Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma.

The influence of polymorphism in the glutathione S-transferase, GSTM3 gene on susceptibility to cutaneous basal cell carcinoma (BCC) has been investigated. We have reported previously two GSTM3 alleles, GSTM3*A and GSTM3*B, distinguished by a recognition motif for the YY1 transcription factor in GSTM3*B. In this study, immunohistochemistry was used to identify GSTM3 expression in the epidermis of skin samples from 11 controls and 9 patients with BCC. A PCR method was used to identify GSTM3*A and GSTM3*B and thereby the GSTM3 AA, GSTM3 AB, and GSTM3 BB genotypes in 300 controls and 286 Caucasians with 1-35 primary BCCs. Genotypes at GSTM1, GSTT1, and the cytochrome P450 CYP1A1 and CYP2D6 loci were also determined. Frequencies of GSTM3, GSTM1, GSTT1, CYP2D6, and CYP1A1 genotypes in the cases and controls were not different. Dividing the BCC cases into groups of 92 patients with 1 lesion and 194 patients with 2-35 lesions showed that the frequencies of GSTM3 BB (2.6%) and GSTM1 A/B (1.3%) in the group with 2-35 tumors were almost significantly lower than in the group with 1 lesion (7.6%, exact P = 0.0601, chi 2(1) = 3.390; 6.5%, exact P = 0.055, chi 2(1) = 4.946, respectively). Within the cases with 2-35 tumors, a Poisson regression model was used to identify genotypes, characteristics such as skin type, and interactions between genotypes and characteristics associated with increasing numbers of tumors. This showed, after correction for male gender and age, that GSTM3 AA was not associated with risk of increased numbers of tumors, although in combination with skin type 1, GSTM1 null, and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio, 1.470 respectively). The data suggest that, like other allelic GST, GSTM3 influences cancer risk. As GSTM3 AA was associated with increased tumor numbers, it appears that YY1 acts as an activator of the recognition motif in GSTM3*B.

Rapid prenatal diagnosis and exclusion of epidermolysis bullosa using novel antibody probes.

Prenatal diagnosis of recessive dystrophic epidermolysis bullosa was successfully achieved at 19 weeks' gestation by indirect immunofluorescence examination of a fetal skin biopsy sample using the monoclonal antibody LH 7:2. The abortus displayed marked blistering and the diagnosis was confirmed by transmission electron microscopy (TEM). In 3 further pregnancies at risk for lethal junctional epidermolysis bullosa the diagnosis was excluded using the polyclonal antibody AA3. In all these studies the results were available within 4 h of receiving the samples. These new techniques offer a quick and simple alternative to TEM for midtrimester prenatal diagnosis of 2 severe recessive forms of epidermolysis bullosa.

Type VII collagen is a normal component of epidermal basement membrane, which shows altered expression in recessive dystrophic epidermolysis bullosa.

The murine monoclonal antibody LH 7:2, which reacts with the basement membrane of stratified squamous epithelia including epidermis, has been characterized biochemically and shown to bind to part of the type VII collagen molecule. Immunoblotting reveals that the antibody binding site lies in the non-helical carboxy terminal region of the type VII collagen dimer and immunoelectron microscopy shows that the epitope is within the lamina densa of the basement membrane. Loss of LH 7:2 binding in the hereditary blistering disease recessive dystrophic epidermolysis bullosa suggests that inadequate synthesis or excessive breakdown of type VII collagen may form the biologic basis for the disease.

Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene.

