Mutations analysis in filaggrin gene in northern China patients with atopic dermatitis

Background Recently, we have reported filaggrin mutations (FLG) of atopic dermatitis in southern China. However, there have been few detailed reports of FLG mutations of patients with AD in northern China by now. Objectives The present aim was to establish the mutation spectrum of FLG gene in AD patients in northern China. Methods A total of 339 cases met Hanifin and Rajka diagnostic criteria of AD were recruited. A comprehensive sequencing of the entire FLG coding region in these patients was conducted. All detected FLG null mutations were screened in a cohort of 301 normal controls. Results Seven novel mutations (478insA, Q1070X, 4026delT, Q1712X, Q2397X, 7145del4 and 8001del4) and eleven reported mutations (3222del4, 3321delA, 4271delAA, S1515X, Q1790X, 5757del4, 6834del5, Q2417X, E2422X, 7945delA and K4671X) in AD were identified. Mutations 3321delA and K4671X were two of the most common mutations in AD. FLG null mutations were present in 26.0% of AD patients. FLG null alleles (compound genotypes) were significantly higher in AD (P < 0.001) than in the controls. The compound genotypes for all FLG variants were significantly associated with IV (P < 0.001) and palmar hyperlinearity (P < 0.001). The common mutation, K4671X, was significantly associated with AD‐coexistent allergic rhinitis (P = 0.005). Conclusions Our study increases the total number of FLG mutations. We clearly demonstrated that FLG loss‐of‐function mutations were significantly associated with AD in northern China. The FLG null mutations in the Chinese population differed not only from that in the European population but also from that in sub‐populations of Asians outside of the Chinese mainland.     

Impact of atopic dermatitis and loss‐of‐function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis

Background Atopic dermatitis (AD) and loss‐of‐function mutations in the filaggrin gene (FLG) are both associated with chronic irritant contact dermatitis (ICD). As FLG mutations also are a major risk factor for AD, it is not clear whether FLG mutations are an independent risk factor for ICD or whether the risk is mediated by AD. Objectives To investigate the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls (vocational school apprentices). Methods A total of 634 patients and 393 controls were genotyped for R501X, 2282del4, R2447X and S3247X. Current or past flexural eczema was used as an indicator of AD. Results FLG mutations were found in 15·9% of the patients with ICD and 8·3% of the controls, with a crude odds ratio (OR) of 2·09 [95% confidence interval (CI) 1·33–3·28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1·62 (95% CI 1·01–2·58). Subjects with AD were at approximately three times higher risk of developing ICD than controls (OR 2·89; 95% CI 2·09–3·99). There was no evidence of an interaction between these two risk factors. Conclusions Our results indicate that both FLG mutations and AD increase the risk of ICD. Individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD.     

Combined occurrence of filaggrin mutations and IL-10 or IL-13 polymorphisms predisposes to atopic dermatitis

Background: Although filaggrin mutations are presently believed to play a key role in the development of atopic dermatitis (AD), obviously also immunological factors involved in acquired immune response are important for the development of allergic inflammation. Objective: To assess the frequency of FLG mutations and the polymorphisms 590 C/T in the IL‐4 gene, ‐1082A/G in the IL‐10 gene and ‐1055C/T in the IL‐13 gene in patients with AD and their correlations between severity of AD and asthma. Methods: R501X and 2282del4 FLG mutations and IL‐4, IL‐10 and IL‐13 polymorphisms were assayed in 163 patients with AD of Polish origin. Results: In the Polish patients with AD, the prevalence of FLG mutations was higher in patients with AD than in the controls and 2282del4 FLG mutation was more frequent than R501X, and it was associated with a 6‐fold higher risk for AD development (P < 0.001; OR: 5.76), moderate or severe disease course, early onset of asthma and palmar hyperlinearity. Significant interactions between the 2282del4 FLG mutation and the CT genotype for IL‐13 or GG genotype for IL‐10 and a higher risk for developing AD were demonstrated. Conclusion: FLG mutation, alone and in combination with certain IL‐10 or IL‐13 polymorphisms, enhances the risk for the development of AD in the Polish population.     

Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis

Background Filaggrin is a key protein involved in maintaining skin barrier function and hydration. Mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and are a major predisposing factor for atopic dermatitis (AD) in individuals of European and Asian descent. It has been proposed that FLG mutations are population specific and a difference in the spectra of mutations between different ancestral groups has been described. However, it is unknown whether FLG mutations in the African population are a causative genetic factor for IV and predispose to AD, or whether other mechanisms are more prominent. Objectives The present aim was to investigate the role of FLG mutations as predisposing factors for IV or AD among individuals from Ethiopia. Methods A case series of Ethiopian patients with AD (n = 103) and IV (n = 7) together with controls (n = 103; subjects without past or present history of AD, dry skin or atopic manifestations) was collected at the outpatient dermatology clinics at ALERT Dermatology Hospital, Tikur Anbessa Hospital and Gondar University Hospital, Ethiopia. AD was diagnosed by a dermatologist using the U.K. Working Party’s diagnostic criteria. The IV diagnosis was based on clinical examination and genetic testing of the steroid sulphatase gene to exclude X‐linked recessive ichthyosis. Patients were studied with direct sequencing (n = 40) and/or allelic discrimination (n = 110). Immunohistochemical analysis was performed for filaggrin expression in the skin of patients (n = 7) and controls (n = 2). Results The Ethiopian patients and controls were genotyped for the four previously described common European FLG null mutations (R501X, 2282del4, S3247X, R2447X) and no carriers were found. In one patient with AD a novel heterozygous 2‐bp deletion, 632del2, leading to a premature stop codon was revealed by direct sequencing. No additional carrier of this deletion or other mutations was found. In addition, no difference in filaggrin expression was detected in AD or IV skin compared with healthy control skin. Conclusions Our results indicate that FLG loss‐of‐function‐variants are less common in patients with IV and AD in the Ethiopian population, suggesting that other factors may be of importance in the pathogenesis in this ethnic group.     

Impact of filaggrin mutations on Raman spectra and biophysical properties of the stratum corneum in mild to moderate atopic dermatitis

Background Atopic dermatitis (AD) is associated with null mutations in the filaggrin (FLG) gene. Objective To assess the impact of FLG null mutations on biophysical properties and the molecular composition of the stratum corneum (SC) in healthy individuals and AD patients. Methods A total of 196 French adults, including 97 with a history of mild to moderate AD, were genotyped for the three major European FLG mutations. Components of the natural moisturizing factor (NMF), lipids and water content in the SC were determined using Raman spectroscopy. In addition, trans‐epidermal water loss, capacitance and pH of the SC were measured. Results Stratum corneum concentrations of total NMF, water, ornithine and urocanic acid (UCA) were significantly lower in AD patients than in healthy controls. Null mutations of FLG were detected in 4% of controls and 10% of AD patients. FLG mutations were associated with increased SC levels of lactate, reduced concentrations of most other NMF components and higher disease severity in AD patients. In AD patients without FLG mutations, the content of NMF constituents decreased with increasing disease severity. The concomittant presence of low concentrations of histidine, alanine and either glycine or pyrrolidone‐5‐carboxylic acid (PCA) in the SC was associated with FLG mutations with 92% specificity. Conclusions Our findings suggest a low prevalence of FLG mutations in mild AD and support an important role for filaggrin in determining the physicochemical parameters of the SC. The combined measurement of several filaggrin breakdown products in the SC may be useful to specifically predict the presence of FLG mutations.     

Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis‐associated IV

Background Ichthyosis vulgaris (IV; OMIM 146700) is a very common inherited skin disorder. Loss‐of‐function mutations in the filaggrin gene (FLG) have been identified as the cause of IV. In a previous study, we found that the percentage of FLG null mutations was lower in IV associated with atopic dermatitis (AD) than in IV not associated with AD (isolated IV). We speculated that some clinical manifestations of IV in patients with AD are not induced by FLG mutations. Objectives In order to clarify this issue, we collected 21 IV pedigrees, 33 patients with sporadic isolated IV and 116 patients with AD‐associated IV to analyse FLG mutation frequency and filaggrin expression in isolated IV and AD‐associated IV. Methods A comprehensive sequencing of the FLG gene in all patients was performed using an overlapping polymerase chain reaction (PCR) strategy. We also studied the immunohistochemistry of profilaggrin/filaggrin protein expression in the skin and measured the mRNA expression using real‐time PCR in seven patients, including one patient with IV harbouring the mutation c.3321delA, two patients with AD‐associated IV harbouring c.3321delA and c.6834del5, and four patients with AD‐associated IV without FLG mutations. Results The percentage of mutations in the FLG gene was 74% and 43% in patients with isolated IV and patients with AD‐associated IV, respectively. Immunohistochemical staining revealed that profilaggrin/filaggrin peptides were remarkably reduced in the epidermis of all the patients. All the patients with either AD or IV showed lower FLG mRNA expression compared with the normal control. Conclusions These results indicate that factors other than FLG gene mutations can downregulate profilaggrin/filaggrin expression, leading to the ichthyosiform phenotype in the context of AD.     

