded by a tonofibril shell. Family involvement suggested a dominant disorder. However, no mutation of keratin genes 1, 6a, 9, or 16 was found.. The histopathologic features of this unique PPK most closely resemble Curth-Macklin ichthyosis for which the genetic basis has not been established. Further genetic studies are needed.

Topics: Biopsy; Diagnosis, Differential; Female; Humans; Hyperkeratosis, Epidermolytic; Keratins; Keratoderma, Palmoplantar; Keratoderma, Palmoplantar, Diffuse; Male; Point Mutation; Skin

In 1901, Vörner described a diffuse keratoderma of palms and soles with autosomal dominant inheritance. Histopathologically, this disease has the typical features of epidermolytic hyperkeratosis. Clinical examination does not allow differentiation between keratoderma of the Vörner type and the keratoderma described by Thost in 1880 and Unna in 1883. Reexamination of the family originally seen by Thost revealed histopathological signs of epidermolytic hyperkeratosis, confirming that keratoderma of the Vörner type is present in this family. The clinical features and variability of this palmoplantar keratoderma were demonstrated on the basis of an examination of 22 families (46 patients). In addition to diffuse hyperkeratosis of palms and soles with a sharp demarcation and erythematous margin, some less well-known features, such as knuckle pad-like keratoses on the finger joints and clubbing of the nails were observed. A genetic analysis of the pedigrees suggests that new mutations causing this disorder rarely occur. Point mutations in the keratin 9 gene, which has been mapped to chromosome 17q21, can be a cause of epidermolytic keratoderma of palms and soles. Five different keratin 9 gene mutations were identified. All these mutations are localized in the highly conserved coil 1A region of the rod domain, which is thought to be relevant for dimer formation in intermediate filaments.

Topics: Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 18; Female; Genes, Dominant; Humans; Keratins; Keratoderma, Palmoplantar, Diffuse; Male; Phenotype; Point Mutation; Skin

Mutations in keratin 9 have been found in families with an epidermolytic form of palmar-plantar keratoderma (PPK). In another form of PPK (Unna-Thost type), epidermolysis is not observed histologically. We studied a pedigree with this non-epidermolytic form of PPK. By gene linkage analysis, the type I keratin locus could be excluded but complete linkage with the type II keratin region was found. Sequence analysis identified a single base change in the amino-terminal V1 variable subdomain of keratin 1, which caused a lysine to isoleucine substitution. This non-conservative mutation completely cosegregated with the disease and was not observed in 50 unrelated unaffected individuals. An examination of keratin amino-terminal sequences revealed a previously unreported 22-residue window in the V1 subdomain that is conserved among most type II keratins. The altered lysine is an invariant residue in this conserved sequence. Previously described keratin mutations affect the central regions important for filament assembly and stability, and cause diseases characterized by cellular degeneration or disruption. This is the first disease mutation in a keratin chain variable end region. The observation that it is not associated with epidermolysis supports the concept that the amino-terminal domain of keratins may be involved in supramolecular interactions of keratin filaments rather than stability. Therefore, hyperkeratosis associated with this mutation may be due to perturbations in the interactions of the keratin end domain with other cellular components.

Topics: Adult; Amino Acid Sequence; Base Sequence; Female; Gene Amplification; Genetic Linkage; Humans; Keratins; Keratoderma, Palmoplantar; Keratoderma, Palmoplantar, Diffuse; Lysine; Male; Molecular Sequence Data; Mutation; Pedigree

Hereditary palmoplantar keratoderma is characterized by hyperkeratosis of the skin of palms and soles. An autosomal dominant form of diffuse non-epidermolytic palmoplantar keratoderma, frequently complicated by fungal infections, is encountered in northern Sweden with a prevalence of 0.3-0.55%. We have examined two families with this type of palmoplantar keratoderma and localized the causative genetic defect to a 14 cM interval on chromosome 12q11-q13, a region known to contain the keratin type II gene cluster as well as the retinoic acid receptor gamma gene. The palmoplantar keratoderma variant investigated in this study is thus genetically different from epidermolytic palmoplantar keratoderma, which recently has been shown to result from mutations in the gene for the type I keratin 9.

Topics: Chromosome Mapping; Chromosomes, Human, Pair 12; DNA; Family; Female; Genes, Dominant; Genetic Linkage; Genetic Markers; Humans; Keratins; Keratoderma, Palmoplantar, Diffuse; Male; Multigene Family; Pedigree; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Sweden

Topics: Chromosome Mapping; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 17; Esophageal Neoplasms; Female; Humans; Keratins; Keratoderma, Palmoplantar, Diffuse; Male; Pedigree