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1.
Medicine (Baltimore) ; 98(16): e15263, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31008968

RESUMO

RATIONALE: Follicular occlusion triad (FOT) is an autosomal recessive inherited disease and no more than 3 variants of the triad have been reported. We give a report in which scrotal elephantiasis is a variant of FOT and further perform a literature review. PATIENT CONCERNS: A 41-year-old man came to us because of a large scrotal cyst and generalized skin lesions that had occurred over the past 10 years. The generalized skin lesions consisted of hidradenitis suppurativa on the perineum and back, acne conglobata in the armpit, and dissecting cellulitis of the scalp. He took antibiotics for a long time but achieved poor effect. Furthermore, he told his father and elder brother also manifested such skin lesions. DIAGNOSES: Magnetic resonance showed a mass in the left scrotum with clear boundaries. A routine blood test showed a high leukocyte level of 12 × 10/L and a hemoglobin content of 78 g/L. C-reactive-protein increased. Series of autoimmune antibody tests were negative. The postoperative pathologic findings showed that the mass was an epidermoid cyst, and hematoxylin and eosin staining showed hyperkeratosis of the skin as well as inflammatory and edematous changes. A diagnosis of a variant of FOT was made. INTERVENTIONS: We removed skin abscesses and lesioned the inner part with hydrogen peroxide. Then we performed an excision of the scrotal lesion. OUTCOME: The patient recovered well and had no evidence of recurrence at a 16-month follow-up. LESSONS: We reported a case in which scrotal elephantiasis was a variant of FOT and surgical intervention played an important role in secondary urologic diseases.


Assuntos
Acne Conglobata/complicações , Celulite (Flegmão)/complicações , Elefantíase/etiologia , Hidradenite Supurativa/complicações , Dermatoses do Couro Cabeludo/complicações , Escroto , Dermatopatias Genéticas/complicações , Acne Conglobata/genética , Adulto , Celulite (Flegmão)/genética , Elefantíase/genética , Elefantíase/patologia , Elefantíase/cirurgia , Hidradenite Supurativa/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Dermatoses do Couro Cabeludo/genética , Escroto/diagnóstico por imagem , Escroto/patologia , Escroto/cirurgia , Dermatopatias Genéticas/genética
3.
Dermatol Clin ; 37(2): 229-239, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850045

RESUMO

The discoveries of new genes underlying genetic skin diseases have occurred at a rapid pace, supported by advances in DNA sequencing technologies. These discoveries have translated to an improved understanding of disease mechanisms at a molecular level and identified new therapeutic options based on molecular targets. This article highlights just a few of these recent discoveries for a diverse group of skin diseases, including tuberous sclerosis complex, ichthyoses, overgrowth syndromes, interferonopathies, and basal cell nevus syndrome, and how this has translated into novel targeted therapies and improved patient care.


Assuntos
Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/terapia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/terapia , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/terapia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Dermabrasão , Fármacos Dermatológicos/uso terapêutico , Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/genética , Eritrodermia Ictiosiforme Congênita/terapia , Inibidores de Janus Quinases/uso terapêutico , Terapia a Laser , Lipoma/diagnóstico , Lipoma/genética , Lipoma/terapia , Técnicas de Diagnóstico Molecular , Mosaicismo , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/terapia , Nevo/diagnóstico , Nevo/genética , Nevo/terapia , Pitiríase Rubra Pilar/diagnóstico , Pitiríase Rubra Pilar/genética , Pitiríase Rubra Pilar/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome de Proteu/diagnóstico , Síndrome de Proteu/genética , Síndrome de Proteu/terapia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Análise de Sequência de DNA , Dermatopatias Genéticas/genética , Protetores Solares/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia , Ustekinumab/uso terapêutico
4.
Oxid Med Cell Longev ; 2019: 8156592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800210

