A randomized side-by-side study comparing alexandrite laser at different pulse durations for port wine stains.

BACKGROUND AND OBJECTIVES: Pulsed dye laser (PDL) represents the gold-standard treatment for port wine stains (PWS). However, approximately 20% of patients are poor responders and yield unsatisfactory end-results. The Alexandrite (Alex) laser may be a therapeutic alternative for selected PWS subgroups, but optimal laser parameters are not known. The aim of this study was to assess clinical PWS clearance and safety of Alex laser at a range of pulse durations. MATERIALS AND METHODS: Sixteen individuals (14 previously PDL-treated) with deep red (n = 4), purple macular (n = 5) and purple hypertrophic (n = 7) PWS were included. Four side-by-side test areas were marked within each lesion. Three test areas were randomized to Alex laser at pulse durations of 3, 5, or 10 ms (8 mm spot, DCD 60/40), while the fourth was untreated. The lowest effective fluence to create purpura within the entire test spot was titrated and applied to intervention areas. Standardized clinical photographs were taken prior to, immediately after laser exposure and at 6-8 weeks follow up. Clinical PWS clearance and laser-related side effects were assessed using clinical photos. RESULTS: Alex laser at 3, 5, and 10 ms pulse durations demonstrated significant clearance compared to untreated controls (P < 0.001). Three milli second pulse duration exhibited improved clearance versus 5 ms (P = 0.016) and 10 ms (P = 0.004), while no difference between five and 10 ms was shown (P = 0.063). Though not significant, good responders (>50% clearance) were more likely to have purple hypertrophic PWS (5/7) compared to purple macular (2/5) and deep red lesions (1/4). Eight laser-exposed test areas (17%) developed hypopigmented atrophic scarring. Side effects tended to be more frequently observed with 5 ms (n = 4) and 10 ms (n = 3) versus 3 ms pulse duration (n = 1). Correspondingly, 3 ms was associated with a superior (n = 6) or comparable (n = 10) overall cosmetic appearance for all individuals. CONCLUSION: Alex laser at 3 ms pulse duration offers superior clinical clearance and safety compared to 5 and 10 ms, and seems best suited for purple hypertrophic PWS. Treatment should be restricted to experienced personnel due to a particularly narrow therapeutic window. Lasers Surg. Med. 49:97-103, 2017. © 2016 Wiley Periodicals, Inc.

Filaggrin compound heterozygous patients carry mutations in trans position.

More than 40 null mutations in the filaggrin (FLG) gene are described. It is therefore possible to find two different null mutations in one individual (compound heterozygosity). It has been generally perceived that homozygous and compound heterozygous individuals were genotypically comparable; however, this has not been scientifically investigated. Two different FLG null mutations in the same individual may be in trans position, meaning that each mutation locates to a different allele functionally equivalent to homozygosity, or may be in cis position, meaning that both mutations locate to the same allele functionally equivalent to heterozygosity. To experimentally investigate allelic in cis versus in trans configuration of the two most common filaggrin (FLG) mutations (R501X and 2282del4) in compound heterozygous individuals. Testing for in cis or in trans allele configuration was performed by means of allele-specific PCR amplification and analysis of PCR products by agarose gel electrophoresis. All R501X/2282del4 compound heterozygous samples collected over a 4-year period of routine FLG mutation testing were investigated. In total, 37 samples were tested. All thirty-seven R501X/2282del4 compound heterozygous individuals were found to carry the two mutations in trans position. FLG null mutation compound heterozygous individuals can be considered functionally equivalent to FLG null mutation homozygosity for any of the two mutations.

Association between loss-of-function mutations in the filaggrin gene and self-reported food allergy and alcohol sensitivity.