Genotype–phenotype associations in filaggrin loss‐of‐function mutation carriers

Background. Loss‐of‐function mutations in the filaggrin gene (FLG) have been reported to be associated with specific phenotypic characteristics such as hyperlinearity and keratosis pilaris. Objectives. To study phenotypic features in patients with occupational irritant contact eczema of the hands in relation to FLG loss‐of‐function mutations. Materials and methods. In a prospective cohort study, genotype was determined for 459 study subjects for four FLG null alleles, and investigated for selected history, clinical and laboratory features. Results. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X, and/or 2282del4. Flexural eczema, xerosis cutis, pityriasis alba, dirty neck, pulpitis sicca, hyperlinear palms, keratosis pilaris and family history of eczema were positively associated with FLG mutations (p < 0.05). Although we observed a statistically significant correlation with higher serum IgE in FLG mutation carriers, allergic rhinoconjunctivitis and allergic asthma were not over‐represented in this group. Conclusion. This study shows further genotype–phenotype correlations in patients with occupational irritant contact eczema and FLG mutation carrier status. These features may help to identify those with FLG mutations on a specific phenotype basis.     

Interactions between FLG mutations and allergens in atopic dermatitis

Filaggrin gene (FLG) mutations and sensitization in patients with atopic dermatitis (AD) have been well documented. However, whether an interaction exists between these mutations and specific sensitization in AD patients is still unknown. The aim of the study was to explore the interaction between FLG mutations and specific sensitization in AD patients. A total of 249 AD outpatients were recruited in the current study. Skin prick tests were conducted to assess the patient??s sensitization to specific allergens. FLG mutations were analyzed through comprehensive sequencing. Logistic regression analyses were conducted to determine the interactions between FLG mutations and sensitization present. The mean age of the patients was 3.5?years, and the mean age of onset of AD was 9.6?months. The mean SCORAD of the patients was 25.8. Fourteen types of mutations were identified in the FLG of 64 patients. A total of 24 (9.6?%) and 29 (11.6?%) cases were mutated with 3321delA and K4671X, respectively. Sensitization to at least one type of allergen was detected in 118 patients (47.4?%). Logistic regression analyses showed that FLG mutations presented an interaction with sensitization to peanut and did not interact with the other detected allergens among AD patients. Sensitization to peanut allergens would have an interaction with the mutation of K4671X and the combined mutations in FLG in patients with atopic dermatitis. However, sensitization to the other common allergens might not interact with FLG mutations in the development of atopic dermatitis.     

Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling

Background Filaggrin gene (FLG) loss‐of‐function mutations have been shown to represent the strongest so far known genetic risk factor for atopic dermatitis (AD). Whereas the barrier characteristics in FLG mutation carriers under baseline conditions have been investigated, there are only limited data on the permeability barrier function in filaggrin‐AD under compromised conditions. Aim We investigated: (i) stratum corneum (SC) integrity/cohesion; (ii) barrier recovery after controlled mechanical and irritant‐induced barrier abrogation; and (iii) the lipid composition of the non‐lesional and lesional skin of AD patients harbouring the European R501X, 2282del4, 3702delG, R2447X or S3247X FLG variants. Methods Thirty‐seven AD patients (14 FLG mutation carriers and 23 non‐carriers) and 20 healthy controls participated in the study. Stratum corneum integrity/cohesion was assessed by measurement of transepidermal water loss (TEWL) and amount of removed protein following sequential tape stripping. Barrier recovery was monitored by repeated measurements of TEWL and erythema up to 96 h after barrier abrogation. Samples for lipid analysis were obtained from non‐lesional and lesional skin using the cyanoacrylate method. Results Tape stripping revealed distinct genotype‐related impairment of the SC integrity/cohesion. No differences in the rate of barrier recovery among the groups were found. The SC lipid analysis revealed significant differences regarding the percentage amount of cholesterol, ceramide/cholesterol ratio and triglycerides in the uninvolved skin as well as the amounts of free fatty acids, CER[EOH] and triglycerides in the skin lesions of the AD FLG mutation carriers. Conclusions Our results provide evidence for discernible FLG‐related barrier integrity phenotypes in atopic eczema.     

