The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron.

Progressive symmetric erythrokeratoderma of Gottron (PSEK) is commonly distinguished from erythrokeratodermia variabilis Mendes da Costa (EKV). However, conclusive proof that the disorders are identical is still lacking. We performed mutation analysis and microsatellite haplotyping in two independently referred patients with PSEK and three patients from a previously published family with EKV. All patients had the same mutation in the GJB4 gene causing the amino acid substitution p.Gly12Asp (G12D). Haplotype analysis showed that all five patients had the same allelic haplotype over 2 Mb covering the disease locus. Apparently, the same GJB4 mutation may cause either an EKV or a PSEK phenotype. A single ancestral founder might have introduced EKV in the Netherlands.

Fumaric acid derivatives evoke a transient increase in intracellular free calcium concentration and inhibit the proliferation of human keratinocytes.

Systemic administration of fumaric acid (FA) derivatives was originally an empirical antipsoriatic treatment, which showed promising clinical results. In the present study, FURA-2-loaded suspensions of cultured normal keratinocytes and SV40-transformed keratinocytes (SVK-14 cells) were used to study the effects of FA derivatives on the intracellular free calcium concentration ([Ca2+]i). Monomethylfumarate (MMF), dimethylfumarate (DMF) and monoethylfumarate (MEF) induced a rapid, transient [Ca2+]i increase in both cell types. This immediate increase reached maximal values of 396 nmol/l 10s after addition of MMF, and fell to basal values within 90-120 s (173 nmol/l for normal keratinocytes and 68 nmol/l for transformed keratinocytes). This increase was not affected by the prior addition of EGTA, indicating that FA derivatives released Ca2+ mainly from intracellular stores into the cytoplasm. Subsequently, dose-dependent inhibitory effects of FA derivatives on keratinocyte proliferation were demonstrated. The results of these experiments revealed that DMF was the most potent, MMF and MEF intermediate, and FA and malonic acid the least potent growth inhibitors. These antiproliferative effects of FA derivatives might be linked to the observed, transient [Ca2+]i elevations.

Genetic linkage between the collagen VII (COL7A1) gene and the autosomal dominant form of dystrophic epidermolysis bullosa in two Dutch kindreds.

Epidermolysis bullosa is a heterogeneous group of heritable blistering skin diseases affecting epidermis and the dermal-epidermal junction zone. Recently, genetic linkage to the type VII collagen gene (Z = 8.77; theta = 0.00) localized on chromosome 3p21 was shown in three Finnish families with the autosomal dominant form of dystrophic epidermolysis bullosa. Two Dutch kindreds with intrafamilial characteristics of both the Cockayne-Touraine type and Bart's syndrome of autosomal dominant dystrophic epidermolysis bullosa have been studied. Two-point linkage analysis in these two families with the COL7A1 marker revealed a combined lod score of Z = 6.08 at theta = 0.00. These data strongly suggest that the type VII collagen gene is the candidate gene in these Dutch pedigrees. At least two (Cockayne-Touraine and Bart) of the three subtypes of dominant dystrophic epidermolysis bullosa seem to represent different forms of expression of the same gene defect.

A randomized treatment duration-finding study of terbinafine in onychomycosis.

Terbinafine is an allylamine antifungal compound shown to be effective in the oral treatment of onychomycosis. Because of the fungicidal activity of the drug, a shorter duration of treatment, compared with the currently used oral treatment modalities, can be expected in onychomycosis of the toenail. In the present randomized study, the efficacy of oral terbinafine treatment (250 mg/day) was assessed for periods of 6, 12, and 24 weeks. All patients were followed for up to 48 weeks after starting treatment. Of the 120 patients with toenail onychomycosis who entered the study, 98 were evaluable for efficacy. The involvement of the toenails was assessed both clinically and mycologically throughout the study. Evaluation at 24 weeks showed that complete cure of toenail onychomycosis was achieved in 67% of patients treated for 6 weeks, 82% treated for 12 weeks, and 85% treated for 24 weeks. At the end of a further 24 weeks of follow-up, cure rates were 40%, 71% and 79%, respectively. The adverse effects of terbinafine were mostly mild-to-moderate gastrointestinal symptoms. Three patients discontinued treatment because of side-effects. In conclusion, oral treatment with terbinafine is effective and generally well tolerated in patients with onychomycosis. Our results demonstrate that, for toenail onychomycosis, a treatment period of 12 weeks is sufficient.