BACKGROUND: Loss-of-function mutations of the filaggrin (FLG) gene cause an impaired skin barrier and increase the risk of atopic dermatitis. Interestingly, FLG mutations have also been found to be associated with a high risk of peanut allergy. OBJECTIVE: We investigated the association of FLG mutations with self-reported food allergy, symptoms of oral allergy syndrome (OAS), and alcohol sensitivity. METHODS: A total of 3,471 adults from the general population participated in a health examination. Information on food allergies, OAS and alcohol sensitivity was obtained by questionnaire. FLG mutation carriers were defined as having at least one null mutation allele of R501X or 2282del4. Primary lactose intolerance (PLI) was defined as the C/C genotype of the rs4988235 polymorphism. RESULTS: FLG mutations were associated with a higher risk of self-reported allergy to eggs (OR 3.22 and 95% CI 1.46-7.11), milk (OR 2.10 and 95% CI 1.12-3.92), fish (OR 4.54 and 95% CI 1.88-10.96) and wheat (OR 3.59 and 95% CI 1.61-8.02), but not with symptoms of OAS (OR 1.05 and 95% CI 0.73-1.51). Serum-specific IgE was measured in a subsample and confirmed the association between FLG and IgE to milk. A significant gene-by-gene interaction between FLG and PLI was observed in relation to self-reported allergy to milk. Furthermore, FLG mutations were associated with a higher risk of alcohol sensitivity. CONCLUSIONS: We found that loss-of-function mutations in the FLG gene were significantly associated with self-reported food allergy and alcohol sensitivity, but not with OAS. These findings, if confirmed, support the idea that skin barrier functions may be involved in the pathogenesis of food allergy.

Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis.

BACKGROUND: Although heterozygous filaggrin gene (FLG) mutation carriers seem to have an increased risk of atopic, irritant and allergic nickel dermatitis, it remains unclear whether the risk of contact sensitization to allergens other than nickel is also elevated in FLG mutation carriers. OBJECTIVES: We hypothesized that heterozygous FLG mutation carriers who suffer from dermatitis will have strongly reduced or even absent filaggrin levels during episodes of inflammation, potentially increasing the penetration of contact allergens, and hence the risk of becoming sensitized. MATERIALS AND METHODS: During 2006-2008, 3335 randomly invited 18-69-year-old adult Danes participated in a general health examination, filled out a questionnaire, and were genotyped for the R501X and 2282del4 mutations in FLG. RESULTS: A logistic regression analysis restricted to individuals who reported atopic dermatitis and frequent episodes of hand eczema showed a strong association between FLG mutations and contact sensitization to allergens other than nickel (odds ratio 5.71; 95% confidence interval 1.31-24.94). In participants without dermatitis, no association was found between contact sensitization and FLG mutations. CONCLUSION: FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel, whereas FLG mutations alone may not, or may only slightly, increase the risk of sensitization.

Carriers of filaggrin gene (FLG) mutations avoid professional exposure to irritants in adulthood.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) are associated with xerosis, atopic dermatitis, and early onset of hand eczema. Irritant exposure is a risk factor for occupational hand eczema, and FLG mutations increase the risk of occupational irritant contact dermatitis on the hands in hospital cohorts. It is unknown whether FLG mutations affect the level of irritant exposure. OBJECTIVES: To evaluate whether exposure to occupational irritants was dependent on FLG mutations, atopic dermatitis, and age at hand eczema onset. METHODS: Randomly chosen Danish adults completed a questionnaire on general health and occupational exposures. Genotyping for FLG mutations (R501X, 2282del4, and R2447X) and patch testing were performed. RESULTS: Overall, 38.7% of subjects reported present or previous occupational exposure to irritants. Among individuals who reported hand eczema onset before entering their work life, 50.6% (45/89) of FLG non-mutation carriers became exposed to irritants, as compared with 28.6% (4/14) of heterozygous and 0% (0/6) of homozygous mutation carriers (p = 0.006). Avoidance was conspicuous among mutation carriers reporting childhood hand eczema and atopic dermatitis (odds ratio 0.08, 95% confidence interval 0.01-0.65). CONCLUSIONS: Carriers of FLG mutations who have had hand eczema onset in childhood avoid occupational exposure to irritants; the association is most marked with homozygous mutation status combined with atopic dermatitis.

The hands in health and disease of individuals with filaggrin loss-of-function mutations: clinical reflections on the hand eczema phenotype.