RESUMO

Ascorbate requiring Fe2+/2-oxoglutarate-dependent dioxygenases located in the nucleoplasm have been shown to participate in epigenetic regulation of gene expression via histone and DNA demethylation. Transport of dehydroascorbic acid is impaired in the endomembranes of fibroblasts from arterial tortuosity syndrome (ATS) patients, due to the mutation in the gene coding for glucose transporter GLUT10. We hypothesized that altered nuclear ascorbate concentration might be present in ATS fibroblasts, affecting dioxygenase activity and DNA demethylation. Therefore, our aim was to characterize the subcellular distribution of vitamin C, the global and site-specific changes in 5-methylcytosine and 5-hydroxymethylcytosine levels, and the effect of ascorbate supplementation in control and ATS fibroblast cultures. Diminished nuclear accumulation of ascorbate was found in ATS fibroblasts upon ascorbate or dehydroascorbic acid addition. Analyzing DNA samples of cultured fibroblasts from controls and ATS patients, a lower global 5-hydroxymethylcytosine level was found in ATS fibroblasts, which could not be significantly modified by ascorbate addition. Investigation of the (hydroxy)methylation status of specific regions in six candidate genes related to ascorbate metabolism and function showed that ascorbate addition could stimulate hydroxymethylation and active DNA demethylation at the PPAR-γ gene region in control fibroblasts only. The altered DNA hydroxymethylation patterns in patient cells both at the global level and at specific gene regions accompanied with decreased nuclear accumulation of ascorbate suggests the epigenetic role of vitamin C in the pathomechanism of ATS. The present findings represent the first example for the role of vitamin C transport in epigenetic regulation suggesting that ATS is a compartmentalization disease.


Assuntos
Artérias/anormalidades , Ácido Ascórbico/metabolismo , Núcleo Celular/metabolismo , Metilação de DNA/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Genoma Humano , Instabilidade Articular/genética , Dermatopatias Genéticas/genética , Malformações Vasculares/genética , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Células Cultivadas , Epigênese Genética , Humanos , Modelos Biológicos , PPAR gama/genética , PPAR gama/metabolismo
5.
J Dermatol Sci ; 93(2): 75-81, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30692041

RESUMO

Dyschromatosis symmetrica hereditaria (DSH) and reticulate acropigmentation of Kitamura (RAK) are rare, inherited pigmentary diseases. DSH shows a mixture of pigmented and depigmented macules on the extremities. RAK shows reticulated, slightly depressed pigmented macules on the extremities. The causative gene of DSH was clarified as ADAR1 by positional cloning including linkage analysis and haplotype analysis in 2003. Ten years later, the causative gene of RAK was identified as ADAM10 by whole-exome sequencing, in 2013. ADAR1 is an RNA-editing enzyme which catalyzes the deamination of adenosine to inosine (A-to-I) in double-stranded RNA substrates during post-transcription processing. Inosine acts as guanine during translation, resulting in codon alterations or alternative splice sites that lead to functional changes in proteins when they occur in coding regions. In 2012, it was clarified that ADAR1 mutations cause Aicardi-Goutières syndrome 6, which is a severe genetic inflammatory disease that affects the brain and the skin. A zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), is involved in the ectodomain shedding of various membrane proteins and shows various functions in vivo. ADAM10 is known to be involved in the ectodomain shedding of Notch proteins as substrates in the skin. We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease similar to RAK) is associated with the Notch signaling pathway. In addition, ADAM10 mutations proved to be associated with late-onset Alzheimer disease. This review comprehensively discusses the updated pathophysiology of those genetic pigmentary disorders.


Assuntos
Proteína ADAM10/genética , Adenosina Desaminase/genética , Secretases da Proteína Precursora do Amiloide/genética , Hiperpigmentação/genética , Proteínas de Membrana/genética , Transtornos da Pigmentação/congênito , Proteínas de Ligação a RNA/genética , Receptores Notch/metabolismo , Dermatopatias Genéticas/genética , Dermatopatias Papuloescamosas/genética , Humanos , Hiperpigmentação/patologia , Mutação , Transtornos da Pigmentação/genética , Transtornos da Pigmentação/patologia , Doenças Raras/genética , Pele/patologia , Dermatopatias Genéticas/patologia , Dermatopatias Papuloescamosas/patologia , Pigmentação da Pele/genética
7.
Nat Commun ; 10(1): 127, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631079

RESUMO

COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.


Assuntos
Proteínas de Transporte/metabolismo , Complexo I de Proteína do Envoltório/metabolismo , Enzimas/metabolismo , Complexo de Golgi/metabolismo , Doenças Ósseas/congênito , Doenças Ósseas/genética , Doenças Ósseas/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Complexo I de Proteína do Envoltório/genética , Nanismo/genética , Nanismo/metabolismo , Glicosilação , Células HEK293 , Células HeLa , Humanos , Mutação , Ligação Proteica , Transporte Proteico , Interferência de RNA , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Int J Mol Sci ; 19(4)2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29587413

RESUMO

The αvß3 integrin, an endothelial cells' receptor-binding fibronectin (FN) in the extracellular matrix (ECM) of blood vessels, regulates ECM remodeling during migration, invasion, angiogenesis, wound healing and inflammation, and is also involved in the epithelial mesenchymal transition. In vitro-grown human control fibroblasts organize a fibrillar network of FN, which is preferentially bound on the entire cell surface to its canonical α5ß1 integrin receptor, whereas the αvß3 integrin is present only in rare patches in focal contacts. We report on the preferential recruitment of the αvß3 integrin, due to the lack of FN-ECM and its canonical integrin receptor, in dermal fibroblasts from Ehlers-Danlos syndromes (EDS) and arterial tortuosity syndrome (ATS), which are rare multisystem connective tissue disorders. We review our previous findings that unraveled different biological mechanisms elicited by the αvß3 integrin in fibroblasts derived from patients affected with classical (cEDS), vascular (vEDS), hypermobile EDS (hEDS), hypermobility spectrum disorders (HSD), and ATS. In cEDS and vEDS, respectively, due to defective type V and type III collagens, αvß3 rescues patients' fibroblasts from anoikis through a paxillin-p60Src-mediated cross-talk with the EGF receptor. In hEDS and HSD, without a defined molecular basis, the αvß3 integrin transduces to the ILK-Snail1-axis inducing a fibroblast-to-myofibroblast-transition. In ATS cells, the deficiency of the dehydroascorbic acid transporter GLUT10 leads to redox imbalance, ECM disarray together with the activation of a non-canonical αvß3 integrin-TGFBRII signaling, involving p125FAK/p60Src/p38MAPK. The characterization of these different biological functions triggered by αvß3 provides insights into the multifaced nature of this integrin, at least in cultured dermal fibroblasts, offering future perspectives for research in this field.


Assuntos
Artérias/anormalidades , Síndrome de Ehlers-Danlos/metabolismo , Integrina alfaVbeta3/metabolismo , Instabilidade Articular/metabolismo , Dermatopatias Genéticas/metabolismo , Malformações Vasculares/metabolismo , Artérias/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Humanos , Instabilidade Articular/genética , Transdução de Sinais , Dermatopatias Genéticas/genética , Malformações Vasculares/genética
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(1): 9-13, 2018 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-29419851

RESUMO

OBJECTIVE To identify potential mutations in two Chinese families affected with primary localized cutaneous amyloidosis. METHODS Peripheral blood samples of the family were collected with informed consent. Genomic DNA was extracted with a phenol chloroform method. All of the 17 exons and their flanking splicing sites of the OSMR gene were amplified with PCR and subjected to Sanger sequencing. Suspected mutations were verified with PCR - restriction fragment length polymorphism and high-resolution melting assays. RESULTS A missense mutation (c.1538G>A) was found in exon 10 of the OSMR gene in all of the six patients from family 1. A missense mutation (c.2081C>T) was found in exon 14 of the OSMR gene in all of the four patients from family 2. The same mutations were not found among the healthy controls. CONCLUSION Two missense mutations (c.1538G>A and c.2081C>T) were detected in the OSMR gene in two Chinese families affected with primary localized cutaneous amyloidosis. Our findings have further confirmed the pathogenicity of such mutations.


