RESUMO
Among the genetic factors playing a key role in the etiology of intellectual disabilities (IDs) and autism spectrum disorders (ASDs), several encode RNA-binding proteins (RBPs). In this study, we deciphered the molecular and cellular bases of ID-ASD in a patient followed from birth to the age of 21, in whom we identified a de novo CSDE1 (Cold Shock Domain-containing E1) nonsense variation. CSDE1 encodes an RBP that regulates multiple cellular pathways by monitoring the translation and abundance of target transcripts. Analyses performed on the patient's primary fibroblasts showed that the identified CSDE1 variation leads to haploinsufficiency. We identified through RNA-seq assays the Wnt/ß-catenin signaling and cellular adhesion as two major deregulated pathways. These results were further confirmed by functional studies involving Wnt-specific luciferase and substrate adhesion assays. Additional data support a disease model involving APC Down-Regulated-1 (APCDD1) and cadherin-2 (CDH2), two components of the Wnt/ß-catenin pathway, CDH2 being also pivotal for cellular adhesion. Our study, which relies on both the deep phenotyping and long-term follow-up of a patient with CSDE1 haploinsufficiency and on ex vivo studies, sheds new light on the CSDE1-dependent deregulated pathways in ID-ASD.
Assuntos
Transtorno do Espectro Autista , Proteínas de Ligação a DNA , Deficiência Intelectual , Proteínas de Ligação a RNA , Via de Sinalização Wnt , Adolescente , Transtorno do Espectro Autista/genética , Adesão Celular/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Proteínas de Ligação a RNA/genética , Adulto Jovem , beta Catenina/genéticaRESUMO
Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.
Assuntos
Deficiência Intelectual/genética , Complexo Mediador/genética , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Mutação de Sentido Incorreto , FenótipoRESUMO
Mowat-Wilson syndrome (MWS) is a rare genetic syndrome characterized by a specific facial gestalt, intellectual deficiency, Hirschsprung disease and multiple congenital anomalies. Heterozygous mutations or deletions in the zinc finger E-box-binding homeobox2 gene (ZEB2) cause MWS. ZEB2 encodes for Smad-interacting protein 1, a transcriptional co-repressor involved in TGF-beta and BMP pathways and is strongly expressed in early stages of development in mice. Eye abnormalities have rarely been described in patients with this syndrome. Herein, we describe four patients (two males and two females; mean age 7 years) with MWS and eye malformations. Ocular anomalies included, iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes with severe visual consequences. All eye malformations were asymmetric and often unilateral and all eye segments were affected, similarly to the nine MWS cases with ophthalmological malformations previously reported (iris/chorioretinal/optic disc coloboma, optic nerve atrophy, retinal epithelium atrophy, cataract, and korectopia). In human embryo, ZEB2 is expressed in lens and neural retina. Using the present report and data from the literature, we set out to determine whether or not the presence of eye manifestations could be due to specific type or location of mutations. We concluded that the presence of eye malformations, although a rare feature in MWS, should be considered as a part of the clinical spectrum of the condition.
Assuntos
Olho/patologia , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Proteínas Repressoras/genética , Adolescente , Atrofia/patologia , Catarata/patologia , Pré-Escolar , Coloboma/patologia , Fácies , Feminino , Humanos , Masculino , Mutação/genética , Nervo Óptico/patologia , Epitélio Pigmentado da Retina/patologia , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND are classified based upon the localization of neutrophils within the skin and clinical features. Recent findings suggest that ND are due to two main mechanisms: i) a polyclonal hereditary activation of the innate immune system (polygenic or monogenic); or ii) a clonal somatic activation of myeloid cells such as encountered in myelodysplastic syndrome or VEXAS syndrome. ND belong to internal medicine as a great number of patients with ND suffer from an underlying condition (such as hematological malignancy, inflammatory bowel disease, auto-immune and auto-inflammatory diseases). ND are diagnoses of exclusion and physicians should always consider differential diagnoses, particularly skin infections. Here, we review the pathophysiology and classification of the main ND (i.e., subcorneal pustular dermatosis (Sneddon-Wilkinson Disease) and Intercellular IgA dermatoses, aseptic pustulosis of the folds, Sweet syndrome, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, erythema elevatum diutinum, neutrophilic urticarial dermatosis and neutrophilic panniculitis), their clinical and histopathological features, and we highlight the investigations that are useful to identify ND-associated diseases and to exclude the differential diagnoses.
