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Diagrammatic representation of the patterns of palmar skin markings observed in a series of 308 English school children aged 7–9 years. The palmar skin features of a total of 792 children were examined by a single experienced dermatologist (S.J.B.). Examination of 484 children led to the observation of three distinct patterns of palmar hyperlinearity and the patterns of palmar markings were then recorded for the subsequent 308 children. The majority of children in this cohort had very smooth palmar skin; within the series of 308 children, 65 had palmar hyperlinearity of whom 18% showed pattern 1, 20% showed pattern 2 and 62% showed pattern 3. Diagrams have been used to illustrate the hyperlinearity patterns as clinical photos were not permitted because of ethical constraints, but examples of the distinct patterns may be seen in published literature.6,22,36–39
Source publication
Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined.
This study investigated the genotype-phenotype association between detailed skin phenotype and FLG genotype data in a population-based coh...
Contexts in source publication
Context 1
... of such a large number of children led to the novel observation that there are several distinct patterns of palmar hyperlinearity, illustrated diagrammatically in Figure 2. The vast majority of children in this cohort had smooth palmar skin; some children had a subtle increase in palmar markings at the margins of the thenar eminence, but this was not classified as palmar hyperlinearity for the purposes of this Genotyping results for all six of the screened mutations (R501X, 2282del4, R2447X, S3247X, 3702delG, 3673delC) were avail- able for these 778 children out of the 792 children included in this cohort study. ...Context 2
... vulgaris cases. The novel observation that there are three distinct patterns of palmar hyperlinearity merits further investigation: it may help to clarify the ultra- structural mechanisms by which filaggrin haploinsufficiency results in hyperlinearity, as the pattern of linear markings running perpendicular to the thenar eminence (pattern 1, Fig. 2) predominates in cases of ichthyosis vulgaris, although the cross-hatched pattern (pattern 3, Fig. 2) is more prevalent overall. These different patterns may be observed in previously published photographs: pattern 1 is shown by O'Regan and Irvine (Fig. 1b) 36 and Judge et al.; 37 pattern 2 is demonstrated by Nomura et al. (Figs 2c and ...Context 3
... merits further investigation: it may help to clarify the ultra- structural mechanisms by which filaggrin haploinsufficiency results in hyperlinearity, as the pattern of linear markings running perpendicular to the thenar eminence (pattern 1, Fig. 2) predominates in cases of ichthyosis vulgaris, although the cross-hatched pattern (pattern 3, Fig. 2) is more prevalent overall. These different patterns may be observed in previously published photographs: pattern 1 is shown by O'Regan and Irvine (Fig. 1b) 36 and Judge et al.; 37 pattern 2 is demonstrated by Nomura et al. (Figs 2c and 2d); 38 while pattern 3 is dem- onstrated by Smith et al. (Figs 1c and 1e), 6 Sandilands et al. ...Context 4
... novel observation that there are three distinct patterns of palmar hyperlinearity merits further investigation: it may help to clarify the ultra- structural mechanisms by which filaggrin haploinsufficiency results in hyperlinearity, as the pattern of linear markings running perpendicular to the thenar eminence (pattern 1, Fig. 2) predominates in cases of ichthyosis vulgaris, although the cross-hatched pattern (pattern 3, Fig. 2) is more prevalent overall. These different patterns may be observed in previously published photographs: pattern 1 is shown by O'Regan and Irvine (Fig. 1b) 36 and Judge et al.; 37 pattern 2 is demonstrated by Nomura et al. (Figs 2c and 2d); 38 while pattern 3 is dem- onstrated by Smith et al. (Figs 1c and 1e), 6 Sandilands et al. (Fig. 1b) 22 and Chen et al. (Figs 1a and 1b). 39 In conclusion, filaggrin haploinsufficiency is a highly pene- trant trait, associated with ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema, with a statistically signifi- cant trend towards more severe eczema. ...Similar publications
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Citations
... The most common cutaneous findings are follicular hyperkeratosis, perifollicular hemorrhages, ecchymoses (or small spots of discoloration in the skin or mucosa, arising from extravasation of blood), xerosis (or dry skin without scaling), leg edema, poor wound healing ( Figure 2), and bent or coiled body hairs [94][95][96]. Of importance, perifollicular hemorrhage with corkscrew hair deformity, resultant of follicular hyperkeratosis, is pathognomonic of scurvy [94,97,98]. ...
Pathophysiology may be defined as a hybrid fundamental science, focusing on changes in the body's major functions during diseases, such as scurvy and other nutritional deficiencies. Mostly, it allows to understand the biological modifications triggering the illness-related manifestations. Thus, the aim of this study is to critically review the pathophysiological and clinical alterations of this metabolic disorder under various age groups (i.e., children, adults, and the elderly). Other vulnerable populations are revised too, for instance, individuals with malnutrition and (or) alcoholism, and diabetes mellitus. Nevertheless, the present work does not discuss in detail the mandatory vitamin C supplementation in scurvy.
... IV and RXLI are considered as common forms whereas LI, HI, and CIE are the rarest types and collectively called autosomal recessive congenital ichthyosis (ARCI) [4,7]. IV is the common sub type of ichthyosis with the prevalence of 1:100 [8]. It is characterized by thin pale grey scales on the body surface except articular flexures and palmo-plantar hyperlinearity [9]. ...
Background and Objectives: Lamellar ichthyosis is a rare skin disease characterized by large, dark brown plate-like scales on the entire body surface with minimum or no erythema. This phenotype is frequently associated with a mutation in the TGM1 gene, encoding the enzyme transglutaminase 1 which plays a catalytic role in the formation of the cornified cell envelop. The present study aimed to carry out clinical and genetic characterization of the autosomal recessive lamellar ichthyosis family from Balochistan. Materials and Methods: A consanguineous family with lamellar ichthyosis was enrolled from Balochistan, Pakistan. PCR amplification of all the exons and splice site junctions of the TGM1 gene followed by Sanger sequencing was performed on the genomic DNA. The identified variant was checked by In silico prediction tools to evaluate the effect of the variant on protein. Results: Sanger sequencing identified a homozygous nonsense variant c.131G >A (p.Trp44*) in the TGM1 gene that segregated in the autosomal recessive mode of inheritance in the family. The identified variant results in premature termination of transcribed mRNA and is predicted to cause a truncated or absent translation product transglutaminase-1 (TGase-1) accompanied by loss of catalytic activity, causing a severe clinical phenotype of lamellar ichthyosis in the patients. Conclusions: Here, we report a consanguineous lamellar ichthyosis family with a homozygous nonsense variant in the TGM1 gene. The variant is predicted as pathogenic by different In silico prediction tools.
... FLG null mutations have been shown to correlate with AD severity and persistence in adulthood [77,88,106,113,114]. Indeed, the observed higher prevalence of adult AD patients with an FLG null mutation (42%) [113] when compared to pediatric patients (13%) [104] argues for a role of FLG status in disease evolution, although this remains to be confirmed in large patient cohorts with different ethnic backgrounds. ...
The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.
... The ichthyoses are a group of lifelong genetic disorders characterized by skin thickening, scaling and underlying cutaneous inflammation. 1,2 The most common types are usually not present at birth: ichthyosis vulgaris, affecting 1 in 100 individuals 3 and recessive X-linked ichthyosis, which manifests in 1 in 4500 male individuals. 4 All congenital subtypes are orphan forms (< 1 in 200 000 individuals). ...
Background:
The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a Th17 immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored.
Objectives:
To analyze the metagenome profile of skin microbiome for major congenital ichthyosis subtypes.
Methods:
Body site-matched skin surface samples were collected from the scalp, upper arm, and upper buttocks of 16 healthy controls and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis.
Results:
Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. C. acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. M. globosa was reduced at all body sites, while M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. M. slooffiae, by contrast, was strikingly increased at all body sites of congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing CIE, LI, and epidermolytic ichthyosis subtypes.
Conclusions:
The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis.
... While cohort studies of children in Europe have observed FLG LoF mutation frequencies of 15.1-20.9% and 5.8-13.0% in AD and non-AD groups, respectively, [231][232][233][234][235][236] Sasaki et al found no difference in FLG LoF mutation frequency between children with and without AD on a subtropical Ishigaki Island where humidity (monthly average, 60.8-78.7%) and temperature (monthly average, 18.5-29.4 ...
Atopic dermatitis (AD) is one of the most common skin conditions in humans. AD affects up to 20% of children worldwide and results in morbidity for both patients and their caregivers. The basis of AD is an interplay between genetics and the environment characterized by immune dysregulation. A myriad of mutations that compromise the skin barrier and/or immune function have been linked to AD. Of these, filaggrin gene (FLG) mutations are the most evidenced. Many other mutations have been implicated in isolated studies that are often unreplicated, creating an archive of genes with potential but unconfirmed relevance to AD. Harnessing big data, polygenic risk scores (PRSs) and genome-wide association studies (GWAS) may provide a more practical strategy for identifying the genetic signatures of AD. Epigenetics may also play a role. Staphylococcus aureus is the most evidenced microbial contributor to AD. Cutaneous dysbiosis may result in over-colonization by pathogenic strains and aberrant skin immunity and inflammation. Aeroallergens, air pollution, and climate are other key environmental contributors to AD. The right climate and/or commensals may improve AD for some patients.
