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1.
Int J Oncol ; 55(4): 925-937, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432155

RESUMO

In colorectal cancer (CRC) with microsatellite instability (MSI), >90% of cases are affected by inactivating frameshift mutations of transforming growth factor ß receptor type 2 (TGFBR2). TGFBR2 deficiency is considered to drive MSI tumor progression by abrogating downstream TGF­ß signaling. This pathway can alter the expression of coding and non­coding RNAs, including microRNAs (miRNAs), which are also present in extracellular vesicles (EVs) as post­transcriptional modulators of gene expression. In our previous study, it was shown that TGFBR2 deficiency alters the protein composition and function of EVs in MSI tumors. To investigate whether mutant TGFBR2 may also affect the miRNA cargo of EVs, the present study characterized miRNAs in EVs and their parental MSI tumor cells that differed only in TGFBR2 expression status. The HCT116­TGFBR2 MSI cell line model enables the doxycycline (dox)­inducible reconstituted expression of TGFBR2 in an isogenic background (­dox, TGFBR2 deficient; +dox, TGFBR2 proficient). Small RNA sequencing of cellular and EV miRNAs showed that the majority of the miRNAs (263/471; 56%) were shared between MSI tumor cells and their EVs. Exploratory data analysis revealed the TGBFR2­dependent cluster separation of miRNA profiles in EVs and MSI tumor cells. This segregation appeared to result from two subsets of miRNAs, the expression of which were regulated in a TGFBR2­dependent manner (EVs: n=10; MSI cells: n=15). In the EV subset, 7/10 miRNAs were downregulated and 3/10 were upregulated by TGFBR2 deficiency. In the cellular subset, 13/15 miRNAs were downregulated and 2/15 miRNAs were upregulated in the TGFBR2­deficient cells. The present study emphasizes the general overlap of miRNA profiles in MSI tumor cells and their EVs, but also highlights the impact of a single tumor driver mutation on the expression of individual miRNAs, as exemplified by the downregulation of miR­381­3p in TGFBR2­deficient MSI tumor cells and their secreted EVs.

2.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454892

RESUMO

Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs function as couriers of proteins, nucleic acids, and lipids in intercellular communication. At a qualitative level, we have previously shown that TGFBR2 deficiency causes overall alterations in the EV protein content. To deepen the basic understanding of altered protein dynamics, this work aimed to determine TGFBR2-dependent EV protein signatures in a quantitative manner. Using a stable isotope labeling with amino acids in cell culture (SILAC) approach for mass spectrometry-based quantification, 48 TGFBR2-regulated proteins were identified in MSI CRC-derived EVs. Overall, TGFBR2 deficiency caused upregulation of several EV proteins related to the extracellular matrix and nucleosome as well as downregulation of proteasome-associated proteins. The present study emphasizes the general overlap of proteins between EVs and their parental CRC cells but also highlights the impact of TGFBR2 deficiency on EV protein composition. From a clinical perspective, TGFBR2-regulated quantitative differences of protein expression in EVs might nominate novel biomarkers for liquid biopsy-based MSI typing in the future.

3.
Gastroenterology ; 157(5): 1352-1367.e13, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362006

RESUMO

BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

4.
Genes (Basel) ; 10(7)2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288483

RESUMO

Kyphoscoliotic Ehlers-Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either PLOD1 or FKBP14. PLOD1 encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating lysyl residues in the collagen helix, which undergo glycosylation and form crosslinks in the extracellular matrix thus contributing to collagen fibril strength. FKBP14 encodes a peptidyl-prolyl cis-trans isomerase that catalyzes collagen folding and acts as a chaperone for types III, VI, and X collagen. Despite genetic heterogeneity, affected patients with mutations in either PLOD1 or FKBP14 are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying PLOD1-kEDS and FKBP14-kEDS, and to identify novel molecular targets that may expand treatment strategies. Transcriptome profiling by RNA sequencing of patient-derived skin fibroblasts revealed differential expression of genes encoding extracellular matrix components that are unique between PLOD1-kEDS and FKBP14-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls. Overall, our study presents the first transcriptomics data in kEDS revealing distinct molecular features between PLOD1-kEDS and FKBP14-kEDS, and serves as a tool to better understand the disease.

