Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening.

The inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis - striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene.

The neuropsychiatric phenotype in Darier disease.

BACKGROUND: Darier disease (DD) is a rare autosomal dominantly inherited skin disorder in which co-occurrence of neuropsychiatric abnormalities has been frequently reported by dermatologists. It is caused by mutations in a single gene, ATP2A2, which is expressed in the skin and brain. OBJECTIVES: To conduct the first systematic investigation of the neuropsychiatric phenotype in DD. METHODS: One hundred unrelated individuals with DD were assessed using a battery of standardized neuropsychiatric measures. Data were also obtained on a number of clinical features of DD. RESULTS: Individuals with DD were found to have high lifetime rates of mood disorders (50%), specifically major depression (30%) and bipolar disorder (4%), and suicide attempts (13%) and suicidal thoughts (31%). These were more common in DD when compared with general population data. The prevalence of epilepsy (3%) in the sample was also higher than the prevalence in the general population. There was no consistent association of specific dermatological features of DD and presence of psychiatric features. CONCLUSIONS: These findings highlight the need for clinicians to assess and recognize neuropsychiatric symptoms in DD. The results do not suggest that neuropsychiatric symptoms are simply a psychological reaction to having a skin disease, but are consistent with the pleiotropy hypothesis that mutations in the ATP2A2 gene, in addition to causing DD, confer susceptibility to neuropsychiatric features. Further research is needed to investigate genotype-phenotype correlations between the types and/or locations of pathogenic mutations within ATP2A2 and the expressed neuropsychiatric phenotypes.

Skin-cancer awareness in Scottish cardiac transplant recipients.

BACKGROUND: Cardiac transplant recipients have a greatly increased risk of nonmelanoma skin cancer, with a relative risk of up to 108. Skin cancer is more aggressive in transplant patients and results in substantial morbidity and mortality. It is therefore important that these patients understand this risk and take adequate sun-protection measures. AIM: To assess awareness of skin cancer risk and sun protection measures used by cardiac transplant recipients and determine the impact of patient education. METHODS: Using a detailed questionnaire, we surveyed 118 patients attending the cardiac transplant clinic at our centre to quantify knowledge of skin cancer risk (maximum total score 10) and behaviour in the sun (maximum total score 15). Of these patients, 50 were then seen by a dermatologist for education about skin cancer risk, sun protection measures and skin cancer screening. Six months later, we asked them to complete the same questionnaire again. RESULTS: The mean knowledge score was 7.3/10 and the mean behaviour score was 11.2/15. In the group that received education, the mean knowledge score improved from 7.2/10 before the dermatology consultation to 7.8/10 after the consultation (P < 0.03). The mean score for the behaviour questions improved even more, from 11.2/15 before to 13.5/15 after the consultation (P < 0.0001). CONCLUSIONS. This study demonstrates that specialist advice can improve self-reported knowledge of skin cancer risk and sun protective behaviour in cardiac transplant recipients. It is hoped that this may reduce the risk of nonmelanoma skin cancer in these patients.

Expression of the sarco/endoplasmic reticulum calcium ATPase type 2 and 3 isoforms in normal skin and Darier's disease.

BACKGROUND: Darier's disease (DD) is caused by mutations in ATP2A2, which encodes the sarco/endoplasmic reticulum calcium ATPase type 2 (SERCA2), a member of a family of calcium pumps important in intracellular calcium signalling. SERCA2 has two isoforms. SERCA2a occurs mainly in cardiac and skeletal muscle, whereas SERCA2b occurs ubiquitously and is coexpressed with the related SERCA type 3 (SERCA3) in many tissues. It is not known why mutations in the widely expressed SERCA2 manifest as a focal skin disease. OBJECTIVES: To provide insight into the pathogenesis of DD by examining SERCA isoform expression in normal skin and DD skin. METHODS: Using immunohistochemistry we studied SERCA2a, SERCA2b and SERCA3 expression in nonlesional and lesional skin from seven patients with DD and normal skin from seven control subjects. We quantified SERCA2a and SERCA2b staining intensity by grey scale analysis of fluorescence intensity. RESULTS: In normal and DD epidermis both SERCA2a and SERCA2b staining was seen. SERCA2a staining in epidermis was less intense relative to pilar muscle whereas SERCA2b staining in epidermis was of marginally greater intensity than in pilar muscle. SERCA3 was not expressed in normal or DD epidermis, but was found in eccrine glands and blood vessels. No reduction was detected in SERCA2a or SERCA2b staining intensity in DD nonlesional epidermis compared with control epidermis. In within-patient comparisons, SERCA2a and SERCA2b staining in lesional epidermis was less intense than in nonlesional epidermis. CONCLUSIONS: Both SERCA2a and SERCA2b are present in epidermis, although the latter may predominate. The absence of coexpressed SERCA3 in epidermis may explain the localization of DD. Comparable SERCA2 staining intensity in nonlesional DD and control epidermis, even in patients predicted to be haploinsufficient, suggests partial compensation by upregulation of the normal allele. Unknown additional factors may trigger focal lesions by overcoming this compensation. Reduced staining intensity in lesional tissue may be secondary, or may reflect local downregulation of SERCA2 expression predisposing to development of focal lesions.

Allergic contact dermatitis in venous leg ulcer patients.