Assuntos
Amiloidose Familiar/genética , Análise Mutacional de DNA/métodos , Mutação de Sentido Incorreto , Subunidade beta de Receptor de Oncostatina M/genética , Dermatopatias Genéticas/genética , Sequência de Aminoácidos , Amiloidose Familiar/etnologia , Amiloidose Familiar/patologia , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Éxons/genética , Saúde da Família , Feminino , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Dermatopatias Genéticas/etnologia , Dermatopatias Genéticas/patologia
11.
Ultrastruct Pathol ; 42(2): 91-96, 2018 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29424602

RESUMO

Geroderma osteodysplasticum (GO) has clinical and histological features that overlap with other causes of wrinkly skin. Here we present the case of a child diagnosed with GO following exome sequencing of a panel of genes covering the wide differential diagnosis. The histological features of the overlapping conditions are presented, highlighting the utility of panel testing for conditions of this type. This is relevant to many genetic conditions and can influence ongoing management as exemplified by this case.


Assuntos
Doenças Ósseas/congênito , Nanismo/diagnóstico , Nanismo/genética , Nanismo/patologia , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Doenças Ósseas/diagnóstico , Doenças Ósseas/genética , Doenças Ósseas/patologia , Cútis Laxa/diagnóstico , Exoma , Feminino , Humanos , Lactente , Recém-Nascido , Mutação
12.
J Dermatol ; 45(4): 385-389, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29349851

RESUMO

Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies and metabolic wasting syndrome due to desmoglein 1 deficiency and the loss of intercellular adhesion or acantholysis. When keratinocytes differentiate from granular cells into cornified cells, desmosomes are transformed into corneodesmosomes and can provide stronger intercellular adhesion. Degradation of corneodesmosomes is a tightly regulated process involving a number of proteases and their inhibitors. Peripheral corneodesmosomes are protected from proteolytic degradation by the tight junction-related structures around them, and this construction provides the basis for the normal basket weave-like structure of the stratum corneum. In Netherton syndrome, which is caused by an absence of the protease inhibitor lymphoepithelial Kazal-type-related inhibitor, premature degradation of corneodesmosomes occurs due to the overactivation of proteases involved in corneodesmosome degradation. Inflammatory peeling skin disease is caused by the absence of corneodesmosin, a unique component of corneodesmosomes. In this disease, corneodesmosomes are structurally abnormal, and their adhesiveness is compromised, which leads to intercellular splitting between the stratum corneum and stratum granulosum. The better we understand desmosome and corneodesmosome ultrastructure in normal and diseased skin, the clearer the physiological and pathological mechanisms of epidermal integrity become.


Assuntos
Desmossomos/patologia , Epiderme/patologia , Queratinócitos/patologia , Dermatopatias Genéticas/patologia , Caderinas de Desmossomos/genética , Caderinas de Desmossomos/metabolismo , Desmossomos/ultraestrutura , Células Epidérmicas , Epiderme/ultraestrutura , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/ultraestrutura , Mutação , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Dermatopatias Genéticas/genética , Junções Íntimas/patologia , Junções Íntimas/ultraestrutura
13.
Ophthalmic Genet ; 39(1): 29-34, 2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28726533

RESUMO

INTRODUCTION: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disease hallmarked by tortuosity, stenosis, and aneurysm development of large- and medium-sized arteries. Mutations in SLC2A10, a gene that encodes the facilitative glucose transporter GLUT10, cause ATS. Several case reports have noted associated ophthalmic findings such as keratoconus, keratoglobus, and myopia without detailed descriptions or standardized examinations. We report the ophthalmic findings in a cohort of compound heterozygous ATS patients and heterozygous carriers of SLC2A10 mutations. METHODS: Five ATS patients and three carriers were identified through an ATS specialty clinic at the Arkansas Children's Hospital in Little Rock, Arkansas. Patients underwent complete eye examinations, including corneal pachymetry, topography, and optical coherence tomography when indicated. RESULTS: All five patients with ATS had myopia and thin corneas with an average central corneal thickness of 426 µm, and three had corneal ectasia, two with early keratoconus and one with keratoglobus and deep stromal corneal opacities. One patient had bilateral high irregular astigmatism, and one had unilateral high regular astigmatism. All carriers had myopia, one had corneal thinning, and one developed keratectasia in one eye many years after laser-assisted in situ keratomileusis (LASIK) surgery. CONCLUSION: We document a spectrum of ophthalmic manifestations of ATS with universal findings of myopia, corneal thinning, and a propensity for corneal ectasia leading to keratoconus or keratoglobus. Heterozygous carriers may develop keratectasia after corneal refractive surgery. Our data support regular eye examinations for all patients carrying SLC2A10 mutations with follow-up tailored to clinical findings.