Allelic variation at the melanocyte stimulating hormone receptor (MC1R) gene has been linked with sun-sensitive skin types, suggesting it is a susceptibility candidate for melanoma. We determined the frequency of the val92met, asp294his, and asp84glu MC1R alleles in 190 Caucasian controls and 306 melanoma cases and studied their association with skin type and hair color. The percentage of controls with at least one val92met, asp294his, or asp84glu allele was 17.3%, 6.8%, and 3.5%, respectively. Individually, frequencies of the val92met, asp294his, or asp84glu alleles in the controls with skin types 3 and 4 were similar to those with skin types 1 and 2. Trend analysis, however, did identify an association (exact p = 0.048, two-sided test) between skin type and MC1R variants in the group comprising all controls with any one or more of these alleles. There was no association between MC1R alleles and hair color. Allele frequencies were not different in melanoma cases and controls. There were no associations between skin types and the proportion of cases with the asp294his or asp84glu alleles, though the association between skin type and the val92met allele approached significance (exact p = 0.09, two-sided test). Unexpectedly, in the group comprising all cases with one or more variant alleles, the proportion of subjects with variant alleles increased with skin types associated with tanning rather than burning, although trend analysis showed that this association did not quite reach statistical significance (exact p = 0.08, two-sided test). Asp84glu (but not val92met or asp294his) variant alleles were more common in subjects with blonde hair, although the relationship between the asp84glu allele and hair color did not achieve statistical significance (chi(2)3 = 6.16, exact p = 0.10). We interpret the data presented as indicating that polymorphism at MC1R does not appear a major determinant of skin type, at least in terms of these allelic variants. Furthermore, considered alone, these alleles are not susceptibility candidates for malignant melanoma.

Risk factors for basal cell carcinoma in the UK: case-control study in 806 patients.

Basal cell carcinoma (BCC) is the commonest malignant neoplasm in white people. We present a large UK case-control study in which conditional logistic regression analysis of age-matched and gender-matched data sets was used to compare, first, cases with controls (n = 403) and second, patients having multiple BCC with those having a single BCC (n = 278). Eye/hair colour, occupation, skin type, social class, tumour site at presentation and smoking history were assessed. Social class 1/2, skin type 1, red/blonde hair and blue/green eyes were all related to BCC risk, social class most strongly (odds ratio 2.36, P = 0.007). Truncal site at presentation was a risk factor for the development of multiple BCC (odds ratio 4.03, P = 0.002). These data support the view that genetically mediated differences in ultraviolet responsiveness are important in BCC, though the scale of their effect is small. They may be exploitable in primary and secondary prevention as well as giving insights into pathogenesis. In particular, the fact that patients presenting with a truncal tumour are at increased risk of further BCC suggests that intermittent exposure in genetically predisposed individuals may contribute to a cancer susceptibility syndrome.

Acute febrile neutrophilic dermatosis in association with erythema nodosum and sarcoidosis.

We report two cases of simultaneous Sweet's syndrome and erythema nodosum. We believe this to be a real association rather than the extension of the neutrophilic infiltrate of Sweet's syndrome into the subcutaneous fat. In one of our cases, concurrent erythema nodosum and Sweet's syndrome was a presentation of sarcoidosis with bilateral hilar lymphadenopathy. To our knowledge, this is the first report of Sweet's syndrome with sarcoidosis.

A prospective study into the value of patch and intradermal tests in identifying topical corticosteroid allergy.

We have prospectively performed patch and intradermal tests on 105 consecutive patients, attending for patch testing, to determine the optimum method of screening for corticosteroid hypersensitivity. Patch tests with Pivalone and a corticosteroid series (all 1% in ethanol) detected all the patients with steroid sensitivity. However, intradermal tests were essential to exclude false positive reactions and detect all relevant steroid allergies in any individual patient.

Hand dermatitis in the pottery industry.

Irritant hand dermatitis has long been recognized in the pottery industry. In our series, among workers handling glaze, sensitization to chromate was common and allergy to other metals and to biocides also occurred. Allergy to oil additives was found in mould makers. Whilst irritant hand dermatitis does occur, allergy to metals and biocides should be looked for in workers handling glazes, and allergy to oil additives in mould makers.

Familial tufted angioma.