Filaggrin Gene Mutations in African Americans with Both Ichthyosis Vulgaris and Atopic Dermatitis

Atopic dermatitis (AD) and ichthyosis vulgaris (IV) are two common disorders of epidermal homeostasis resulting in dry skin. The profilaggrin gene, located on chromosome 1q22, encodes a keratin filament aggregating protein (filaggrin) that is essential to forming the epidermal barrier and maintaining hydration. Null mutations in filaggrin have been found to underlie IV and are common in patients with AD, but the minority of African Americans with AD or IV show these mutations in filaggrin. We have selectively studied African Americans with both AD and IV to maximize the possibility of finding filaggrin null mutations in this population. DNA was collected using buccal swabs from 18 African American children with both AD and IV and 17 African American controls without either of these diseases. Purified genomic DNA was amplified using polymerase chain reaction from three regions of the filaggrin gene, exon 3, including R501X, 2282del4, E2554X, R2447X, 1249insG, R826X, 2767insT, and E2422X. Of the African American children with both AD and IV, 22.2% were heterozygous for filaggrin null mutations. Out of the control group, one carried a null mutation and was later discovered to have a history of asthma. Null mutations found in this population included R501X (n = 1), 2282del4 (n = 2), and R826X (n = 2, including the control patient). Our data demonstrate a prevalence of filaggrin mutations in the African American population that exceeds previously published data, although the overall prevalence is still lower than in other populations. It is likely that factors other than known FLG mutations are involved in African American patients.     

Clinical course of occupational irritant contact dermatitis of the hands in relation to filaggrin genotype status and atopy

Background Filaggrin loss‐of‐function mutations and atopy may alter the clinical course of irritant contact dermatitis (ICD). Objective To investigate the clinical course of patients with occupational ICD according to loss‐of‐function mutations in the filaggrin gene (FLG) and atopy. Methods In a prospective cohort study, the clinical course, use of topical corticosteroids, sick leave, recovery rate and job continuation were investigated in 459 inpatients treated for occupational ICD of the hands. Patients were genotyped for four FLG mutations, examined for atopy and followed for up to 3 years after discharge. Results Our study included 327 (71·2%) atopic individuals and 132 nonatopic individuals. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X and 2282del4 (60 atopic and eight nonatopic). Nonatopic patients with ICD responded well to therapeutic approaches, while atopy status made subjects more resistant to therapy, resulting in lower rates of recovery and job continuation and higher use of topical corticosteroids. Carriage of FLG loss‐of‐function mutations in combination with atopy worsened the course. The risk of abandoning one’s profession in this group was significantly increased when compared with ‘pure’ ICD (odds ratio 3·1) after 3 years. Conclusions Patients with atopy are a special risk population for ICD. In the presence of atopy, FLG mutations seem to be a modifier of the severity of the clinical course in ICD. Early‐stage identification of this subgroup may result in additional emphasis to these patients regarding the importance of adherence to specific therapeutic interventions.     

Eczema severity in preadolescent children and its relation to sex,filaggrin mutations,asthma, rhinitis,aggravating factors and topical treatment: a report from the BAMSE birth cohort

Background Filaggrin (FLG) mutations are major genetic determinants for eczema, but their role in eczema severity needs further investigation. Children with eczema are at higher risk of having asthma and rhinitis but it is not known if this risk is associated with the severity of eczema. Objectives To investigate eczema severity in relation to sex, FLG mutations, asthma, rhinitis and topical treatment among preadolescent children in a population‐based cohort. Methods Parental questionnaires were used to obtain data on symptoms of eczema, asthma, and rhinitis among 3301 preadolescent children. Eczema severity was evaluated based on sleep disturbance, extent of disease and total time with eczema the previous year. Genotyping was performed in 1854 individuals for three common FLG mutations (R501X, R2447X and 2282del4). Results Eczema was more prevalent among girls (14·5%) than boys (9·4%). FLG mutations were detected in 13·1% of children with mild eczema and 12·5% with moderate‐to‐severe eczema. Of children with moderate‐to‐severe eczema, 45·1% had rhinitis and 22·0% had asthma compared with 32·7% and 13·8% of children with mild eczema, respectively. Children with moderate‐to‐severe eczema used moisturizers and topical glucocorticoids more frequently than children with mild eczema. Boys used moisturizers less frequently than girls. Conclusions More preadolescent girls than boys had eczema. FLG mutations did not influence eczema severity in our population‐based cohort. Prevalence of rhinitis and asthma was associated with eczema severity, with the highest prevalence among boys with moderate‐to‐severe eczema.     

