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.

Acral self-healing collodion baby: report of a new clinical phenotype caused by a novel TGM1 mutation.

A minority of collodion babies, called 'self-healing collodion babies', heal spontaneously. We describe a novel clinical phenotype of acral self-healing collodion baby caused by a new TGM1 mutation. The proband, born to healthy parents, presented at birth as a collodion baby strictly localized to the extremities. The skin condition returned to normal at the age of 3 weeks. The older sister was born as a generalized collodion baby; the condition then developed into lamellar ichthyosis. Molecular analysis of TGM1 revealed three novel mutations in the family. The proband was compound heterozygous for the p.Val359Met and p.Arg396His mutations, whereas the older sister was compound heterozygous for p.Arg396His and a deletion mutation c.1922_1926+2delGGCCTGT. Structural modelling of the p.Val359Met mutation suggested a minor disruption of the protein structure, whereas a modification of protein-protein interaction was predicted for p.Arg396His. These predictions corroborated the analysis of recombinant transglutaminase (TGase)-1 proteins carrying the p.Val359Met and p.Arg396His mutations. Both showed decreased levels of protein expression: p.Val359Met displayed residual activity (12.8%), while p.Arg396His caused a dramatic loss of activity (3.3%). These observations demonstrate for the first time that TGM1 mutations can be associated with acral self-healing collodion baby, and expand the clinical spectrum of TGase-1 deficiency.

Ichthyosis vulgaris: novel FLG mutations in the German population and high presence of CD1a+ cells in the epidermis of the atopic subgroup.

BACKGROUND: Ichthyosis vulgaris (IV) is a genetic disorder with a prevalence of 1:250-1000 caused by filaggrin (FLG) mutations, which also predispose to atopic diseases. OBJECTIVES: To study the genotype/phenotype relationship in IV and to analyse whether the suggested skin barrier defect is associated with differences of epidermal dendritic cells. PATIENTS/METHODS: We evaluated a cohort of 26 German patients with IV, established an IV severity score and analysed epidermal ultrastructure, histology, filaggrin and CD1a antigens. Mutations were screened by restriction enzyme analysis. Particular sequencing techniques allowed the complete FLG analysis to reveal novel mutations. RESULTS: The combined null allele frequency of R501X and 2282del4 was 67.3%. Patients also showed the mutations S3247X and R2447X as well as five novel FLG mutations: 424del17 and 621del4 (profilaggrin S100 domain), 2974delGA (repeat 2), R3766X (repeat 10(1)) and E4265X (repeat 10(2)). Their combined allele frequency in controls was <0.7%. No mutation was found in one IV patient, all in all approximately 27% were heterozygous, and the majority (approximately 69%) showed two null alleles. The IV severity score and ultrastructure showed a significant correlation with genotypes. Interestingly, CD1a cell counts showed a significant difference between nonatopic and atopic IV patients both with eczema and without eczema. CONCLUSIONS: We confirm that the mutations R501X and 2282del4 represent the most frequent genetic cause in German IV patients. The novel mutations are probably population and family specific. The observed differences of CD1a cells support the hypothesis that there is a barrier defect that predisposes to atopic manifestations, possibly independent of atopic eczema.

Plasminogen activator inhibitor-2 is expressed in different types of congenital ichthyosis: in vivo evidence for its cross-linking into the cornified cell envelope by transglutaminase-1.

BACKGROUND: Plasminogen activator inhibitor-2 (PAI-2), a regulatory serpin of the plasminogen activator (PA) system, has been described as a potential component of the cornified cell envelope (CE). Protease inhibitors are essential for skin homeostasis and in particular for the regulation of the desquamation process. Therefore, an aberrant expression of PAI-2 could be involved in the pathogenesis of certain cornification disorders. OBJECTIVES: Evaluation of the expression of PAI-2 in different types of congenital ichthyosis, especially in lamellar ichthyosis/nonbullous congenital ichthyosiform erythroderma (LI/NCIE) and in Netherton syndrome (NTS). Demonstration of the functional relationship between PAI-2 and transglutaminase (TGase)-1. PATIENTS AND METHODS: Using immunohistochemistry we evaluated cryosections from individuals suffering from LI/NCIE (n=67), NTS (n=6), ichthyosis-follicularis-atrichia-photophobia syndrome (n=2) and Harlequin ichthyosis (n=1) in comparison with psoriasis vulgaris and healthy skin. Moreover, we assessed the respective TGase-1 activity and the presence of TGase-1 protein. A functional assay was developed to elucidate whether PAI-2 is a substrate for TGase-1. RESULTS: PAI-2 is expressed in different types of congenital ichthyosis and there is a strong correlation between TGase-1 activity and PAI-2 protein signal. Double staining revealed a strong colocalization of TGase-1 activity and PAI-2 protein. The epidermal incorporation of the specific PAI-2 peptide containing a TGase binding site revealed a strong pericellular staining in the stratum granulosum in healthy skin. In contrast, TGase-1-deficient skin showed only a lamellar staining in the stratum corneum. CONCLUSIONS: We provide in vivo evidence that PAI-2 is a substrate of TGase-1. The normal expression of PAI-2 in a large group of TGase-1-proficient LI/NCIE patients makes it rather unlikely that PAI-2 alone is a primary molecular cause of LI/NCIE.