5.
Hum Mutat ; 40(12): 2318-2333, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347739

RESUMO

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations.

7.
J Hum Genet ; 64(7): 609-616, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31015584

RESUMO

Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.


Assuntos
Transtornos do Crescimento/diagnóstico , Proteínas de Neoplasias/genética , Doenças do Nervo Óptico/diagnóstico , Anomalia de Pelger-Huët/diagnóstico , Agamaglobulinemia/sangue , Agamaglobulinemia/fisiopatologia , Cútis Laxa/diagnóstico , Cútis Laxa/genética , Cútis Laxa/patologia , Diagnóstico Diferencial , Tecido Elástico/ultraestrutura , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Humanos , Lactente , Fígado/enzimologia , Fígado/patologia , Masculino , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Anomalia de Pelger-Huët/genética , Anomalia de Pelger-Huët/patologia , Progéria/diagnóstico , Progéria/genética , Pele/patologia , Síndrome , Sequenciamento Completo do Exoma , Adulto Jovem
8.
Mol Ther ; 27(5): 986-998, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30930113

RESUMO

Gene editing constitutes a novel approach for precisely correcting disease-causing gene mutations. Frameshift mutations in COL7A1 causing recessive dystrophic epidermolysis bullosa are amenable to open reading frame restoration by non-homologous end joining repair-based approaches. Efficient targeted deletion of faulty COL7A1 exons in polyclonal patient keratinocytes would enable the translation of this therapeutic strategy to the clinic. In this study, using a dual single-guide RNA (sgRNA)-guided Cas9 nuclease delivered as a ribonucleoprotein complex through electroporation, we have achieved very efficient targeted deletion of COL7A1 exon 80 in recessive dystrophic epidermolysis bullosa (RDEB) patient keratinocytes carrying a highly prevalent frameshift mutation. This ex vivo non-viral approach rendered a large proportion of corrected cells producing a functional collagen VII variant. The effective targeting of the epidermal stem cell population enabled long-term regeneration of a properly adhesive skin upon grafting onto immunodeficient mice. A safety assessment by next-generation sequencing (NGS) analysis of potential off-target sites did not reveal any unintended nuclease activity. Our strategy could potentially be extended to a large number of COL7A1 mutation-bearing exons within the long collagenous domain of this gene, opening the way to precision medicine for RDEB.

9.
Matrix Biol ; 74: 62-76, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30466509

RESUMO

Integrin α3ß1, a major epidermal adhesion receptor is critical for organization of the basement membrane during development and wound healing. Integrin α3 deficiency leads to interstitial lung disease, nephrotic syndrome and epidermolysis bullosa (ILNEB), an autosomal recessive multiorgan disease characterized by basement membrane abnormalities in skin, lung and kidney. The pathogenetic chains from ITGA3 mutation to tissue abnormalities are still unclear. Although integrin α3 was reported to regulate multiple extracellular proteins, the composition of the extracellular compartment of integrin α3-negative keratinocytes has not been resolved so far. In a comprehensive approach, quantitative proteomics of deposited extracellular matrix, conditioned cultured media as well as of the intracellular compartment of keratinocytes isolated from an ILNEB patient and from normal skin were performed. By mass spectrometry-based proteomics, 167 proteins corresponding to the GO terms "extracellular" and "cell adhesion", or included in the "human matrisome" were identified in the deposited extracellular matrix, and 217 in the conditioned media of normal human keratinocytes. In the absence of integrin α3, 33% and 26% respectively were dysregulated. Dysregulated proteins were functionally related to integrin α3 or were known interaction partners. The results show that in the absence of integrin α3 ILNEB keratinocytes produce a fibronectin-rich microenvironment and make use of fibronectin-binding integrin subunits αv and α5. The most important results were validated in monolayer and organotypic coculture models. Finally, the in vivo relevance of the most dysregulated components was demonstrated by immunostainings of skin, kidney and lung samples of three ILNEB patients.