Assuntos
Pioderma Gangrenoso , Dermatopatias Vesiculobolhosas , Síndrome de Sweet , Vasculite Leucocitoclástica Cutânea , Humanos , Síndrome de Sweet/diagnóstico , Síndrome de Sweet/patologia , Pioderma Gangrenoso/diagnóstico , Dermatopatias Vesiculobolhosas/diagnóstico , Neutrófilos/patologiaRESUMO
INTRODUCTION: Tumor Necrosis Factor Type 1 Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autosomal autoinflammatory disease associated with mutations in the TNF type 1 receptor gene (TNFRSF1A). It is characterized by relatively long recurrent febrile seizures with an average duration of 7 days accompanied by arthralgia, myalgia, and usually a rash. In a patient of Mediterranean origin with recurrent fever, familial Mediterranean fever is the first diagnosis to be suspected by argument of frequency. METHODS: A retrospective observational study was conducted on patients from Mediterranean origin followed for TRAPS and included in the "Juvenile Inflammatory Rheumatism" (JIR) observational cohort in the national French autoinflammatory center. The age of onset of symptoms, age of diagnosis, number of years of wandering and treatments received were collected for each index case. RESULTS: Nine patients from 6 families of Mediterranean origin were included. A molecular diagnosis confirmed TRAPS in all patients. The median age at diagnosis was 26 years, the mean number of years of wandering was 17 years. The diagnosis of FMF was made first in all patients. AA amyloidosis revealed TRAPS in 2 patients. Colchicine was started without any efficacy in all cases. Five patients were treated with interleukin-1 inhibitory biotherapy with 100% efficacy. CONCLUSION: In a patient of Mediterranean origin presenting with recurrent febrile abdominal pain of AA amyloidosis, the first diagnosis to be suspected is FMF. Long relapses, dominant transmission, a non-Mediterranean relative, and the ineffectiveness of colchicine should evoke TRAPS.
Assuntos
Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Mutação , Receptores Tipo I de Fatores de Necrose TumoralRESUMO
Neonatal hyperinsulinism is a life-threatening disease that, when treated by total pancreatectomy, leads to diabetes and pancreatic insufficiency. A more conservative approach is now possible since the separation of the disease into a nonrecurring focal form, which is cured by partial surgery, and a diffuse form, which necessitates total pancreas removal only in cases of medical treatment failure. The pathogenesis of the disease is now divided into K-channel disease (hyperinsulinemic hypoglycemia, familial [HHF] 1 and 2), which can mandate surgery, and other metabolic causes, HHF 3 to 6, which are treated medically in most patients. The diffuse form is inherited as a recessive gene on chromosome 11, whereas most cases of the focal form are caused by a sulfonylurea receptor 1 defect inherited from the father, which is associated with a loss of heterozygosity on the corresponding part of the mother's chromosome 11. The rare bifocal forms result from a maternal loss of heterozygosity specific to each focus. Paternal disomy of chromosome 11 is a rare cause of a condition similar to Beckwith-Wiedemann syndrome. A preoperative PET scan with fluorodihydroxyphenylalanine and perioperative frozen-section confirmation are the types of studies done before surgery when needed. Adult variants of the disease are less well defined at the present time.
Assuntos
Hiperinsulinismo Congênito , Transportadores de Cassetes de Ligação de ATP/genética , Biópsia , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Hiperinsulinismo Congênito/fisiopatologia , Hiperinsulinismo Congênito/terapia , Secções Congeladas , Humanos , Lactente , Recém-Nascido , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Síndrome de Munchausen/diagnóstico , Nesidioblastose/patologia , Pâncreas/embriologia , Canais de Potássio/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Receptores de SulfonilureiasRESUMO
INTRODUCTION: Myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) syndrome, a maternally inherited disorder that is among the most common mitochondrial DNA (mtDNA) diseases, is usually associated with the m.3242A>G mutation of the mitochondrial tRNA(leu) gene. Very few data are available with respect to prenatal diagnosis of this serious disease. The rate of mutant versus wild-type mtDNA (heteroplasmy) in fetal DNA is indeed considered to be a poor indicator of postnatal outcome. MATERIALS AND METHODS: Taking advantage of a novel semi-quantitative polymerase chain reaction test for m.3243A>G mutant load assessment, we carried out nine prenatal diagnoses in five unrelated women, using two different fetal tissues (chorionic villi v amniocytes) sampled at two or three different stages of pregnancy. RESULTS: Two of the five women, although not carrying m.3243A>G in blood or extra-blood tissues, were, however, considered at risk for transmission of the mutation, as they were closely related to MELAS-affected individuals. The absence of 3243A>G in the blood of first degree relatives was associated with no mutated mtDNA in the cardiovascular system (CVS) or amniocytes, and their three children are healthy, with a follow-up of 3 months-3 years. Among the six fetuses from the three carrier women, three were shown to be homoplasmic (0% mutant load), the remaining three being heteroplasmic, with a mutant load ranging from 23% to 63%. The fetal mutant load was fairly stable at two or three different stages of pregnancy in CVS and amniocytes. Although pregnancy was terminated in the case of the fetus with a 63% mutant load, all other children are healthy with a follow-up of 3 months-6 years. CONCLUSION: These data suggest that a prenatal diagnosis for MELAS syndrome might be helpful for at-risk families.
