Novel ABCC6 Mutations in Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in an ABC (ATP-Binding Cassette) transporter gene (ABCC6), which manifests with cutaneous, ophthalmologic, and cardiovascular findings. We studied a cohort of 19 families with PXE, and identified 16 different mutations, nine of which were novel variants. The mutation detection rate was about 77%. We found that arginine codon 518 was, with the previously described R1141X and EX23_29del, a recurrently mutated amino acid (11.5% of the mutations detected for each variant R518Q and R518X). No clear delineation of genotype/phenotype correlation was identified, and marked intra-familial variability of the disease was seen in one family. One family with pseudodominant inheritance displayed three distinct ABCC6 mutations, providing further evidence for the probable exclusive recessive transmission of PXE. These data contribute to the expanding database of ABCC6 mutations, to the description of phenotypic variability, and inheritance in PXE, and should be helpful for genetic counselling

Ichthyosis

[EN]The ichthyoses are a large, heterogeneous group of skin cornification disorders. They can be inherited or acquired, and result in defective keratinocyte differentiation and abnormal epidermal barrier formation. The resultant skin barrier dysfunction leads to increased transepidermal water loss and inflammation. Disordered cornification is clinically characterized by skin scaling with various degrees of thickening, desquamation (peeling) and erythema (redness). Regardless of the type of ichthyosis, many patients suffer from itching, recurrent infections, sweating impairment (hypohidrosis) with heat intolerance, and diverse ocular, hearing and nutritional complications that should be monitored periodically. The characteristic clinical features are considered to be a homeostatic attempt to repair the skin barrier, but heterogeneous clinical presentation and imperfect phenotype–genotype correlation hinder diagnosis. An accurate molecular diagnosis is, however, crucial for predicting prognosis and providing appropriate genetic counselling. Most ichthyoses severely affect patient quality of life and, in severe forms, may cause considerable disability and even death. So far, treatment provides only symptomatic relief. It is lifelong, expensive, time-consuming, and often provides disappointing results. A better understanding of the molecular mechanisms that underlie these conditions is essential for designing pathogenesis-driven and patient-tailored innovative therapeutic solutions. [ES]Las ictiosis son un grupo heterogéneo de desórdenes de la cornificación. Pueden ser hereditarios o adquiridos y resultan en una diferenciación defectuosa de los queratinocitos y una formación anormal de la barrera epidérmica. Esta disfunción de la barrera cutánea incrementa la perdida de agua transepidérmica y la inflamación. La cornificación desorganizada se caracteriza clínicamente por piel escamosa con diferentes grados de hiperqueratosis (engrosamiento cutáneo), descamación y eritema (rojez) Independientemente del tipo de ictiosis, muchos pacientes presentan prurito (picor), infecciones recurrentes, hipohidrosis (defectos en la sudoración) con intolerancia al calor y diversas complicaciones oculares, auditivas y nutricionales que deben ser controladas periódicamente. Se considera que las características clínicas comunes a estas enfermedades son un intento homeostático de reparar la barrera cutánea, pero la heterogeneidad en la presentación clínica y la baja correlación fenotipo-genotipo dificulta el diagnóstico. Un diagnóstico molecular es por ello, crucial para predecir el pronóstico y realizar un consejo genético apropiado. La mayoría de las ictiosis afectan gravemente a la calidad de vida del paciente y las formas más graves pueden causar discapacidad o incluso muerte. Hasta ahora, el tratamiento sólo proporciona alivio sintomático y es crónico, caro, laborioso y no proporciona resultados en todos los pacientes. Un mejor conocimiento de los mecanismos moleculares que subyacen a estas enfermedades es esencial para diseñar estrategias terapéuticas innovadoras

Corneodesmosomal Cadherins Are Preferential Targets of Stratum Corneum Trypsin- and Chymotrypsin-like Hyperactivity in Netherton Syndrome

SPINK5 (serine protease inhibitor Kazal-type 5), encoding the protease inhibitor LEKTI (lympho-epithelial Kazal-type related inhibitor), is the defective gene in Netherton syndrome (NS), a severe inherited keratinizing disorder. We have recently demonstrated epidermal protease hyperactivity in Spink5−/− mice resulting in desmosomal protein degradation. Herein, we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS. We demonstrated that, in a majority of patients, desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) were dramatically reduced in the upper most living layers of the epidermis. These defects were associated with premature degradation of corneodesmosomes. Stratum corneum tryptic enzyme (SCTE)-like and stratum corneum chymotryptic enzyme (SCCE)-like activities were increased, suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins. SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced. In contrast, a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations. This suggests a degree of correlation between cadherin degradation and clinical severity. This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression

Prevalence of inherited ichthyosis in France: a study using capture-recapture method

International audienceBACKGROUND:Inherited ichthyoses represent a group of rare skin disorders characterized by scaling, hyperkeratosis and inconstant erythema, involving most of the tegument. Epidemiology remains poorly described. This study aims to evaluate the prevalence of inherited ichthyosis (excluding very mild forms) and its different clinical forms in France.METHODS:Capture - recapture method was used for this study. According to statistical requirements, 3 different lists (reference/competence centres, French association of patients with ichthyosis and internet network) were used to record such patients. The study was conducted in 5 areas during a closed period.RESULTS:The prevalence was estimated at 13.3 per million people (/M) (CI95%, [10.9 - 17.6]). With regard to autosomal recessive congenital ichthyosis, the prevalence was estimated at 7/M (CI 95% [5.7 - 9.2]), with a prevalence of lamellar ichthyosis and congenital ichthyosiform erythroderma of 4.5/M (CI 95% [3.7 - 5.9]) and 1.9/M (CI 95% [1.6 - 2.6]), respectively. Prevalence of keratinopathic forms was estimated at 1.1/M (CI 95% [0.9 - 1.5]). Prevalence of syndromic forms (all clinical forms together) was estimated at 1.9/M (CI 95% [1.6 - 2.6]).CONCLUSIONS:Our results constitute a crucial basis to properly size the necessary health measures that are required to improve patient care and design further clinical studies

Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis

Twenty-six families with keratinopathic ichthyoses (epidermolytic ichthyosis, superficial epidermolytic ichthyosis or congenital reticular ichthyosiform erythroderma) were studied. Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. In this study mutations were found in KRT1, KRT2 and KRT10, including 7 mutations that are novel pathogenic variants. Novel clinical features found in patients with congenital reticular ichthyosiform erythroderma are described, such as mental retardation, spasticity, facial dysmorphisms, symblepharon and malposition of the 4th toe

LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome

SPINK5, encoding the putative multi-domain serine protease inhibitor LEKTI, was recently identified as the defective gene in the severe autosomal recessive ichthyosiform skin condition, Netherton syndrome (NS). Using monoclonal and polyclonal antibodies, we show that LEKTI is a marker of epithelial differentiation, strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. LEKTI expression was also demonstrated in normal differentiated human primary keratinocytes (HK) through detection of a 145 kDa full-length protein and a shorter isoform of 125 kDa. Both proteins are N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least three C-terminal fragments of 42, 65 and 68 kDa, also identified in conditioned media. Processing of the 145 and 125 kDa precursors was prevented in HK by treatment with a furin inhibitor. In addition, in vitro cleavage of the recombinant 145 kDa precursor by furin generated C-terminal fragments of 65 and 68 kDa, further supporting the involvement of furin in LEKTI processing. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from NS patients. Defective expression of LEKTI in skin sections was a constant feature in NS patients, whilst an extended reactivity pattern was observed in samples from other keratinizing disorders, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of NS. The identification of novel processed forms of LEKTI provides the basis for future functional and structural studies of fragments with physiological relevanc

Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations

Chéilite granulomateuse essentielle (traitement par injection intralésionnelle de crotidoïdes retard)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Alternariose cutanée humaine (étude de quatre cas chez des patients transplantés)

L'alternariose cutanée humaine est une mycose opportuniste due à des champignons filamenteux du genre Alternaria. L alternariose demeure rare mais le nombre de cas rapportés est en constante augmentation. Les patients atteints sont le plus souvent immunodéprimés et généralement transplantés. L Alternaria est essentiellement responsable de lésions cutanées dermiques se localisant préférentiellement en zones découvertes. Les lésions cutanées sont uniques ou multiples. L aspect le plus commun est celui de nodules ou de plaques de couleur rouge violacée. Notre étude portant sur quatre cas d alternariose chez des patients transplantés ainsi qu une revue de la littérature nous a permis d établir les facteurs favorisant le développement de la maladie, les critères diagnostiques, ainsi que les différentes stratégies thérapeutiques.TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rôle des phospholipases A2 et des lysophospholipides (acide lysophosphatidique) dans la physiologie du kératinocyte humain

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF