Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile.

BACKGROUND: Ichthyosis vulgaris (IV) is caused by loss-of-function mutations in the profilaggrin (FLG) gene. Filaggrin drives complex interrelated functions, with strategic roles in establishing structural and chemical barrier function, hydration of the skin and maintaining epidermal homeostasis. Data on the effect of FLG mutations on epidermal barrier function in IV are very scarce. OBJECTIVES: A primary aim of this study was to determine in vivo characteristics of epidermal permeability barrier function such as transepidermal water loss (TEWL), skin hydration and skin surface pH in homozygous or compound heterozygous (FLG(-/-)) and heterozygous (FLG(+/-)) subjects with IV. METHODS: We evaluated a cohort of 15 patients with IV, analysed epidermal ultrastructure and investigated epidermal barrier function by measurement of TEWL, skin surface pH and skin hydration. Mutations were screened by restriction enzyme analysis and/or complete sequencing. Ten patients were homozygous or compound heterozygous (FLG(-/-)), while five patients were heterozygous (FLG(+/-)). Twenty healthy individuals served as controls. RESULTS: In FLG(-/-) subjects, a moderate increase of TEWL from 5.41 ± 0.32-7.54 ± 0.90 g/m(2) h (P < 0.03) and a moderate decrease of skin hydration from 29.20 ± 1.96 to 20.17 ± 3.60 (P < 0.05) in comparison with the control group were observed. Changes in skin surface pH were not significant. FLG(+/-) subjects did not suffer from significant changes in all variables. CONCLUSIONS: A complete, but not a partial deficiency is associated with moderate changes in TEWL and skin hydration, revealing surprisingly only a mild disturbance of the epidermal permeability barrier function.

Topographic and biomechanical evaluation of cornea in patients with ichthyosis vulgaris.

PURPOSE: To compare the topographic and biomechanical properties of corneas in eyes of patients with ichthyosis vulgaris (IV) and eyes of healthy individuals. METHODS: Thirty healthy individuals (control group) and 30 patients with IV (study group) were enrolled in this prospective study. Topographic measurements, including keratometry values, irregularity, and surface asymmetry index in the right eye of each participant were obtained using Scheimpflug camera with a Placido disc topographer (Sirius). Corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated intraocular pressure (IOPcc) and Goldman-related intraocular pressure (IOPg) were measured using the Reichert Ocular Response Analyzer (ORA). Central corneal thickness (CCT) was also measured with ultrasonic pachymetry and the Sirius corneal topography system. RESULTS: Topographic parameters were not significantly different between both groups (p>0.05). Although mean CH was not significantly different between the groups, the CRF was significantly lower in patients with IV (p=0.249 and p=0.005, respectively). The CCT was significantly lower in patients with IV compared to healthy controls (p<0.001). The IOPg and IOPcc were significantly lower in the patients with ichthyosis than in healthy controls (p=0.001 and p=0.004, respectively). CONCLUSIONS: The study demonstrated that while the eyes of patients with IV had corneal topographic findings and corneal hysteresis similar to those of healthy controls, some of corneal biomechanical properties such CRF and CCT and IOP values such as IOPg and IOPcc were significantly lower in patients with IV. These results should be taken into account when planning a corneal refractive surgery and glaucoma screening for patients with IV.

One remarkable molecule: filaggrin.

The discovery, in 2006, that loss-of-function mutations in the filaggrin (FLG) gene are the cause of ichthyosis vulgaris-the most common disorder of keratinization-and also a strong genetic risk factor for atopic eczema, marked a significant breakthrough in the understanding of eczema pathogenesis. Subsequent investigations of the role of FLG-null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis, and peanut allergy. However, many questions remain to be answered in relation to the precise mechanisms by which deficiency of an intracellular protein expressed primarily in the differentiating epidermis may contribute to the development of cutaneous and systemic pathology. This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical, and therapeutic implications, and to consider possible future directions for ongoing investigation.

Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.

Although it is widely accepted that filaggrin (FLG) deficiency contributes to an abnormal barrier function in ichthyosis vulgaris and atopic dermatitis, the pathomechanism of how FLG deficiency provokes a barrier abnormality in humans is unknown. We report here that the presence of FLG mutations in Caucasians predicts dose-dependent alterations in epidermal permeability barrier function. Although FLG is an intracellular protein, the barrier abnormality occurred solely via a paracellular route in affected stratum corneum. Abnormal barrier function correlated with alterations in keratin filament organization (perinuclear retraction), impaired loading of lamellar body contents, followed by nonuniform extracellular distribution of secreted organelle contents, and abnormalities in lamellar bilayer architecture. In addition, we observed reductions in corneodesmosome density and tight junction protein expression. Thus, FLG deficiency provokes alterations in keratinocyte architecture that influence epidermal functions localizing to the extracellular matrix. These results clarify how FLG mutations impair epidermal permeability barrier function.

Filaggrin in the frontline: role in skin barrier function and disease.

Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the approximately 400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.

The role of filaggrin loss-of-function mutations in atopic dermatitis.

PURPOSE OF REVIEW: To provide a comprehensive summary of recent genetic advances as they relate to the pathogenesis of atopic dermatitis. RECENT FINDINGS: Atopic dermatitis is a common inflammatory skin disease with a complex cause, resulting from an elaborate interplay between environmental, immunological and genetic factors. The disease is often the prelude to an atopic diathesis that includes asthma and other allergic diseases. The identification of mutations in the barrier protein filaggrin as conferring major susceptibility to atopic dermatitis and atopic dermatitis related asthma has reconfigured our understanding of disease mechanisms and highlights the importance of epidermal barrier disruption as a primary event in the disease. SUMMARY: In this review we highlight recent advances in our understanding of how filaggrin might influence the environmental-immune interface, impacting disease penetrance, severity and trajectory, and the implications for both research and therapeutics in this field. Focusing on the downstream biological consequences of altered filaggrin expression and the sequence of immunological and environmental triggers that ensue will provide the rationale for targeted therapeutics capable of restoring or preventing disruption of barrier function.

