RESUMO
BACKGROUND: Autosomal-recessive congenital ichthyosis (ARCI) is a heterogeneous group of ichthyoses presenting at birth. Self-improving congenital ichthyosis (SICI) is a subtype of ARCI and is diagnosed when skin condition improves remarkably (within years) after birth. So far, there are sparse data on SICI and quality of life (QoL) in this ARCI subtype. This study aims to further delineate the clinical spectrum of SICI as a rather unique subtype of ARCI. OBJECTIVES: This prospective study included 78 patients (median age: 15 years) with ARCI who were subdivided in SICI (n = 18) and non-SICI patients (nSICI, n = 60) by their ARCI phenotype. METHODS: Quality of life (QoL) was assessed using the (Children's) Dermatology Life Quality Index. Statistical analysis was performed with chi-squared and t-Tests. RESULTS: The genetically confirmed SICI patients presented causative mutations in the following genes: ALOXE3 (8/16; 50.0%), ALOX12B (6/16; 37.5%), PNPLA1 (1/16; 6.3%) and CYP4F22 (1/16; 6.3%). Hypo-/anhidrosis and insufficient vitamin D levels (<30 ng/mL) were often seen in SICI patients. Brachydactyly (a shortening of the 4th and 5th fingers) was statistically more frequent in SICI (P = 0.023) than in nSICI patients. A kink of the ear's helix was seen in half of the SICI patients and tends to occur more frequently in patients with ALOX12B mutations (P = 0.005). QoL was less impaired in patients under the age of 16, regardless of ARCI type. CONCLUSIONS: SICI is an underestimated, milder clinical variant of ARCI including distinct features such as brachydactyly and kinking of the ears. Clinical experts should be aware of these features when seeing neonates with a collodion membrane. SICI patients should be regularly checked for clinical parameters such as hypo-/anhidrosis or vitamin D levels and monitored for changes in quality of life.
Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Aciltransferases , Genes Recessivos , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Ictiose/diagnóstico , Ictiose/genética , Ictiose Lamelar/genética , Lipase/genética , Mutação , Estudos Prospectivos , Qualidade de VidaRESUMO
BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause nonsyndromic forms of ARCI. To date, only 10 distinct pathogenic mutations in PNPLA1 have been reported. OBJECTIVES: To identify new causative PNPLA1 mutations. METHODS: We screened genetically unresolved cases, including our ARCI collection, comprising more than 700 families. Screening for mutations was performed either by direct Sanger sequencing or in combination with a multigene panel, followed by sequence and mutation analysis. RESULTS: Here we report on 16 novel mutations present in patients from 17 families. While all previously reported mutations and most of our novel mutations are located within the core patatin domain, we report five novel PNPLA1 mutations that are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than the core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. CONCLUSIONS: We estimate the frequency of PNPLA1 mutations among patients with ARCI to be around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotypic variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs.
Assuntos
Ictiose Lamelar/genética , Lipase/genética , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genes Recessivos/genética , Humanos , Ictiose Lamelar/diagnóstico , Lactente , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Linhagem , Fenômenos Fisiológicos da Pele/genética , Adulto JovemRESUMO
BACKGROUND: Several autosomal dominant disorders may manifest in mosaic patterns with cutaneous involvement. Genomic mosaicism results from postzygotic autosomal mutations, giving rise to clonal proliferation of two genetically distinct cell groups, which clinically present as lesions following the lines of Blaschko. OBJECTIVE: To increase the awareness of the clinical variability of mosaic manifestations in autosomal dominant skin disorders in order to avoid delayed diagnosis. METHODS: Clinicopathologic correlation in a case series including three patients with mosaic manifestations of different autosomal dominant skin diseases. RESULTS: Here, we describe a patient with type 1 segmental mosaicism of epidermolytic ichthyosis (case 1) and two patients with either type 1 (case 2) or type 2 (case 3) segmental neurofibromatosis 1 (NF1). CONCLUSION: Dermatologists should be familiar with mosaic manifestations of autosomal dominant skin diseases to ensure appropriate guidance of the affected patient. Genetic counselling is mandatory as even limited forms of mosaicism may involve the patient's germline with a moderately increased risk to transmit the mutation to their offspring, resulting in a more severe, generalized form of the respective disease.
Assuntos
Genes Dominantes , Mosaicismo , Dermatopatias/patologia , Adolescente , Criança , Feminino , Humanos , Masculino , Dermatopatias/genéticaRESUMO
Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.
Assuntos
Códon sem Sentido/genética , Dermatite/genética , Desmogleína 1/genética , Hipersensibilidade/genética , Ceratodermia Palmar e Plantar/genética , Adolescente , Feminino , Homozigoto , Humanos , Síndrome de Emaciação/genéticaRESUMO
BACKGROUND: Autosomal recessive congenital ichthyoses (ARCIs) are keratinization disorders caused by impaired skin barrier function. Mutations in the genes encoding the lipoxygenases 12R-LOX and eLOX-3 are the second most common cause of ARCIs. In recent years, human skin equivalents recapitulating the ARCI phenotype have been established. OBJECTIVES: To develop a murine organotypic tissue culture model for ARCI. METHODS: Epidermal keratinocytes were isolated from newborn 12R-LOX-deficient mice and cocultivated with mouse dermal fibroblasts embedded in a scaffold of native collagen type I. RESULTS: With this experimental set-up the keratinocytes formed a well-organized multilayered stratified epithelium resembling skin architecture in vivo. All epidermal layers were present and the keratinocytes within showed the characteristic morphological features. Markers for differentiation and maturation indicated regular epidermal morphogenesis. The major components of epidermal structures were expressed, and were obviously processed and assembled properly. In contrast to their wild-type counterparts, 12R-LOX-deficient skin equivalents showed abnormal vesicular structures in the upper epidermal layers correlating with altered lipid composition and increased transepidermal water loss, comparable with 12R-LOX-deficient mice. CONCLUSIONS: The mouse skin equivalents faithfully recapitulate the 12R-LOX-deficient phenotype observed in vivo, classifying them as appropriate in vitro models to study molecular mechanisms involved in the development of ARCI and to evaluate novel therapeutic agents. In contrast to existing human three-dimensional skin models, the generation of these murine models is not constrained by a limited supply of material and does not depend on in vitro expansion and/or genetic manipulations that could result in inadvertent genotypic and phenotypic alterations.