... Palmar hyperlinearity was the clinical feature most strongly associated with FLG null genotype in a population-based study of children aged 7-9 years (heterozygote odds ratio 19.3 (95% confidence interval 11.7-31.7)) 2 but hyperlinearity can also occur in FLG wild-type individuals (those with no FLG mutations). 2 In addition to causing the monogenic dry skin condition of ichthyosis vulgaris, FLG null mutations also increase risk of the common complex trait atopic eczema. 3 The strongest and most highly significant effect of FLG null genotype on eczema risk is present in earlyonset, persistent and severe disease 4 associated with multiple other atopic conditions, including asthma and food allergy. ...
Background
Palmar hyperlinearity is a feature of ichthyosis vulgaris, the monogenic skin disorder caused by FLG loss-of-function mutations.
Objective
To investigate how well the presence or absence of hyperlinear palms (HLP) detect FLG genotype in children.
Methods
STARD criteria are used to report this diagnostic accuracy study. Phenotype and genotype data (four most prevalent FLG null mutations) were obtained from a total of 3656 children in three studies: the UK CLOTHES trial (children 1-5 years with moderate-severe atopic eczema); UK BEEP trial (2-year-olds at high risk of developing atopic eczema); UK-Irish eczema case collection (0 to 16-year-olds with atopic eczema). All participants included in analyses of HLP as the index test and FLG genotype as the reference were of white European ancestry.
Results
32% of participants (1159/3656) had FLG null mutation(s) and 37% (1347/3656) had HLP. In 13% (464/3656) HLP was recorded as ‘unsure’ or not recorded. The sensitivity and specificity of HLP for detecting FLG mutations in each of the studies was: 67% (95% CI 55-78%) and 75% (67-82%) in CLOTHES; 46% (36-55%) and 89% (86-91%) in BEEP; 72% (68-75%) and 60% (57-62%) in the UK-Irish case collection. Positive and negative likelihood ratios were: 2.73 (1.95-3.81) and 0.44 (0.31-0.62) in CLOTHES; 4.02 (2.99-5.40) and 0.61 (0.52-0.73) in BEEP; 1.79 (1.66-1.93) and 0.47 (0.42-0.53) in the UK-Irish collection.
Discussion
Trained observers were able to define palmar hyperlinearity in the majority (3191/3656, 87%) of cases. The presence of HLP is not a reliable sign to detect FLG mutations, but the absence of HLP excludes FLG null genotype with a reasonable degree of certainty.
Registration
This retrospective study was not pre-registered.
... The polymorphism of other genes related to the immune system and extracellular matrix reinforces the notion of skin homeostasis breakage in AD [36,50,51]. It increases the severity of the disease and susceptibility to infection by Staphylococcus aureus and other viral infections [14,52,53]. Furthermore, Th2 cytokines IL-4 and IL-13 also modulate the downregulation of the FLG gene and other epidermal barrier genes in some AD patients [54]. ...
Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.
... In populations of European ancestry, two most common mutations are 2282del4 (rs558269137) and R501X (rs61816761) [7]. Despite the fact that in heterozygotes, penetrance of the mutations ranges from 73% for 2282del4 to 96% for R501X [7], [9], any explanation of the difference between the frequencies of homo-and heterozygotes for FLG null mutations (13.0%) and prevalence of ichthyosis (1.3%) has not been proposed yet [2], [7], [10]. At the same time, epigenetic studies of eczema and atopic dermatitis demonstrated that the risk of the diseases is associated with methylation level of FLG gene [11], [12], [13]. ...
... We tested а hypothesis about folate metabolism polymorphisms impact on the phenotypic expression of FLG null mutations in patients with ichthyosis vulgaris for England and Scotland only. This was because all the necessary data on the prevalence of the disease and frequencies of the FLG mutations and one-carbon metabolism polymorphisms were available for this region [2], [10], [75]. The frequencies of FLG heterozygotes and the predisposing genotype MTHFR 677CT/MTHFR 1298AA/MTR 2756AA+AG/MTRR 66AG are 0.13 and 0.092 in the region; thus, the combined probability of the clinical manifestation of ichthyosis vulgaris should be 0.012, that is not statistically different from the prevalence of the disease reported for the region -0.013 (p = 0.857). ...
BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris. AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris. METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p<0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002). CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.
... The most common form of ichthyosis is IV, with a prevalence of up to 1:100 (3). It is caused by autosomal semi-dominant inherited loss-of-function mutations in the filaggrin gene (FLG). ...
Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80-90% of cases can be resolved at present. Further methods covering the whole exome sequencing (WES) or whole genome sequencing (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.
... Його поширеність у Балаклійському районі складала 1:4568, у Близнюківському -1:2403, у Зміївському -1:11999, у Ізюмському -1:6763 [14], середнє значення по чотирьох районах -1:5740. У Білорусі цей показник дорівнює 1:15500, у Ростовській області Російської Федерації -1:22067, а у Боснії й Герцеговині -1:129870, в Англії -1:80-1:250 [1,7,26,40]. ...