Lyme borreliosis presenting as acrodermatitis chronica atrophicans.

A patient is described who developed acrodermatitis chronica atrophicans, arthralgias and polyneuropathy as manifestations of Lyme borreliosis. The clinical diagnosis was confirmed by histological and serological examinations. Despite a long delay before the diagnosis was established, the patient responded very well to treatment with doxycycline.

Hygiene, skin infections and types of water supply in Venda, South Africa.

The impact of the installation of a system to supply chlorinated drinking water in Venda, South Africa, on water quality, water use and health status was evaluated by means of questionnaires, examination for skin infections, and microbiological analysis of water samples. Although the water collection journey became shorter in comparison with use of traditional water supplies such as boreholes and unprotected springs, water use per caput showed no increase. The improved water supply showed no contamination with coliforms even after storage. Borehole water exhibited low coliform counts at the source, but after storage a 10- to 15-fold increase took place. Water samples from unprotected springs exhibited high coliform counts, which declined during storage. The prevalence of infectious skin diseases (27.5%) and diarrhoea (3.7%) among pre-schoolchildren showed no correlation with the quality of drinking water or the use of water per caput. Although the prevalence of infectious skin diseases did exhibit a negative correlation with the frequency of washing, no significant health benefit of the improved water supply could be demonstrated in this limited study.

A case of seminal fluid allergy successfully treated with immunotherapy in a one-day rush procedure.

A 28-year-old woman was treated for seminal fluid allergy with immunotherapy using a one-day 'rush' procedure. Apart from minor anaphylactic symptoms, no serious side effects were noted during or after hyposensitization or boostering. Five weeks after the start of the hyposensitization, she was free of symptoms after unprotected coitus.

The Rapp-Hodgkin syndrome.

We report on a family with the Rapp-Hodgkin ectodermal dysplasia syndrome. Four affected family members are described and a review of the literature is given.

[Fumaric acid therapy in psoriasis; a double-blind, placebo-controlled study]. / Fumaarzuurtherapie tegen psoriasis; een dubbelblind, placebo-gecontroleerd onderzoek.

Thirty-nine patients with psoriasis (12 females, 27 males) entered a randomised, double-blind, placebo-controlled study on the efficacy of fumaric acid therapy in an outpatient setting. During 16 weeks the patients were treated with tablets containing a combination of dimethylfumarate and different salts of monoethylfumarate, with octylhydrogen fumarate or with placebo tablets. All patients were treated with identical indifferent topical therapy and followed an elimination diet (avoidance of spices, wine and nuts). Thirty-four patients completed the study. Five patients dropped out because of side effects or aggravation of the skin lesions. The patients treated with the combination of monoethyl- and dimethylfumarate showed a significantly better therapeutic response compared with those who were treated with placebo or octylhydrogen fumarate. Side effects of the fumarate containing tablets were flushing, diarrhoea, a reversible elevation of transaminases, lymphocytopenia and eosinophilia. One patient developed a disturbance of the kidney function which normalised after discontinuation of the therapy.

Ras oncogene mutations in basal cell carcinomas and squamous cell carcinomas of human skin.

Activated ras oncogenes have been detected in a variety of human malignancies. Activation of ras oncogenes usually occurs by point mutations within specific codons of the H-ras, N-ras, and K-ras genes. For the present study, DNA was isolated from 30 basal cell carcinomas (BCC) and 12 squamous cell carcinomas (SCC). After amplification of genomic DNA by using the polymerase chain reaction, the occurrence of point mutations was investigated with 32P-labeled synthetic oligonucleotides. These probes are complementary to the known point-mutated nucleotide sequences of the ras genes. In four out of the 30 BCC studied, point mutations were detected at codon 12 of the K-ras gene and at codon 61 of the H-ras gene. The K-ras mutations involve glycine to cysteine and glycine to asparagine amino acid changes. The mutation at codon 61 of the H-ras gene is consistent with a replacement of glutamine by histidine. In one SCC, a point mutation was detected at codon 12 of the K-ras gene, involving a glycine to cysteine substitution in the gene product. These findings demonstrate that mutational activation of ras genes takes place in skin carcinomas, but the rate at which these mutations occur seems to be relatively low.

[Acute kidney insufficiency in patients treated with fumaric acid esters for psoriasis]. / Acute nierinsufficiëntie bij patiënten behandeld met fumaarzuuresters wegens psoriasis.

We describe four female patients with psoriasis treated with fumaric acid esters. In two patients acute renal failure developed during this therapy. Histological investigation of renal biopsy in one patient was compatible with the diagnosis of acute tubular necrosis; her renal function was reversible after cessation of the medication. The histological diagnosis of the other patient was tubulo-interstitial nephritis, possibly as a reaction to acute tubular necrosis. The recovery of her renal function was incomplete after 9 months.

[Acute kidney insufficiency in the treatment of psoriasis using fumaric esters]. / Akute Niereninsuffizienz bei der Behandlung der Psoriasis mit Fumarsäure-Estern.

We describe two patients who developed acute renal failure during therapy with fumaric acid-esters. Histologic findings after renal biopsy in one patient were compatible with the diagnosis of acute tubular necrosis (ATN), and renal function was restored after cessation of the medication. The histologic diagnosis in the other patient was tubulo-interstitial nephritis (TIN), possibly reactive to ATN. The recovery of renal function was incomplete after 9 months. Two other patients had deterioration of renal function and proteinuria during therapy with fumaric acid-esters. The symptoms were completely reversible in one patient after discontinuation of the medication, and incompletely reversible in the other. The literature is reviewed and a comparison is drawn with the maleic acid model in the rat.

Expression of EGF receptor, involucrin, and cytokeratins in basal cell carcinomas and squamous cell carcinomas of the skin.

The distribution of several markers of keratinocyte differentiation was studied in normal epidermis, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) using the immunoperoxidase technique on frozen sections of punch biopsy specimens. As markers a panel of chain-specific monoclonal antibodies (MoAbs) directed against cytokeratin (CK) 4, 8, 10, 13, 18 and 19, a polyclonal antiserum against involucrin, as well as a MoAb against the epidermal growth factor (EGF) receptor were used. In 15 out of 19 BCCs tested, expression of CK 8 was seen. Only a few individual cells in a limited number of BCCs showed positive staining for CK 4, 18, or 19. No expression of CK 10 was seen except for some foci of cell keratinization. Involucrin was not found in BCCs except for some squamous horn cysts. In all BCC cells expression of EGF receptor was found. In the suprabasal layers of normal epidermis from SCC patients, positive staining for CK 10 was seen. A few individual cells in a limited number of SCCs showed positive staining for CK 4, 8, or 18. Involucrin was expressed in the center of SCCs and in the upper layers of normal epidermis. Expression of EGF receptor was found in all SCC cells. These results demonstrate differences in cellular origin and differentiation between BCC and SCC.

Further evidence for localization of the gene of erythrokeratodermia variabilis.

Close genetic linkage between erythrokeratodermia variabilis (EKV) and the Rh blood group system has been reported by our group. Here we describe the results of a linkage analysis in another EKV kindred, in which the disease segregated with the CDe genotype. Among 18 informative individuals, 1 recombinant was found. A maximum lod score of 4.21 was calculated at a recombination fraction of 0.03-0.04. Addition of this lod score to the earlier reported results gives a maximum lod score of 9.93 for linkage between EKV and Rh at a recombination fraction of 0.03 (95% confidence limits 0.008-0.11).

Autosomal dominant epidermolysis bullosa dystrophica: are the Cockayne-Touraine, the Pasini and the Bart-types different expressions of the same mutant gene?

We report on a family with autosomal dominant dystrophic epidermolysis bullosa and congenital localized absence of skin, resembling the features of Bart's Syndrome. This type of epidermolysis bullosa and the Cockayne-Touraine and Pasini types may represent different expressions of the same gene defect.