During the last 2 years, we have performed filaggrin genotyping in patients with eczema seen in our hand eczema clinic. We present pictures of healthy and diseased hands from individuals with filaggrin gene (FLG) mutations to describe a clinical entity of hand eczema. We show that xerosis and hyperkeratosis on the dorsal aspects of the hands and fingers, as well as palmar hyperlinearity, should alert the clinician about a possible inherited barrier abnormality of the skin resulting from FLG mutations. The series of photographs range from the hands of an individual with FLG mutations but no history of eczema, to the hands of individuals with typical and atypical filaggrin hand eczema, and finally to the hands of an individual with FLG mutations and hand eczema caused by exposure to irritants and allergens. We briefly discuss this possible subtype of hand eczema, present pathomechanisms, and indicate the signs that should alert the clinicians about a possible inherited skin barrier defect.

Nickel reactivity and filaggrin null mutations--evaluation of the filaggrin bypass theory in a general population.

BACKGROUND: It was recently shown that filaggrin null mutation carrier status was associated with nickel allergy and self-reported intolerance to costume jewellery. Because of the biochemical characteristics of filaggrin, it may show nickel barrier properties in the stratum corneum. OBJECTIVES: To investigate whether subjects with filaggrin null mutations report nickel dermatitis at an earlier age than wild-type individuals, and to analyse whether null mutation carriers have stronger patch test reactivity to nickel sulfate than do wild-type individuals. MATERIALS: A total of 3471 Danes (18-69 years of age) answered a questionnaire about general health, and underwent patch testing and filaggrin genotyping. RESULTS: The mean number of years at risk of developing nickel dermatitis was significantly lower for the filaggrin null genotype than for the wild-type genotype when ear piercing status was considered. In positive patch test readings, the proportion of null mutants increased with increasing reaction strength. CONCLUSIONS: Filaggrin null mutations may lower the age of onset of nickel dermatitis. The hypothesis that ear piercings obscure the effect of filaggrin null mutations on the development of nickel allergy in statistical analyses was supported. An association between the null genotype and increased nickel sensitivity was indicated by patch test reading and questionnaire data.

Susceptibility and reactivity in polysensitized individuals following controlled induction.

BACKGROUND: It is uncertain whether polysensitized patients acquire multiple allergies only because of a high degree of exposure to environmental allergens, or because of being highly susceptible to developing contact allergy. OBJECTIVES: The aim of this study was to investigate and compare susceptibility and reactivity in polysensitized and monosensitized individuals, and in healthy controls. PATIENTS/METHODS: We sensitized 66 adult individuals (21 polysensitized, 22 monosensitized, and 23 healthy controls) with diphenylcyclopropenone and assessed challenge responses with visual scoring and ultrasound. We compared sensitization rates using a chi-square test and logistic regression analyses, and calculated linear regression lines of the elicitation responses for each individual. The mean values of the slopes and the intercepts for each group were used to measure the strength of the elicitation response, and were compared using the Mann-Whitney test. RESULTS: Sensitization ratio was equal in the three groups: 57% for the polysensitized, 59% for the monosensitized, and 65% for the healthy control group. There was a lowered elicitation threshold in the polysensitized group compared with that in the monosensitized and healthy control groups and, although not statistically significant, a stronger elicitation response was observed in the polysensitized group. CONCLUSION: Increased reactivity was found in the polysensitized group, demonstrated by a lowered elicitation threshold, compared with that in the monosensitized and healthy control groups.

Formaldehyde exposure and patterns of concomitant contact allergy to formaldehyde and formaldehyde-releasers.