10.
Hum Mutat ; 39(10): 1305-1313, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30011118

RESUMO

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing.

11.
Mol Ther Nucleic Acids ; 11: 68-78, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29858091

RESUMO

Recessive dystrophic epidermolysis bullosa is a severe skin fragility disease caused by loss of functional type VII collagen at the dermal-epidermal junction. A frameshift mutation in exon 80 of COL7A1 gene, c.6527insC, is highly prevalent in the Spanish patient population. We have implemented gene-editing strategies for COL7A1 frame restoration by NHEJ-induced indels in epidermal stem cells from patients carrying this mutation. TALEN nucleases designed to cut within the COL7A1 exon 80 sequence were delivered to primary patient keratinocyte cultures by non-integrating viral vectors. After genotyping a large collection of vector-transduced patient keratinocyte clones with high proliferative potential, we identified a significant percentage of clones with COL7A1 reading frame recovery and Collagen VII protein expression. Skin equivalents generated with cells from a clone lacking exon 80 entirely were able to regenerate phenotypically normal human skin upon their grafting onto immunodeficient mice. These patient-derived human skin grafts showed Collagen VII deposition at the basement membrane zone, formation of anchoring fibrils, and structural integrity when analyzed 12 weeks after grafting. Our data provide a proof-of-principle for recessive dystrophic epidermolysis bullosa treatment through ex vivo gene editing based on removal of pathogenic mutation-containing, functionally expendable COL7A1 exons in patient epidermal stem cells.

12.
Dermatol Ther (Heidelb) ; 8(2): 313-321, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29777447

RESUMO

The association of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) and aplasia cutis congenita (ACC) was described by El Shafie et al. (J Pediatr Surg 14(4):446-449, 1979) and Carmi et al. (Am J Med Genet 11:319-328, 1982). Most patients die in the first weeks of life, and no curative treatment options are available so far. We describe a patient with JEB-PA and ACC (OMIM # 226730) who was treated for extensive areas of ACC by Integra®-Dermal Regeneration Template and split-thickness skin grafting (STSG). Clinically, the dermal template changed into well-vascularized neodermis, and after STSG, full take of the transplants was detected. No infections of the huge ACC areas were seen. Further studies must validate this treatment option in severe and acute cases of JEB-PA with ACC. Based on clinical findings, we postulate that placement of Integra®-Dermal Regeneration Template with STSG could be a new treatment option for patients having JEB-PA with ACC to prevent severe infection, compartment-syndrome-like conditions, and deformities. Based on literature findings, we assume that Integra®-Dermal Regeneration Template with STSG could even be able to prevent new blistering and thereby be a treatment option in cases of ACC and JEB.

14.
Neurology ; 90(16): e1372-e1378, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29549224

RESUMO

OBJECTIVE: To explore the recurrence of cervical artery dissection (CeAD). METHODS: A single-center consecutive series of 282 CeAD patients was prospectively recruited during first admission from 1995 to 2012. Patients with a follow-up of at least 1 year (n = 238) were eligible for the current analysis. All patients with clinical symptoms or signs of recurrent CeAD on ultrasound were examined by MRI. Dermal connective tissue morphology was studied in 108 (45.4%) patients. RESULTS: Median follow-up was 52 months (range 12-204 months). In all, 221 (92.8%) patients presented with monophasic CeAD, including 188 (79.0%) patients with a single CeAD event, 11 (4.6%) with simultaneous dissections in multiple cervical arteries, and 22 (9.2%) with subsequent events within a single phase of 4 weeks. Seventeen patients (7.1%) had late (>1 month after the initial event) recurrent CeAD events, including 5 (2.1%) with multiple recurrences. Patients with late recurrences were younger (37.5 ± 6.9 years) than those without (43.8 ± 9.9; p = 0.011). Ischemic stroke occurred in 164 (68.9%) patients at first diagnosis, but only 4 of 46 (8.7%) subsequent events caused stroke (p < 0.0001), while 19 (41.3%) were asymptomatic. Connective tissue abnormalities were found in 54 (56.3%) patients with monophasic and 8 (66.7%) with late recurrent dissections (p = 0.494). CONCLUSION: Twenty-two (9.2%) patients had new CeAD events within 1 month and 17 (7.1%) later recurrences. The risk for new events was significantly higher (about 60-fold) during the acute phase than during later follow-up. Connective tissue abnormalities were not more frequent in patients with late recurrent events than in those with monophasic CeAD.

