Background
Food‐dependent exercise‐induced anaphylaxis (FDEIA) is a serious food allergy in which anaphylaxis develops when exercise is performed within several hours after food intake. The precise ...mechanism underlying allergic sensitization in FDEIA has been an important issue but remains poorly understood.
Objectives
We aimed to elucidate the pathomechanism including the route of allergen sensitization involved in FDEIA.
Methods
A Japanese family with wheat‐dependent exercise‐induced anaphylaxis (WDEIA), a specific form of FDEIA, were clinically examined. Mutation analysis of the gene encoding filaggrin (FLG) was also performed.
Results
Two of the family members were confirmed as WDEIA on the basis of their medical history and positive provocation test results. Notably, the two affected individuals in the family had concomitant ichthyosis vulgaris. Mutation analysis of FLG revealed that they carry one or more loss‐of‐function mutations that have not been described in the Japanese population.
Conclusion
These results indicate that FLG mutations might be involved in the pathogenesis of WDEIA in the present case.
Summary
Background Lipoid proteinosis (LiP) is a rare autosomal recessive disorder characterized by a hoarse voice, warty skin infiltration and scarring. Mutations within the extracellular matrix ...protein 1 (ECM1) gene cause LiP. Since the early 1970s it has been recognized that South Africa has one of the largest groups of LiP patients worldwide, suggesting a probable founder effect. As LiP patients present with considerable clinical variability, this group of patients offers a unique opportunity for genotype–phenotype correlation.
Objectives To assess the clinical features and the molecular basis of LiP in patients from the Namaqualand area of the Northern Cape province of South Africa and to examine molecular evidence for a founder effect.
Subjects and methods The LiP patient cohort consisted of 29 Coloured patients from Namaqualand and a further seven Caucasoid patients from other areas of South Africa. The control group included 100 healthy geographically and ethnically matched individuals from Namaqualand. Samples were collected after informed consent and with ethics committee approval from the University of the Witwatersrand. LiP patients were examined clinically and a structured recording sheet was completed. A brief neurological evaluation was also performed. The LiP founder effect was investigated at the molecular level by ECM1 mutation detection and haplotype analysis.
Results The most consistent clinical signs for a diagnosis of LiP in this group were a hoarse voice and thickened sublingual frenulum leading to restricted tongue movement. Homozygosity for a nonsense mutation in exon 7 of the ECM1 gene, Q276X, was identified in all patients (Coloured and Caucasoid). Despite this genetic homogeneity, considerable clinical variability in skin presentation and psychiatric involvement was observed. Haplotype analysis using markers from a 9·98‐Mb region around the ECM1 locus confirmed the founder effect with a founder core haplotype, 19‐Q276X‐12 (ND1‐ECM1‐D1S2343), in all but four LiP‐associated alleles (n = 58). A LiP carrier rate of 1 in 9 was observed among the 100 Namaqualand controls, predicting a LiP incidence of 1 in 324 in this community.
Conclusions Although several consistent clinical features in LiP patients homozygous for the Q276X mutation in the ECM1 gene were observed, there remains considerable clinical variability. This suggests the action of genetic and environmental modifiers of disease severity. Strong molecular evidence supports a single founder effect for the high prevalence of LiP in South Africans, both Coloured and Caucasoid.
Summary
Background Pachyonychia congenita (PC) is a rare keratin disorder that typically presents with nail dystrophy and focal plantar keratoderma. We present seven cases of PC with transgrediens ...involvement of the dorsal feet.
Objectives To document the extension of their disease to the dorsum of the feet in patients with mutation‐confirmed PC, to report the natural history of PC with such transgrediens involvement, to generate hypotheses regarding aetiology, and to suggest prevention and treatment modalities.
Methods Genetically confirmed cases of PC with transgrediens foot involvement were verified through the International Pachyonychia Congenita Research Registry (IPCRR) and characterized via telephone survey and photography.
Results Seven patients with PC in the IPCRR were confirmed to have transgrediens lesions on the dorsal feet (six KRT6A mutations; one KRT16 mutation). Six cases had pre‐existing nontransgrediens keratoderma and all cases reported standing, wearing shoes, foot moisture, and/or infection as exacerbating or predisposing factors. Improvement, reported in six cases, was attributed to use of antibiotics or gentian violet, or improved footwear.
Conclusions Transgrediens involvement of the dorsal feet is a rare manifestation of mutation‐confirmed PC and may be more common in patients who carry a KRT6A mutation. Trauma, friction, infection and wound healing may exacerbate or predispose toward transgrediens lesions. It remains to be proven whether transgrediens‐associated infection is causal or represents a primary or secondary process. Patients with PC who develop transgrediens lesions may benefit from fungal and bacterial cultures, followed by appropriate antimicrobial treatments. Efforts to decrease skin friction and moisture may also improve and/or prevent transgrediens spread.
Summary
Background
Several studies have identified an association between water hardness and atopic eczema (AE); however, there is a paucity of longitudinal data in early life.