Assuntos
Modelos Animais de Doenças , Ictiose Lamelar/genética , Animais , Araquidonato 12-Lipoxigenase/deficiência , Técnicas de Cultura de Células/métodos , Epiderme/fisiologia , Queratinócitos/fisiologia , Lipídeos/fisiologia , Camundongos , Engenharia TecidualRESUMO
BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.
Assuntos
Epidermólise Bolhosa/genética , Integrina alfa6beta4/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , DNA/análise , Epidermólise Bolhosa/patologia , Evolução Fatal , Feminino , Imunofluorescência , Genótipo , Humanos , Lactente , Integrina beta4/genética , Masculino , Microscopia Eletrônica , Fenótipo , Pele/ultraestruturaAssuntos
Ictiose Lamelar/genética , Queratinas/metabolismo , Fenótipo , Criança , Humanos , Ictiose Lamelar/fisiopatologia , Masculino , TemperaturaRESUMO
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.
Assuntos
Epiderme/fisiopatologia , Ictiose Vulgar/genética , Proteínas de Filamentos Intermediários/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Epiderme/ultraestrutura , Feminino , Proteínas Filagrinas , Humanos , Ictiose Vulgar/fisiopatologia , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Permeabilidade , Adulto JovemRESUMO
A 21-year-old man presented with generalized erythema, erosions and hyperkeratoses since birth. Histology revealed epidermolytic hyperkeratosis with degeneration of the upper epidermis and perinuclear deposits of abnormal keratin aggregations. Epidermolytic ichthyosis was diagnosed. This congenital Ichthyosis occurs due to mutations of keratin 1 or 10 genes that leads to defects of intra- and intercellular structural integrity in the spinous and granular layers with compensatory hyperkeratosis. After childhood, life expectancy is normal but lifelong therapeutic and skin care measures are required.
Assuntos
Hiperceratose Epidermolítica/diagnóstico , Hiperceratose Epidermolítica/terapia , Diagnóstico Diferencial , Humanos , Hiperceratose Epidermolítica/genética , Masculino , Adulto JovemRESUMO
BACKGROUND: Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes. In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants. OBJECTIVES: To identify the underlying mutations in patients with EI and to correlate genotype and phenotype. METHODS: Mutation analysis was performed in 28 patients with EI by direct sequencing of KRT1 and KRT10 genes. RESULTS: We identified 14 different mutations, of which four have not been published previously. CONCLUSIONS: Identification of novel mutations and genotype-phenotype correlations in EI allows improved understanding of disease pathogenesis as well as better patient management.
Assuntos
Bases de Dados Genéticas , Hiperceratose Epidermolítica/genética , Queratinas/genética , Mutação/genética , Genótipo , Humanos , Hiperceratose Epidermolítica/patologia , Fenótipo , Análise de Sequência de DNAAssuntos
Hipopigmentação/genética , Ceratodermia Palmar e Plantar/genética , Mutação de Sentido Incorreto/genética , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Somatomedinas/genética , Adolescente , Adulto , Calcinose/genética , Feminino , Antebraço , Heterozigoto , Humanos , Masculino , LinhagemRESUMO
We want to report and discuss the indication for open surgery for an asymptomatic penetrating aortic ulcer (PAU) in the era of thoracic endovascular aortic repair (TEVAR). A 31-year-old female presented with the diagnosis of an aneurysm in the distal aortic arch. With respect to the patients young age, the controversial status of connective tissue disorders and in the absence of concomitant disease, open repair was indicated. There was no proof of a mycotic plaque or connective tissue disease in the microbiological-, pathological analysis and at electron-microscopy. The patient was discharged on the thirteenth postoperative day. In spite of good preliminary results of TEVAR in PAU, in selective cases there is still an indication for open surgery.
Assuntos
Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular , Úlcera/cirurgia , Adulto , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/diagnóstico , Aortografia/métodos , Biópsia , Feminino , Humanos , Microscopia Eletrônica de Transmissão , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Úlcera/diagnósticoRESUMO
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.
Assuntos
Antígenos CD1/genética , Dermatite Atópica/genética , Epiderme/ultraestrutura , Ictiose Vulgar/genética , Proteínas de Filamentos Intermediários/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/imunologia , Epiderme/imunologia , Feminino , Proteínas Filagrinas , Predisposição Genética para Doença , Genótipo , Humanos , Ictiose Vulgar/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Adulto JovemAssuntos
Aberrações Cromossômicas , Genes Dominantes/genética , Leucoceratose da Mucosa Hereditária/genética , Doenças Raras , Biópsia , Deleção Cromossômica , Diagnóstico Diferencial , Éxons/genética , Triagem de Portadores Genéticos , Humanos , Lactente , Queratina-4/genética , Leucoceratose da Mucosa Hereditária/diagnóstico , Leucoceratose da Mucosa Hereditária/patologia , Masculino , Mucosa Bucal/patologiaRESUMO
Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.