15.
PLoS Genet ; 14(3): e1007242, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29561836

RESUMO

Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-ß in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.


Assuntos
Doenças Ósseas/congênito , Nanismo/metabolismo , Osteoblastos/patologia , Proteoglicanas/metabolismo , Dermatopatias Genéticas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Diferenciação Celular , Decorina/metabolismo , Dermatan Sulfato/metabolismo , Modelos Animais de Doenças , Nanismo/patologia , Feminino , Fraturas Ósseas/genética , Glicosilação , Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/metabolismo , Transdução de Sinais , Dermatopatias Genéticas/patologia , Proteínas de Transporte Vesicular/genética
16.
Mol Genet Genomic Med ; 6(3): 441-445, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29441698

RESUMO

BACKGROUND AND PURPOSE: A recurrent duplication of chromosome 16p13.1 was associated with aortic dissection as well as with cervical artery dissection. We explore the segregation of this duplication in a family with familial aortic disease. METHODS: Whole exome sequencing (WES) analysis was performed in a patient with a family history of aortic diseases and ischemic stroke due to an aortic dissection extending into both carotid arteries. RESULTS: The index patient, his affected father, and an affected sister of his father carried a large duplication of region 16p13.1, which was also verified by quantitative PCR. The duplication was also found in clinically asymptomatic sister of the index patient. WES did not detect pathogenic variants in a predefined panel of 11 genes associated with aortic disease, but identified rare deleterious variants in 14 genes that cosegregated with the aortic phenotype. CONCLUSIONS: The cosegregation of duplication 16p13.1 with the aortic phenotype in this family suggested a causal relationship between the duplication and aortic disease. Variants in known candidate genes were excluded as disease-causing in this family, but cosegregating variants in other genes might modify the contribution of duplication 16p13.1 on aortic disease.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Adulto , Idoso , Aorta/fisiologia , Doenças da Aorta/genética , Doenças da Aorta/fisiopatologia , Estruturas Cromossômicas/genética , Cromossomos Humanos Par 16/genética , Bases de Dados Genéticas , Exoma , Família , Feminino , Duplicação Gênica/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
20.
J Dtsch Dermatol Ges ; 15(10): 1053-1065, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28976107

RESUMO

Ichthyoses are a group of rare genetic skin disorders that pose numerous clinical challenges, in particular with respect to the correct diagnosis and appropriate management. The present update of the German ichthyosis guidelines addresses recent diagnostic advances that have resulted in the Sorèze consensus classification. In this context, we provide an updated diagnostic algorithm, taking into account clinical features as well as the molecular genetic basis of these disorders. Moreover, we highlight current therapeutic approaches such as psychosocial support, balneotherapy, mechanical scale removal, topical therapy, and systemic retinoid therapy. General aspects such as the indication for physical therapy, ergotherapy, or genetic counseling are also discussed. The present update was consented by an interdisciplinary consensus conference that included dermatologists, pediatricians, human geneticists, and natural scientists as well as representatives of the German patient support organization Selbsthilfe Ichthyose e. V.


Assuntos
Fidelidade a Diretrizes , Ictiose/diagnóstico , Ictiose/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença/genética , Alemanha , Humanos , Ictiose/classificação , Ictiose/genética , Lactente , Recém-Nascido , Masculino , Gravidez , Prognóstico , Adulto Jovem
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