Objectives
To examine ...whether water hardness is associated with an increased risk of AE and skin barrier dysfunction in infants and to assess effect modification by filaggrin (FLG) loss‐of‐function variants.
Methods
We performed a longitudinal analysis of data from infants in the Enquiring About Tolerance (EAT) study, who were enrolled at 3 months and followed up until 36 months of age.
Results
Of 1303 infants enrolled in the EAT study, 91·3% (n = 1189) attended the final clinic visit and 94·0% (n = 1225) of participants’ families completed the 36‐month questionnaire. In total, 761 (58·4%) developed AE by 36 months. There was no overall association between exposure to harder (> 257 mg L−1 CaCO3) vs. softer (≤ 257 mg L−1 CaCO3) water: adjusted hazard ratio (HR) 1·07, 95% confidence interval (CI) 0·92–1·24. However, there was an increased incidence of AE in infants with FLG mutations exposed to hard water (adjusted HR 2·72, 95% CI 2·03–3·66), and statistically significant interactions between hard water plus FLG and both risk of AE (HR 1·80, 95% CI 1·17–2·78) and transepidermal water loss (0·0081 g m−2 h−1 per mg L−1 CaCO3, 95% CI 0·00028–0·016).
Conclusions
There is evidence of an interaction between water hardness and FLG mutations in the development of infantile AE.
What's already known about this topic?
Several cross‐sectional studies have found an association between domestic water hardness exposure and atopic eczema (AE) risk.
Loss‐of‐function mutations in the skin barrier gene filaggrin (FLG) are the strongest genetic risk factor for AE.
What does this study add?
There was no overall association between AE risk and exposure to harder vs. softer domestic water in a large, well‐phenotyped cohort of infants living in England and Wales followed up at 3–36 months of age.
However, infants with at least one FLG loss‐of‐function mutation exposed to harder water have a threefold increased risk of developing AE up to age 36 months compared with infants with wild‐type FLG exposed to softer water.
Linked Comment: Arents and Leonardi-Bee. Br J Dermatol 2020; 183:203–204.
Plain language summary available online
Type I and type II keratins form the heteropolymeric intermediate filament cytoskeleton, which is the main stress-bearing structure within epithelial cells. Pachyonychia congenita (PC) is a group of ...autosomal dominant disorders whose most prominent phenotype is hypertrophic nail dystrophy accompanied by other features of ectodermal dysplasia. It has been shown previously that mutations in either K16 or K6a, which form a keratin expression pair, produce the PC-1 variant (MIM 184510). Mutations in K17 alone, an unpaired accessory keratin, result in the PC-2 phenotype (MIM 184500). Here, we describe a family with PC-2 in which the K17 locus on 17q was excluded and linkage to the type II keratin locus on 12q was obtained (Zmax 3.31 at θ = 0). Mutation analysis of candidate keratins revealed the first reported missense mutation in K6b, implying that this keratin is the previously unknown expression partner of K17, analogous to the K6a/K16 pair. Co-expression of these genes was confirmed by in situ hybridization and immunohistochemical staining. These results reveal the hitherto unknown role of the K6b isoform in epithelial biology, as well as genetic heterogeneity in PC-2.
Background:
Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy. Filaggrin (FLG) loss‐of‐function variants (null‐alleles) are associated with eczema and asthma in ...association with eczema. The aim was to assess the contribution of FLG null‐alleles to pediatric IBD susceptibility and to coexistent atopy (eczema, asthma, allergic rhinitis, or food allergy).
Methods:
FLG variants (R501X and 2282del4) were genotyped in 403 children with IBD, 683 parents, and 996 population controls.
Results:
In all, 11% of IBD patients carried at least 1 FLG null‐allele compared to 11% of population controls (P > 0.4). Carriage of 1 or more null‐alleles in patients with atopy (present in 52% of IBD patients) differed from IBD patients without atopy (14% versus 6%, P = 0.01; odds ratio OR 2.4, 95% confidence interval CI 1.2–5.1). The effect of FLG null‐alleles was strongest for eczema (19% versus 7%, P = 0.0003; OR 3.3, 95% CI 1.7–6.6) and food allergy (28% versus 8%, P = 0.0001; OR 4.5, 95% CI 2.0–10.0). The presence of more than 1 atopic disease tended to increase the associated OR: eczema + asthma (23% versus 7%, P = 0.001; OR 3.9, 95% CI 1.6–9.1), eczema + asthma + allergic rhinitis (29% versus 7%, P = 0.0006; OR 5.4, 95% CI 1.9–15.4) and eczema + asthma + allergic rhinitis + food allergy (45% versus 6%, P < 10−4; OR 12.2, 95% CI 3.2–46.3). Logistic regression analysis of IBD cases confirmed the association of carriage of an FLG null‐allele with atopy (P = 0.01; OR 2.4, 95% CI 1.2–5.1) and co‐occurrence of different forms of atopy (P = 0.003; OR 3.5, 95% CI 1.5–8.1).
Conclusions:
Filaggrin null‐alleles have no effect on IBD susceptibility but contribute to coexistent eczema and food allergy. (Inflamm Bowel Dis 2009)
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