Assuntos
DNA Mitocondrial , Desenvolvimento Fetal/genética , Genes Mitocondriais/genética , Síndrome MELAS/diagnóstico , Diagnóstico Pré-Natal/métodos , Acidose Láctica/diagnóstico , Acidose Láctica/embriologia , Acidose Láctica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Humanos , Lactente , Síndrome MELAS/embriologia , Síndrome MELAS/genética , Masculino , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/embriologia , Encefalomiopatias Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/embriologia , Doenças Musculares/genética , Linhagem , Reação em Cadeia da Polimerase , Gravidez , RNA de Transferência de Leucina/genética , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/embriologia , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND: Congenital hyperinsulinism and Beckwith-Wiedemann syndrome both lead to beta islet hyperplasia and neonatal hypoglycaemia. They may be related to complex genetic/epigenetic abnormalities of the imprinted 11p15 region. The possibility of common pathophysiological determinants has not been thoroughly investigated. OBJECTIVE: To report abnormalities of the ploidy in two unrelated patients with congenital hyperinsulinism. METHODS: Two patients with severe congenital hyperinsulinism, one overlapping with Beckwith-Wiedemann syndrome, had pancreatic histology, ex vivo potassium channel electrophysiological studies, and mutation detection of the encoding genes. The parental genetic contribution was explored using genome-wide polymorphism, fluorescent in situ hybridisation (FISH), and blood group typing studies. RESULTS: Histological findings diverged from those described in focal congenital hyperinsulinism or Beckwith-Wiedemann syndrome. No potassium channel dysfunction and no mutation of its encoding genes (SUR1, KIR6.2) were detected. In patient 1 with congenital hyperinsulinism and Beckwith-Wiedemann syndrome, paternal isodisomy for the whole haploid set was homogeneous in the pancreatic lesion, and mosaic in the leucocytes and skin fibroblasts (hemihypertrophic segment). Blood group typing confirmed the presence of two erythroid populations (bi-parental v paternal only contribution). Patient 2 had two pancreatic lesions, both revealing triploidy with paternal heterodisomy. Karyotype and FISH analyses done on the fibroblasts and leucocytes of both patients were unremarkable (diploidy). CONCLUSIONS: Diploid (biparental/paternal-only) mosaicism and diploid/triploid mosaicism were present in two distinct patients with congenital hyperinsulinism. These chromosomal abnormalities led to paternal disomy for the whole haploid set in pancreatic lesions (with isodisomy or heterodisomy), thereby extending the range and complexity of the mechanisms underlying congenital hyperinsulinism, associated or not with Beckwith-Wiedemann syndrome.
Assuntos
Anormalidades Congênitas/genética , Hiperinsulinismo/congênito , Hiperinsulinismo/genética , Mosaicismo , Ploidias , Aberrações Cromossômicas , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
Respiratory chain complex I deficiency represents a genetically heterogeneous group of diseases resulting from mutations in mitochondrial or nuclear genes. Mutations have been reported in 13 of the 14 subunits encoding the core of complex I (seven mitochondrial and six nuclear genes) and these result in Leigh or Leigh-like syndromes or cardiomyopathy. In this study, a combination of denaturing high performance liquid chromatography and sequence analysis was used to study the NDUFS3 gene in a series of complex I deficient patients. Mutations found in this gene (NADH dehydrogenase iron-sulphur protein 3), coding for the seventh and last subunit of complex I core, were shown to cause late onset Leigh syndrome, optic atrophy, and complex I deficiency. A biochemical diagnosis of complex I deficiency on cultured amniocytes from a later pregnancy was confirmed through the identification of disease causing NDUFS3 mutations in these cells. While mutations in the NDUFS3 gene thus result in Leigh syndrome, a dissimilar clinical phenotype is observed in mutations in the NDUFV2 and NDUFS2 genes, resulting in encephalomyopathy and cardiomyopathy. The reasons for these differences are uncertain.
Assuntos
Complexo I de Transporte de Elétrons/genética , Doença de Leigh/etiologia , Doença de Leigh/genética , Mutação/genética , NADH Desidrogenase/genética , Subunidades Proteicas/genética , Criança , Complexo I de Transporte de Elétrons/deficiência , Evolução Fatal , Humanos , Proteínas Ferro-Enxofre/deficiência , Proteínas Ferro-Enxofre/genética , Doença de Leigh/enzimologia , Doença de Leigh/patologia , Masculino , NADH Desidrogenase/deficiência , Subunidades Proteicas/deficiênciaRESUMO
Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.