Filaggrin and the great epidermal barrier grief.

One of the principal functions of human skin is to form an effective mechanical barrier against the external environment. This involves the maturation and death of epidermal keratinocytes as well as the assembly of a complex network of differentially and spatially expressed proteins, glycoproteins and lipids into the keratinocyte cell membrane and surrounding extracellular space. In 2006, the key role of the granular cell layer protein filaggrin (filament-aggregating protein) in maintaining the skin barrier was determined with the identification of loss-of-function mutations in the profilaggrin gene (FLG). These mutations have been shown to be the cause of ichthyosis vulgaris and a major risk factor for the development of atopic dermatitis, asthma associated with atopic dermatitis as well as systemic allergies. Mutations in the FLG gene are extremely common, occurring in approximately 9% of individuals from European populations. The remarkable discovery of these widespread mutations is expected to have a major impact on the classification and management of many patients with ichthyosis and atopic disease. It is also hoped that the genetic discovery of FLG mutations will lead to the future development of more specific, non-immunosuppressive treatments capable of restoring effective skin barrier function and alleviating or preventing disease in susceptible individuals.

Disaggregation of corneocytes from surfactant-treated sheets of stratum corneum in hyperkeratosis on psoriasis, ichthyosis vulgaris and atopic dermatitis.

To elucidate the pathogenesis of impaired barrier function and the influence of surfactant on the stratum corneum in hyperkeratosis, we investigated morphological alterations of the corneocytes with soap solution. Groups of five patients each with psoriasis vulgaris (PV), ichthyosis vulgaris (IV), atopic dermatitis (AD), and normal controls were examined. Four samples of the horny layer were obtained from the same site by cyanoacrylate adhesive biopsy. The first sample was used for the superficial layer, and the fourth, for the basal horny layers. Each sample was agitated in 1% stirred soap solution at 60 degrees C. The number and size of isolated corneocytes and the morphologic changes were investigated. The release of corneocytes was greater and the swelling and morphological changes of corneocytes exposed to soap solutions were less in PV and AD than in IV or in healthy subjects. In IV, the release was markedly less than in controls. The release and swelling were greater in the superficial than in the basal horny layers. It was concluded that the cohesiveness of corneocytes was probably less in PV and AD and greater in IV than in normals. It was also suggested that the cohesion of corneocytes from the superficial horny layer was less than that from the deep layer. The permeability of the cornified envelope in PV and AD patients was less than in IV or healthy subjects. It was confirmed that highly potent soaps induce loss of many corneocytes and reduce the barrier function of the stratum corneum.

A statistical study on in vivo sorption and desorption of water in ichthyosis vulgaris.

Experiments on the variation of electrical conductance on sorption and desorption of water were performed on the skin of 34 subjects: 17 ichthyosis vulgaris patients and 17 normal subjects, matched for age and gender, under different ambient conditions. An exponential model of the form ft = theta oe theta t, where ft denotes fractional conductance at time t, describes the process of desorption with high accuracy. The parameter theta, identifiable as the rate of desorption, is significantly different between the ichthyotic and normal populations. The study discusses the impaired barrier function of the ichthyotic skin.

Barrier function parameters in various keratinization disorders: transepidermal water loss and vascular response to hexyl nicotinate.

In this study, we characterized the stratum corneum barrier function in 39 patients with various keratinization disorders (autosomal dominant ichthyosis vulgaris [ADI] [n = 7], X-linked recessive ichthyosis [XRI] [n = 6], autosomal recessive congenital ichthyosis [CI] [n = 10], dyskeratosis follicularis [Darier's disease; DD] [n = 8], erythrokeratoderma variabilis [EKV] [n = 8]), and 21 healthy volunteers, using two non-invasive methods: transepidermal water loss (TEWL) measuring outward transport of water through the skin by evaporimetry, and the vascular response to hexyl nicotinate (HN) penetration into the skin as determined by laser-Doppler flowmetry. Significantly increased TEWL values were found on the volar forearm in all three forms of ichthyosis, compared with the healthy control group, with the highest TEWL values in the CI group. The penetration of HN on the volar forearm was accelerated in patients with ADI, XRI and CI, as indicated by a shorter lag time (t0) between HN application and initial vascular response. However, differentiation between CI and the other ichthyoses was not possible by this method. When using both methods in DD and EKV, no differences compared with the healthy controls could be detected on the volar forearm, where the skin was principally unaffected; only the measurements from the affected skin on alternative sites demonstrated significantly increased TEWL values. In ADI and CI, however, normal-appearing skin also showed impaired values. We conclude that both TEWL and the vascular response to penetration of HN are suitable methods to monitor the skin barrier function in keratinization disorders, and are helpful in discriminating between these disorders.

[Sweat-gland function in patients with X-linked ichthyosis]. / Studio della funzionalità sudoripara in pazienti con ittiosi X-linked.

Literature reports that patients affected by X-linked ichthyosis (XLI) have a reduction of sweat glands and a decrease of sweat production. The sweat physiology of 28 patients, 14 with XLI, 7 with lamellar ichthyosis, 7 with dominant ichthyosis and 28 control subjects were examined with sweat test, performed by pilocarpine iontophoresis. In the same patients we have performed skin biopsy to evaluate quantitative and qualitative reduction of sweat glands.