Tufted angioma is a rare slowly progressive vascular lesion found typically in children and young adults. Cases appear sporadically and clinically have been confused with low grade angiosarcoma, Kaposi's sarcoma, and multiple glomus tumours. We report a case of a patient with tufted angioma in whom a strong family history of similar lesions is apparent, transmitted in an autosomal-dominant mode of inheritance.

Toxic epidermal necrolysis localized to an area of lymphoedema.

We present a man who, on two occasions, developed toxic epidermal necrolysis initially localized to an area of lymphoedema. To our knowledge, lymphoedema as a site of prediliction has not previously been reported.

Follicular toxic pustuloderma associated with allopurinol.

Allopurinol is widely prescribed for primary and secondary hyperuricaemia, and cutaneous adverse reactions are seen in 0.8-2.1% of recipients. The majority of these are mild and include pruritus, diffuse or maculo-papular erythema, urticaria and ichthyosis. More severe reactions are well recognized and include exfoliative dermatitis, toxic epidermal necrolysis and a generalized hypersensitivity syndrome. The latter typically comprises fever, rash, hepatic and renal dysfunction and eosinophil leucocytosis. The occurrence of toxic pustuloderma due to allopurinol, confirmed by re-challenge, is reported.

Identification of an epidermal basement membrane defect in recessive forms of dystrophic epidermolysis bullosa by LH 7:2 monoclonal antibody: use in diagnosis.

LH 7:2 is a monoclonal antibody that was raised against an extract of human epidermal cells and identifies an epitope within the lamina densa of the basement membrane of stratified squamous epithelia. Using indirect immunofluorescence we found intense labelling with LH 7:2 at the epidermal basement membrane (EBM) of normal skin, and in skin samples from patients with simplex, junctional, dominantly inherited dystrophic and acquired forms of epidermolysis bullosa (EB), as well as bullous pemphigoid. Staining was absent or only very faint in generalized recessive dystrophic EB (RDEB), and patchily reduced in the localized form of RDEB. We conclude that LH 7:2 recognizes an EBM antigen which may be important in the pathogenesis of RDEB. Moreover, the antibody provides a useful probe for the rapid diagnosis of RDEB and is of special value in helping to discriminate between localized RDEB and typical dominant dystrophic EB--conditions which closely resemble each other clinically and which cannot be distinguished by means of transmission electron microscopy.

An oculocerebral hypopigmentation syndrome: a case report with clinical, histochemical, and ultrastructural findings.

A 4 year old boy is reported with tyrosinase positive hypopigmentation, mental retardation, ataxia, and myopia. Radiological investigation showed occipital cerebral atrophy, coxa valga, and generalised osteoporosis. The skin histology and electron microscopy are reported and discussed. The clinical features are similar to those of the oculocerebral hypopigmentation syndrome described by Preus et al.

Epidermolysis bullosa simplex (Dowling-Meara). A clinicopathological review.

The clinicopathological features of 22 cases of the Dowling-Meara form of epidermolysis bullosa simplex (DM-EBS) (11 males, 11 females; aged 5 days-46 years) were reviewed using data collected over a 10-year period. All cases presented clinically within the first 5 days of life. Early blisters were often large (up to 5 cm in diameter), and were mostly acral and particularly periungual. Some cases presented with more widespread erosive skin changes, and two neonates with extensive skin involvement died as a result of overwhelming sepsis. After the neonatal period a different pattern of blistering occurred with more proximal haemorrhagic, herpetiform clusters of blisters. Central healing with recurrent blistering at the margins of these areas was frequently noted. Other physical signs included varying degrees of intra-oral blistering, nail shedding, nail dystrophy, minor scarring, palmo-plantar keratoderma, a lack of seasonal variation and improvement during later childhood. The underlying pathological mechanism in DM-EBS is basal cell cytolysis, or rarely acantholysis, in association with tonofilament (TF) clumping. TF clumping was found in lesional, perilesional and some non-lesional skin, suggesting that the tonofilament abnormality may be of primary aetiological significance in DM-EBS. TF clumping may be due to specific keratin abnormalities because the altered TF were found in a distribution similar to the known distribution of the basal cell keratins, K5 and K14. The level of blistering was invariably very low within the epidermal basal layer and often less than 0.5 microns above the basement membrane. We conclude that DM-EBS is a distinct, and probably under-recognized genodermatosis which tends to have a good prognosis. However, the disease can occasionally be severe, especially during the neonatal period, when it may be confused with junctional or severe recessive dystrophic EB. Electron microscopy is the best means for demonstrating the characteristics cytoskeletal disorder and confirming the diagnosis.

