Epidemiology and clinical characteristics of bullous congenital ichthyosiform erythroderma (keratinolytic ichthyosis) in Japan: results from a nationwide survey.

BACKGROUND: Detailed nationwide surveys of the epidemiologic and clinical characteristics of bullous congenital ichthyosiform erythroderma (BCIE) (novel synonym: keratinolytic ichthyosis) in a large population have not been performed previously to our knowledge. OBJECTIVE: We sought to estimate the number of patients with BCIE who visited dermatology departments in Japan in 2002 and to clarify the clinical and epidemiologic features of the disease. METHODS: A nationwide mail survey was sent to dermatology departments and consisted of an initial survey to estimate the number of individuals with BCIE and a second survey to obtain data on the clinical characteristics of these patients. RESULTS: The total number of patients with BCIE in Japan was estimated to be 55 (95% confidence interval, 35-75). Clinical data were able to be collected from 28 cases. Clinical manifestations included rash in 27 cases (96.4%), erythroderma in 19 cases (67.9%), and generalized blistering in 15 cases (57.7%). Approximately 75% of patients younger than 20 years showed generalized blistering. Hystrixlike scales were present in 8 female patients (57.1%), whereas large scales were present in 8 male patients (57.1%). Among the 19 patients for whom histopathological information was available, 17 (89.5%) showed granular degeneration. LIMITATIONS: Patients with BCIE who have few subjective symptoms may not have visited a dermatology department, potentially resulting in an underestimation of the number of patients with BCIE. CONCLUSION: Important epidemiologic and clinical information on characteristics of BCIE in Japan was obtained, including an estimate of the total number of patients with BCIE in Japan.

Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings.

A Danish-Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations.

The cellular and molecular biology of keratins: beginning a new era.

The past year has been extremely fruitful for research on intermediate filaments in general, and keratins in particular. Unprecedented progress has been made in our understanding of the structural requirements for keratin filament assembly and network formation, the dynamism characterizing keratin filaments, their function, and implication in human genetic disorders primarily affecting the skin. These exciting findings have several implications for future research.

Arsenic exposure, dermatological lesions, hypertension, and chromosomal abnormalities among people in a rural community of northwest Iran.

Chronic exposure to arsenic compounds is one of the major public-health problems in many developing and some developed countries. The aim of this study was to investigate the effects of chronic exposure to arsenic on dermatological lesions, hypertension, and chromosomal abnormalities among people in a community in the northwest of Iran. The occurrence of dermatological lesions, hypertension, and chromosomal abnormalities was investigated in two groups: Ghopuz village, including 101 subjects with chronic exposure to arsenic in drinking-water and Mayan village, including 107 subjects with no exposure. Daily/yearly absorbed amounts of arsenic were calculated for all subjects. Cumulative arsenic index for each individual was then estimated on the basis of age, water consumption, and location of residence. Arsenic concentration in drinking-water sources in Ghopuz and Mayan villages was 1031 +/- 1103 microg/L and non-detectable respectively. The mean systolic blood pressure in the exposure group [n=137, 95% confidence interval (CI 132-142)] was significantly higher than that in the control group (n=107, 95% CI 99.9-114). A similar significant difference was observed for diastolic blood pressure (exposed: n=82, 95% CI 79-85 vs non-exposed: n=71, 95% CI 66-75). The incidence of hyperkeratosis was 34 times higher among the exposure group compared to the control subjects [odds ratio (OR)=34, p<0.001)]. A significant difference was also observed in the occurrence of skin-pigmentation between the two groups (OR=2.4, p<0.007). Location and severity of the pigmentations were statistically different between the two groups. Twenty-five percent of the subjects in the exposure group showed chromosomal abnormalities (p=0.05). Arsenic exposure was a serious health problem in the region. More studies are needed to investigate the long-term effects and dose-response relationship of arsenic in the region and similar areas. Wide-ranging monitoring programmes for drinking-water sources should be implemented by public-health authorities.

Prenatal diagnosis of epidermolytic hyperkeratosis by direct gene sequencing.

Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma) is an autosomal dominant skin disorder caused by defects in the suprabasal keratins. Recently, mutations in the keratins 1 and 10 have been identified in patients with this disease. In this study, direct gene sequencing was used to establish the prenatal diagnosis in 15-week gestation twins at risk for epidermolytic hyperkeratosis. Direct sequence analysis of genomic DNA from the affected father and from both chorionic villus samples revealed a tyrosine to asparagine mutation at position 14 within the highly conserved 1A alpha-helical segment of keratin 10. None of the unaffected family members that were analyzed exhibit this mutation nor have polymorphic variations been observed in the normal population at this position. This residue is invariant in all type I keratins sequenced to date and is also conserved in related intermediate filament proteins such as vimentin and lamin. Given this high degree of conservation it is probable that any mutation at this position is deleterious and will result in disease.

Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations.

In West Bengal, India more than 6 million people are exposed to high levels of arsenic through drinking water. Since, only 15-20% of the exposed individuals show arsenic-induced skin lesions, it is assumed that genetic variation might play an important role in arsenic toxicity and carcinogenicity. Arsenic exposure often leads to the development of hyperkeratosis, the precursor of arsenic-induced skin cancer. ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2) is a nucleotide excision repair pathway gene, and its SNPs have been implicated in several types of epithelial cancers. We investigated the possible association of ERCC2 codon 751 A-->C polymorphism (lysine to glutamine) with arsenic-induced hyperkeratosis and correlated ERCC2 genotypes with increased frequencies of chromosomal aberration to ascertain whether any genotype leads to sub-optimal DNA repair. For this association study, 318 unrelated arsenic exposed subjects (165 with hyperkeratosis and 153 without any arsenic-induced skin lesions), drinking water contaminated with arsenic to a similar extent, were recruited. Genotyping was done through PCR-RFLP procedure. Lys/Lys genotype was significantly over-represented in the arsenic-induced hyperkeratosis-exhibiting group [odds ratio (OR) = 4.77, 95% confidence interval (CI) = 2.75-8.23]. A statistically significant increase in both CA/cell and percentage of aberrant cells was observed in the individuals with AA genotype compared to those with AC or CC genotype combined (P < 0.01) in each of the two study groups, as also, in the total study population. This study indicates that ERCC2 codon 751 Lys/Lys genotype is significantly associated with arsenic-induced premalignant hyperkeratosis and is possibly due to sub-optimal DNA repair capacity of the ERCC2 codon 751 Lys/Lys genotype.