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations

Background  Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD. Objectives  To investigate further the spectrum of FLG‐null mutations in Chinese patients and to compare it with that in other populations. Methods  We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate‐to‐severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results  In total, 22 FLG‐null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher’s exact test; P = 5·3 × 10^?9; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher’s exact test; P = 9·0 × 10^?15; OR 5·8), keratosis pilaris (Fisher’s exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063). Conclusions  This study emphasizes the wider genetic landscape of FLG‐null mutations in Asia that is slowly emerging.     

Association between P478S polymorphism of the filaggrin gene and risk of psoriasis in a Chinese population in Taiwan

Abnormal keratinocyte terminal differentiation is one of the important characteristics of psoriatic lesions. Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis. Thus, FLG genetic variants may modify the risk of psoriasis. In total, 314 patients with psoriasis and 611 control subjects were analyzed for the presence of FLG R501X, 2282del4 mutations, and P478S (rs11584340, C/T base change) polymorphism by polymerase chain reaction (PCR). The analysis revealed that both the R501X and 2282del4 mutations were not present in a subset of 200 patients (64%) with psoriasis. In contrast, a marginally significant difference (P = 0.020) was found in the distribution of rs11584340 genotype frequencies between psoriatic patients and controls. The frequency of the TT genotype in psoriasis patients was significantly higher than in controls (37.9% vs. 29.1%, respectively, P = 0.007). The T allele frequency of patients (60.5%) was also significantly higher than that of controls (53.9%) (P = 0.007). After adjusting for age and gender, carriers of the TT genotype were 1.46 (95% CI, 1.08–1.96) times more likely than non-carriers to have psoriasis (P = 0.013). In conclusion, our results suggest that FLG P478S polymorphism may confer susceptibility to the development of psoriasis among Taiwanese Chinese.     

Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis

Background Loss‐of‐function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients’ susceptibility to recurrent skin infection. Objectives To investigate the association between FLG‐null mutations and the risk of recurrent skin infection among a series of patients with AD in Singapore. Methods This study included 228 Singaporean Chinese patients with AD with at least 1 year of follow‐up at the time of recruitment between January 2008 and December 2009 at the National Skin Centre in Singapore. Each patient had their medical records reviewed for history of skin infection in the preceding year and was genotyped for 22 FLG‐null mutations. Results Compared with those without the FLG‐null mutations, patients with AD who had FLG mutation(s) had approximately a seven times increased risk of more than four episodes of skin infection requiring antibiotics in the past year (odds ratio 6·74; 95% confidence interval 2·29–19·79). This risk was much greater in those with mild or moderate disease, and was present in both users and nonusers of oral steroids. Conclusion This study highlights a novel association between FLG‐null mutations and an increased susceptibility to recurrent bacterial skin infection among patients with AD.     

Novel FLG null mutations in Korean patients with atopic dermatitis and comparison of the mutational spectra in Asian populations

Filaggrin is essential for the development of the skin barrier. Mutations in the gene encoding filaggrin have been identified as major predisposing factors for atopic disorders. Molecular analysis of the FLG gene in this study showed nine null and one unclassified mutation in 13 of 81 Korean patients with atopic dermatitis (AD): five novel null mutations (i.e. p.S1405*, c.5671_5672delinsTA, p.W1947*, p.G2025* and p.E3070*); four reported null mutations (i.e. c.3321delA, p.S1515*, p.S3296* and p.K4022*); and one unclassified mutation (i.e. c.306delAAAGCACAG). These variants are nonsense, premature termination codon or in‐frame deletion expected to cause loss‐of‐function of FLG. Genotype–phenotype correlation is not obvious in Korean AD patients with FLG null mutations. According to a review of the mutational spectra of the FLG gene in the Asian populations, FLG null mutations appeared to be unique in each population but some mutations such as p.R501*, c.3321delA, p.S1515*, p.S3296* and p.K4022* were commonly found in at least two of the selected Asian populations including Korean, Japanese, Chinese, Singaporean Chinese or Taiwanese. Further investigations on a larger group of Korean AD would be necessary to elucidate its clinical pathogenesis and mutational spectrum related to specific FLG null mutations for AD.     

Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age

Background Filaggrin loss‐of‐function (FLG) mutations are associated with eczema and skin barrier impairment, but it is unclear whether skin barrier impairment precedes phenotypic eczema in FLG mutation carriers. Objectives To study the association between FLG mutations, skin barrier impairment and clinical eczema at 3 months of age. Methods A total of 88 infants were examined for eczema. Disease severity was determined by the SCORAD eczema severity score. Transepidermal water loss (TEWL) was measured on unaffected forearm skin. Venous blood samples were screened for the four most common FLG mutations found in the U.K. white population (R501X, 2282del4, R2447X and S3247X). Median SCORAD and TEWL measurements in children with and without eczema and FLG mutations were compared. Results Thirty‐three per cent (29/88) of children had clinical eczema. Median SCORAD was 10·6 (range 3·5–31·0). TEWL (g m^?2 h^?1) was higher in children with eczema compared with unaffected infants (median TEWL 14·24 vs. 11·24, P < 0·001). Higher TEWL was associated with more severe disease (r = 0·59, P < 0·001, median TEWL, SCORAD < 15, 13·1 vs. 29·6, SCORAD ≥ 15, P = 0·029). Clinically dry skin was associated with higher TEWL, even in the absence of eczema (median TEWL 17·55 vs. 11·08, P = 0·008). Seventeen per cent (15/88) of children carried at least one FLG mutation. FLG mutation carriers were significantly more likely to have clinically dry skin, even in the absence of eczema [odds ratio (OR) 8·50, 95% confidence interval (CI) 1·09–66·58, P = 0·042]. FLG mutation carriers were also more likely to have eczema by 3 months of age (OR 4·26, 95% CI 1·34–13·57, P = 0·014). FLG mutations were significantly associated with higher median TEWL (all children, FLG‘yes’ 21·59 vs. FLG‘no’ 11·24, P < 0·001), even without clinical eczema (FLG‘yes’ 15·99 vs. FLG‘no’ 10·82, P = 0·01). Conclusions By the age of 3 months, FLG mutations are associated with an eczema phenotype, dry skin and TEWL. The observation that TEWL is elevated in unaffected FLG mutation carriers suggests that skin barrier impairment precedes clinical eczema.     

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study

Summary Background Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. Objectives To investigate the association between FLG null mutations and hand eczema. Methods A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. Results Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2·98; 95% confidence interval (CI) 1·27–7·01], but not in subjects without atopic dermatitis (OR 0·82; 95% CI 0·41–1·67). Conclusions FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.     

Usefulness of a global clinical ichthyosis vulgaris scoring system for predicting common FLG null mutations in an adult caucasian population

Background Loss of function FLG alleles were first identified as causative of ichthyosis vulgaris (IV) and were subsequently found to be major predisposing factors for atopic dermatitis (AD) and atopic disorders. Objectives To identify independent factors associated with the clinical IV phenotype in adult caucasian patients with AD and to assess the performance of a global clinical severity score of IV in predicting common FLG null mutations. Patients and methods This was a prospective study conducted from January 2007 to June 2008. Adult patients attending the department of dermatology with a diagnosis of AD with or without IV were eligible to participate. For each patient, five clinical signs of IV were scored from 0 to 3 – diffuse xerosis, hyperlinearity of palms, scales on legs, scalp desquamation and keratosis pilaris – and a global IV clinical severity score was derived (0–15). Age of onset of AD, SCORAD (SCORing of Atopic Dermatitis), family and personal history for other signs of atopy, and total immunoglobulin E were recorded. Genotyping was performed for R501X and 2282del4. Univariate and multivariate analysis for factors associated with AD or AD + IV were conducted. Results In univariate analysis, family history of atopy, global clinical severity scoring and 2282del4 FLG mutation were positively correlated with the AD + IV phenotype. Using multivariate analysis, SCORAD for AD (OR 0·94, P = 0·01) and global clinical severity scoring for AD + IV (OR 2·62, P < 0·0001) were found to be independent factors. Conclusions The 2282del4 FLG mutation was confirmed as a good marker of early‐onset disease. Moreover, our global clinical severity score yielded a good negative predictive value of common caucasian null FLG mutations.