BACKGROUND: Formaldehyde and formaldehyde-releasers are widely used in consumer products and may often cause contact allergy. OBJECTIVE: To investigate the prevalence of concomitant contact allergy to formaldehyde and formaldehyde-releasers in dermatitis patients, and to determine the sources of formaldehyde exposure based on personal and occupational products obtained from dermatitis patients. METHODS: Patch test data from referred dermatitis patients with a positive patch test reaction to formaldehyde or formaldehyde-releasers were analysed. For the period 2000-2008, the formaldehyde content in products obtained from formaldehyde-allergic patients was analysed by chromotropic acid test and/or acetylacetone test. RESULTS: Patients allergic to a formaldehyde-releaser often had simultaneous contact allergy to formaldehyde. Other combinations were also prevalent. In patients who reacted to more than two formaldehyde-releasers, nearly all reacted simultaneously to formaldehyde. Seventy-five percent of the formaldehyde-allergic patients used a product that contained formaldehyde. The main source of formaldehyde exposure was cosmetics (78%). CONCLUSIONS: Concomitant contact allergy to formaldehyde and formaldehyde-releaser remains common. Furthermore, contact allergy to a formaldehyde-releaser was nearly always concomitant with another formaldehyde-releaser. Formaldehyde was commonly found in personal products used by formaldehyde-allergic patients.

Temporal trends of preservative allergy in Denmark (1985-2008).

BACKGROUND: Most cosmetics and industrial products contain preservatives. Preservative allergy is common and, historically, changing contact allergy epidemics caused by preservatives have been observed. In 1997, Alan Dillarstone predicted a stable development of preservative allergy following mandatory ingredient labelling on cosmetic products. OBJECTIVES: To investigate the development in the prevalence of preservative allergy in Denmark over a 24-year period (1985-2008) and to challenge the prediction made by Dillarstone. PATIENTS/METHODS: A retrospective analysis of patch test data was performed (n = 18179). Comparisons were made using a chi(2) test. Logistic regression analyses were used to test for associations. RESULTS: The development of preservative allergy mirrored those of other European patch test centres. The development was not dependent on sex or age group. The prevalence was higher among women and those aged 41-60 years. Formaldehyde allergy was persistently prevalent over the study years. The overall prevalence of preservative allergy increased significantly (P(trend) = 0.001), mainly because of patch testing with additional preservatives in recent years. CONCLUSIONS: Dillarstone's prediction was confirmed as the prevalence of contact allergy to individual preservatives remained relatively stable. However, the overall burden of preservative allergy seemed to increase. Introduction of new preservatives may add to the burden of contact allergy.

[Dermatologic laser surgery].

In this article we give an overview of which skin conditions that are currently treated with laser and explains the basic principles of treatment. In addition, we summarize recommendations of the Danish Dermatological Society for demarcation of medical treatments which can be provided free of charge from cosmetic self-payment treatments.

Distinguishing hyperhidrosis and normal physiological sweat production: new data and review of hyperhidrosis data for 1980-2013.

BACKGROUND: Hyperhidrosis is a condition in which the production of sweat is abnormally increased. No objective criteria for the diagnosis of hyperhidrosis exist, mainly because reference intervals for normal physiological sweat production at rest are unknown. OBJECTIVE: The main objective of this study was to establish reference intervals for normal physiological axillary and palmar sweat production. METHODS: Gravimetric testing was performed in 75 healthy control subjects. Subsequently, these results were compared with findings in a cohort of patients with hyperhidrosis and with the results derived from a review of data on hyperhidrosis published between 1980 and 2013. RESULTS: Approximately 90% of the controls had axillary and palmar sweat production rates of below 100 mg/5 min. In all except one of the axillary and palmar hyperhidrosis studies reviewed, average sweat production exceeded 100 mg/5 min. CONCLUSIONS: A sweat production rate of 100 mg/5 min as measured by gravimetric testing may be a reasonable cut-off value for distinguishing axillary and palmar hyperhidrosis from normal physiological sweat production.

A novel multiplex analysis of filaggrin polymorphisms: a universally applicable method for genotyping.