Transient re-emergence of oil of turpentine allergy in the pottery industry.

Allergy to oil of turpentine has diminished largely due to the use of cheaper substitutes in many occupations. However, 2 particular areas still reliant on real oil of turpentine are those of the perfume industry and ceramic decoration. We report 24 cases of hand dermatitis in pottery workers involved in ceramic decoration, paintresses, liners, gilders, enamellers and a fine china painter, seen in a 6-month period following a change from Portuguese to Indonesian turpentine, of whom 14 were sensitive to Indonesian turpentine, 8 to alpha-pinene, 4 to delta-3-carene and 2 positive to turpentine peroxides. Previous reports suggest that delta-3-carene is the main allergen and reports of sensitivity to alpha-pinene in the absence of sensitivity to turpentine peroxide, in particular to the hydroperoxide of delta-3-carene, are few. Turpentine allergy continues to be a problem in the pottery industry and is more common than allergy to the heavy metals of the colours used in ceramic decoration. alpha-Pinene, an unusual allergen, appears to be the most common in our area. Reversion to Portuguese turpentine seems to have alleviated the problem.

GB3 monoclonal antibody for the diagnosis of junctional epidermolysis bullosa: results of a multicenter study.

GB3 monoclonal antibody detects a normal basement membrane component (GB3 antigen) that is variably expressed in junctional epidermolysis bullosa. To assess the accuracy of GB3 in the diagnosis of junctional epidermolysis bullosa, we have reviewed its use in 250 cases of the major types of epidermolysis bullosa. In the majority of cases of the simplex and dystrophic forms of epidermolysis bullosa, GB3 antigen is normally expressed. In the Herlitz variant of junctional epidermolysis bullosa, GB3 antigen expression is consistently abnormal, but in the non-Herlitz and indeterminate forms of junctional epidermolysis bullosa, 40% of cases express GB3 antigen normally. We propose that GB3 monoclonal antibody is useful in the accurate identification of patients with Herlitz junctional epidermolysis bullosa and may prove equal to electron microscopy for the diagnosis of this disease. For the non-Herlitz variants, it should not be used as an alternative to electron microscopy but may be of special value in the determination of prognosis.

Abnormal binding of an anti-amnion antibody to epidermal basement membrane provides a novel diagnostic probe for junctional epidermolysis bullosa.

AA3 is a novel antibody raised against human amnion, which reacts with the basement membrane of various epithelia of ectodermal origin. We used AA3 to examine the epidermal basement membrane zone in normal skin and different genetically determined types of epidermolysis bullosa (EB), by indirect immunofluorescence. AA3 staining was normal in dystrophic and simplex EB, but was markedly reduced in lesional and non-blistered skin in severe forms of junctional EB. In non-lethal junctional EB, the intensity of staining was variable and appeared to be inversely associated with disease severity, but did not correlate with demonstrable abnormalities of hemidesmosomes. AA3 binding was not reduced in pemphigoid lesions or normal suction blisters. It appeared to localize to the lamina lucida, but with different characteristics compared with antibodies to laminin and bullous pemphigoid antigen. These finding suggest that AA3 recognizes an antigen (or antigens) which may be involved in a primary biochemical defect in junctional EB. Moreover, this antibody may act as a new probe for this potentially lethal mechano-bullous disease.