Assuntos
Artérias/anormalidades , Córnea/patologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Heterozigoto , Instabilidade Articular/diagnóstico , Ceratocone/diagnóstico , Mutação , Miopia/diagnóstico , Dermatopatias Genéticas/diagnóstico , Malformações Vasculares/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Paquimetria Corneana , Topografia da Córnea , Dilatação Patológica , Feminino , Humanos , Instabilidade Articular/genética , Ceratocone/genética , Masculino , Miopia/genética , Dermatopatias Genéticas/genética , Tomografia de Coerência Óptica , Malformações Vasculares/genética , Adulto Jovem
14.
Anticancer Res ; 38(1): 471-476, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29277811

RESUMO

BACKGROUND/AIM: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. MATERIALS AND METHODS: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. RESULTS: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. CONCLUSION: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies.


Assuntos
Síndrome do Nevo Basocelular/genética , Folículo Piloso/anormalidades , Hamartoma/genética , Receptor Patched-1/genética , Dermatopatias Genéticas/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Folículo Piloso/patologia , Hamartoma/diagnóstico , Hamartoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/patologia , Neoplasias Cutâneas/patologia , Adulto Jovem
15.
Best Pract Res Clin Endocrinol Metab ; 32(6): 941-954, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30665554

RESUMO

Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of PTH/PTHrP lead to features caused by non-responsiveness of target organs, in turn leading to manifestations similar to the deficiency of the hormone itself. Pseudohypoparathyroidism (PHP) and related disorders derive from a defect of the α subunit of the stimulatory G protein (Gsα) or of downstream effectors of the same pathway, such as the PKA regulatory subunit 1A and the phosphodiesterase type 4D. The increasing knowledge on these diseases made the actual classification of PHP outdated as it does not include related conditions such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), so that a new nomenclature and classification has been recently proposed grouping these disorders under the term "inactivating PTH/PTHrP signaling disorder" (iPPSD). This review will focus on the pathophysiology, clinical and molecular aspects of these rare, heterogeneous but closely related diseases.


Assuntos
Resistência a Medicamentos , Doenças do Sistema Endócrino , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/fisiologia , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Resistência a Medicamentos/genética , Disostoses/genética , Disostoses/metabolismo , Doenças do Sistema Endócrino/genética , Doenças do Sistema Endócrino/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Ossificação Heterotópica/genética , Ossificação Heterotópica/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/genética , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/metabolismo , Transdução de Sinais/genética , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/metabolismo , Síndrome
16.
Int J Dermatol ; 56(12): 1406-1413, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29130490

RESUMO

BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.


Assuntos
Doenças Raras/genética , Dermatopatias Genéticas/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Aldeído Oxirredutases/genética , Vesícula/genética , Colágeno Tipo VII/genética , Consanguinidade , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Simples/genética , Exoma , Feminino , Flavoproteínas/genética , Homozigoto , Humanos , Mutação INDEL , Eritrodermia Ictiosiforme Congênita/genética , Ictiose Vulgar/genética , Ictiose Lamelar/genética , Proteínas de Filamentos Intermediários/genética , Queratina-14/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipoxigenase/genética , Masculino , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linhagem , Doenças Periodontais/genética , Fenótipo , Transtornos de Fotossensibilidade/genética , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genética , Síndrome de Sjogren-Larsson/genética , Fatores de Transcrição/genética , Xeroderma Pigmentoso/genética
17.
Annu Rev Genet ; 51: 123-141, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29178821