BACKGROUND: The filaggrin protein is expressed as profilaggrin mainly in stratum granulosum cells of the epidermis. The profilaggrin gene codes for 10-12 filaggrin repeats. The filaggrin protein is important for skin barrier function. Filaggrin deficiency due to functional null-polymorphisms affects 8-10% of the people in Northern Europe and is a strong risk factor for several diseases. Here, we describe a novel method for efficient, multiplexed genotyping of variations in the profilaggrin gene. METHODS: Five known techniques were combined: i) allele-specific PCR, ii) PCR with tagged primers, iii) asymmetric PCR, iv) multiplex PCR, and v) hybridization of single-stranded PCR products to spectrally coded microbeads carrying tag sequences as capture probes. Asymmetry of PCR was accomplished by having the tagged and allele-specific forward primers present in limiting concentrations. Asymmetry ensured that the later PCR cycles generated only single-stranded reverse-strand products. This greatly improved the assay sensitivity and allowed for simple optimization. RESULTS: The specificity of the tags was verified with single PCR in wildtype and homozygous samples. Only the PCR products with the appropriate anti-tag hybridized to the corresponding beads, demonstrating the specificity of the signal. The hybridization signal is strongly dependent on single-stranded PCR products. After 46 PCR cycles, double-stranded products are clearly present, but only the single-stranded products generated in later cycles hybridize to the beads and elicit the strong signals that allow for unambiguous genotyping. CONCLUSIONS: We have tested 17,000 samples for three filaggrin polymorphisms using this method, with a call rate exceeding 99% and a reagent cost of US $ 0.75 per sample. The method is universally applicable for multiplex genotyping of e.g. hereditary hemochromatosis, lactose intolerance, or cystic fibrosis.

Latex allergy and filaggrin null mutations.

OBJECTIVES: Natural rubber latex (NRL) contains over 200 proteins of which 13 have been identified as allergens and the cause of type I latex allergy. Health care workers share a high occupational risk for developing latex allergy. Filaggrin null mutations increase the risk of type I sensitizations to aeroallergens and it is possible that filaggrin null mutations also increase the risk of latex allergy. The aim of this paper was to examine the association between filaggrin null mutations and type I latex allergy. METHODS: Twenty latex allergic and 24 non-latex allergic dentists and dental assistants, occupationally exposed to latex, were genotyped for filaggrin null mutations R501X and 2282del4. Latex allergy was determined by a positive reaction or a historical positive reaction to a skin prick test with NRL. RESULTS: 41 individuals were successfully genotyped. Three individuals were filaggrin mutation carriers. One (2.4%) was a 2282del4 heterozygote and two (4.9%) were R501X heterozygote. No homozygote or compound heterozygote carriers were detected. No association between filaggrin null mutations and type I latex allergy was found (p=0.24). Patients with type I latex allergy more often reported contact dermatitis. CONCLUSIONS: This is the first study to examine a highly plausible association between filaggrin null mutations and type I latex allergy. The study subjects were occupationally exposed to latex but no association between latex allergy and filaggrin mutations were detected. Sensitization to latex in the cases in this study may not have occurred through direct skin contact but through the respiratory organs via latex proteins that are absorbed in glove powder and aerosolized.

A possible association between a dysfunctional skin barrier (filaggrin null-mutation status) and diabetes: a cross-sectional study.

Background Filaggrin proteins are located in the skin and prevent epidermal water loss and impede the entry of micro-organisms, allergens and chemicals. Filaggrin null mutations are strongly associated with ichthyosis vulgaris and atopic dermatitis. Objective The authors aimed to investigate the association between filaggrin null mutations, atopic dermatitis and diabetes. Design A random sample of 3335 adults from the general population in Denmark was filaggrin-genotyped for R501X and 2282del4 null-mutations and questioned about atopic dermatitis and diabetes. Furthermore, two independent study populations of patients with type 1 (n=104) or 2 (n=774) diabetes were genotyped. Results In a crude data analysis, a positive association was detected between the filaggrin null genotype and, respectively, subjects from the general population who reported diabetes (p=0.04) and patients with established type 2 diabetes (p=0.073). Adjustment for age and gender resulted in significant associations for patients with type 2 diabetes (p=0.048) and subjects with self-reported diabetes (p=0.032). Conclusions Adult Danes with a filaggrin null genotype had a significantly increased prevalence of self-reported diabetes. This finding was replicated when an independent sample of Danish patients with established type 2 diabetes was compared with control subjects from the general population.