Our aim was to determine the frequency and nature of contact sensitivity in venous leg ulcer patients in Lanarkshire. We performed patch testing with the European standard series, antimicrobials and medicaments on 200 patients referred to our leg ulcer clinics. Positive patch tests were found in 136 (68%) patients. Multiple allergies occurred in 102 (51%). The most frequent allergen groups were fragrances (30.5%), antimicrobials (19.5%), topical excipients (19.5%), rubber accelerators (13.5%) and topical corticosteroids (8%). We also found a high prevalence of positive patch tests to Intrasite gel (9.5%) and Hioxyl cream (8.5%), medicaments which are commonly used to treat leg ulcers in our area. Contact sensitivity is common in venous leg ulcer patients and has important implications for patient management. The allergens involved vary depending on local nursing practice. We suggest that all venous leg ulcer patients be patch tested with a locally relevant patch test series.

Leucocytoclastic vasculitis and influenza vaccination.

Influenza vaccination is recommended for all people over 75 years of age and for an expanding range of other indications. Side-effects of influenza vaccination are usually mild but we describe four cases of leucocytoclastic vasculitis following influenza vaccination. The four patients, who were all elderly, presented with cutaneous vasculitis but all had abnormal urinalysis suggestive of associated renal involvement. Since 1974 only 10 cases of vasculitis following influenza vaccination have been reported in the literature. The clinical features of these cases are reviewed. As the use of influenza vaccination is likely to increase, dermatologists should be aware of the possible association with vasculitis.

Genetic epidemiology of Darier's disease: a population study in the west of Scotland.

BACKGROUND: Darier's disease has a world-wide distribution, but estimates of prevalence have varied. The discovery that the disease is due to mutations in ATP2A2 provides the opportunity to study the genetic epidemiology of the disease in localized populations. OBJECTIVES: To survey the prevalence of Darier's disease in the west of Scotland and look for founder effects in this population. METHODS: We ascertained cases of Darier's disease in the west of Scotland and used genealogy and mutational analysis to seek common ancestry. RESULTS: Seventy-eight current cases were identified, giving a prevalence of approximately 1 : 30 000. While 63 cases gave a history of Darier's disease in previous generations, conventional genealogy identified only two pairs of two family groups with common ancestry within the last 180 years. Eleven patients (14%; three of whom had in total four affected children) had probable de novo mutations. Causative mutations in ATP2A2 have been identified in 11 of 15 pedigrees screened for mutation, but no two share the same mutation. CONCLUSIONS: High estimates of prevalence are likely to be due to intensive ascertainment, rather than founder effects. Darier's disease is likely to be more common than has been recognized in other populations.

Platelet and cardiac function in Darier's disease.

ATP2A2, the gene that is abnormal in Darier's disease, encodes SERCA2, a calcium pump that is expressed in many tissues. The wide expression of SERCA2 might suggest that ATP2A2 mutations would cause a multisystem disease. There is however, no evidence of consistent extracutaneous manifestations of Darier's disease. We have conducted preliminary studies in patients with Darier's disease, in two extracutaneous systems in which SERCA2 is known to be important, in order to investigate whether subtle defects have been overlooked. We found no evidence for altered cardiac function in 10 patients using two-dimensional, colour and Doppler echocardiography. There were no consistent defects in platelet function in 12 patients, using bleeding time and aggregation studies. We conclude that the skin is sensitive to defects in SERCA2 function to which other systems appear robust.

Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case.

The risk of azathioprine-induced myelosuppression can be predicted by detecting patients with intermediate or low thiopurine methyltransferase (TPMT) activity. Population studies have shown that 89% of whites have high TPMT activity, 11% have intermediate TPMT activity, and 0.3% have low TPMT activity. Three specific mutations in the TPMT gene that cause decreased TPMT activity have recently been identified. Patients homozygous for the TPMT mutations have low TPMT activity, and patients heterozygous for TPMT mutations have intermediate TPMT activity. This has led to the development of a technique for TPMT genotype analysis that will identify patients at risk of azathioprine-induced myelosuppression. We report a case of a patient with bullous pemphigoid who experienced azathioprine-induced myelosuppression and who was later found to be homozygous for TPMT mutant alleles. Using the cost of treatment required for this patient and the estimated population prevalence of TPMT mutations, we examined the cost impact of screening for TPMT mutations in all patients being considered for azathioprine therapy. We calculated that screening is cost-neutral assuming patients homozygous for TPMT mutations experience myelosuppression, and that it is cost-beneficial assuming patients heterozygous for TPMT mutations also experience myelosuppression while receiving azathioprine. Screening patients for TPMT mutations will reduce the risk of azathioprine-induced myelosuppression, and our study suggests that it may also be a cost-attractive strategy.

Clustering of fixation targets in multifixation campimetry.

The multifixation campimeter has a central test stimulus and a series of numbered fixation targets and uses the patient's eye movements to position the stimulus in the visual field. The stimulus is constantly exposed so that the patient reads the numbers and identifies any which are associated with its disappearance. The aim of this study is to identify the effect of clustering fixation targets on sensitivity. Two hundred and seventy-two eyes of 139 normal individuals were tested with a multifixation campimeter in which either one or two of the fixation targets corresponded to the physiological blind spot. Sixty-nine individuals (138 eyes) were tested with chart A and 70 individuals (134 eyes) with chart B. The second fixation target increased the blind spot detection rate from 65% to 85% of the eyes respectively. In 10% of eyes the blind spot was detected on only one of two examinations. The performance of multifixation campimetry is improved if fixation targets are clustered in vulnerable parts of the field and distributed so as to test the blind spot repeatedly during the examination. Inconsistent results are an indication for re-examination of selected points, with intermittent stimulus presentation.