RESUMO

Genetic mosaicism arises when a zygote harbors two or more distinct genotypes, typically due to de novo, somatic mutation during embryogenesis. The clinical manifestations largely depend on the differentiation status of the mutated cell; earlier mutations target pluripotent cells and generate more widespread disease affecting multiple organ systems. If gonadal tissue is spared-as in somatic genomic mosaicism-the mutation and its effects are limited to the proband, whereas mosaicism also affecting the gametes, such as germline or gonosomal mosaicism, is transmissible. Mosaicism is easily appreciated in cutaneous disorders, as phenotypically distinct mutant cells often give rise to lesions in patterns determined by the affected cell type. Genetic investigation of cutaneous mosaic disorders has identified pathways central to disease pathogenesis, revealing novel therapeutic targets. In this review, we discuss examples of cutaneous mosaicism, approaches to gene discovery in these disorders, and insights into molecular pathobiology that have potential for clinical translation.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Mosaicismo , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Dermatopatias Genéticas/genética , Ectoderma/metabolismo , Ectoderma/patologia , Embrião de Mamíferos , Endoderma/metabolismo , Endoderma/patologia , Humanos , Queratina-1/genética , Queratina-1/metabolismo , Queratina-10/genética , Queratina-10/metabolismo , Microdissecção e Captura a Laser , Mesoderma/metabolismo , Mesoderma/patologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Dermatopatias Genéticas/metabolismo , Dermatopatias Genéticas/patologia , Fatores de Tempo , Sequenciamento Completo do Exoma
18.
PLoS One ; 12(10): e0185785, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29040284

RESUMO

BACKGROUND: Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE). METHODS: Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months. RESULTS: Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32-50] vs. 52 [43-65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age <45 years and a family history of VTE were independent predictors for unprovoked VTE with HT (odds ratio, 9.435 [2.45-36.35]; P = 0.001 and 92.667 [14.95-574.29]; P < 0.001). CONCLUSIONS: About 15% of patients with unprovoked VTE had HT. A positive family history of VTE and age <45 years were independent predictors for unprovoked VTE caused by HT.


Assuntos
Deficiência de Antitrombina III/fisiopatologia , Conjuntivite/fisiopatologia , Plasminogênio/deficiência , Deficiência de Proteína C/fisiopatologia , Deficiência de Proteína S/fisiopatologia , Dermatopatias Genéticas/fisiopatologia , Trombofilia/fisiopatologia , Tromboembolia Venosa/fisiopatologia , Adulto , Idoso , Antitrombina III/genética , Deficiência de Antitrombina III/complicações , Deficiência de Antitrombina III/diagnóstico , Deficiência de Antitrombina III/genética , Conjuntivite/complicações , Conjuntivite/diagnóstico , Conjuntivite/genética , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Plasminogênio/genética , Proteína C/genética , Deficiência de Proteína C/complicações , Deficiência de Proteína C/diagnóstico , Deficiência de Proteína C/genética , Proteína S/genética , Deficiência de Proteína S/complicações , Deficiência de Proteína S/diagnóstico , Deficiência de Proteína S/genética , República da Coreia , Estudos Retrospectivos , Análise de Sequência de DNA , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Trombofilia/diagnóstico , Trombofilia/etiologia , Trombofilia/genética , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/genética
19.
Pediatr Dermatol ; 34(6): e345-e346, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29023873

RESUMO

We report the case of a 6-year-old Caucasian girl with clinical and histopathologic features of Buschke-Ollendorff syndrome. Histologic examination of skin lesions showed thick, curly, elastic fibers in the derma. Bone lesions compatible with Buschke-Ollendorff syndrome were found in the girl's mother. Mutations in LEMD3 are pathogenic for Buschke-Ollendorff syndrome. Analysis of all exons and exon-intron junctions of LEMD3 did not reveal any germline mutations.


Assuntos
Proteínas de Membrana/genética , Proteínas Nucleares/genética , Osteopecilose/genética , Dermatopatias Genéticas/genética , Pele/patologia , Criança , Tecido Elástico/patologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Análise de Sequência de DNA
20.
Am J Med Genet A ; 173(12): 3201-3204, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28884927

RESUMO

Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings.


Assuntos
Dermatite Esfoliativa/genética , Proteínas S100/genética , Dermatopatias Genéticas/genética , Adolescente , Dermatite Esfoliativa/diagnóstico , Dermatite Esfoliativa/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Linhagem , Análise de Sequência de DNA , Pele/patologia , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/patologia
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