Assuntos
DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Doença de Leigh/genética , MasculinoRESUMO
Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The 2 subunits of the K(+)(ATP) channel are encoded by either the sulfonylurea receptor gene (SUR1 or ABCC8) or the inward-rectifying potassium channel gene (KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [(18)F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio/genética , Receptores de Droga/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Criança , Pré-Escolar , Hiperinsulinismo Congênito/patologia , Hiperinsulinismo Congênito/cirurgia , Diazóxido/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Mutação , Pancreatectomia , Canais de Potássio/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Receptores de Droga/fisiologia , Receptores de Sulfonilureias , Vasodilatadores/uso terapêuticoRESUMO
A female with congenital microgastria, Pierre Robin sequence and partial trismus is described. This is a previously undescribed association and the etiology of the association is discussed.
Assuntos
Síndrome de Pierre Robin/patologia , Estômago/anormalidades , Trismo/patologia , Feminino , Humanos , Recém-NascidoRESUMO
Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 22/genética , Duplicação Gênica , Fatores de Transcrição NFATC/genética , Fatores de Transcrição/genética , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Feminino , Doenças Fetais/genética , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino , Adulto JovemRESUMO
The activity of deoxyguanosine kinase (DGUOK), a mitochondrial enzyme involved in the anabolism of mitochondrial (mt) deoxyribonucleotides, governs the maintenance of the mtDNA. Deleterious mutations of the DGUOK gene are thus associated with mtDNA depletion and result in combined deficiencies of mtDNA-encoded respiratory chain enzymes. With the aim to estimate the prevalence of DGUOK mutations in a cohort of 30 patients with hepatocerebral disease and combined respiratory chain deficiencies, we studied the DGUOK gene and identified previously unreported mutations in five families. Two patients and their affected sibs, born to non-consanguineous parents, were homozygous for a missense mutation (M1T, and L250S, respectively). One patient presented a homozygous 4 pb insertion (796 insTGAT) and two other patients, and their affected sibs, were compound heterozygous (E165V/L266R and E211G/L266R, respectively). These findings allowed us to propose prenatal diagnosis in two families. In conclusion, we observed a high prevalence of DGUOK mutations (17%) in patients with hepatic involvement and combined respiratory chain deficiencies with hepatic involvement.
Assuntos
Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Sequência de Aminoácidos , Sequência de Bases , DNA/genética , Análise Mutacional de DNA , DNA Mitocondrial/metabolismo , Feminino , Humanos , Lactente , Fígado/fisiopatologia , Masculino , Doenças Mitocondriais/fisiopatologia , Dados de Sequência Molecular , Mutação , Homologia de Sequência de AminoácidosRESUMO
Congenital hyperinsulinism (HI), the most important cause of hypoglycaemia in early infancy, is a heterogeneous disease with two types of histological lesions, focal and diffuse, with major consequences in terms of surgical approaches. In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessively inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism. Thus, dominant HI disorders always correspond to diffuse HI, where most hypoglycaemia occur in infancy, and are sensitive to medical treatment. Channel causes could be due to dominant negative mutation with one abnormality in channels composed of four Kir6.2 subunits and four SUR1 subunits, leading to a complete destruction of the channel structure or function, or due to haploinsufficiency with only one functional allele, leading to 50% of functional protein, which is not sufficient to obtain enough opened channels to maintain the membrane depolarized. Metabolic causes are due to a gain of function of enzyme activity (deregulated enzymes), except for physical exercise-induced hyperinsulinaemic hypoglycaemia, of still-unknown cause. Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy (Aynsley-Green et al 2000; Cornblath et al 1990; Pagliara et al 1973; Thomas et al 1977). The inappropriate oversecretion of insulin is responsible for profound hypoglycaemia that requires aggressive treatment to prevent severe and irreversible brain damage (Volpe 1995). HI is a heterogeneous disease associated with several genes, various mechanisms of pathogenic mutations and different transmissions (Dunne et al 2004).
Assuntos
Hiperinsulinismo/genética , Hipoglicemia/genética , Exercício Físico , Genes Dominantes , Glucoquinase/genética , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/patologia , Hiperinsulinismo/cirurgia , Hipoglicemia/etiologia , Hipoglicemia/patologia , Hipoglicemia/cirurgia , Insulina/metabolismo , Insulina/fisiologia , Secreção de Insulina , Mutação/genética , Receptor de Insulina/genéticaRESUMO
Based on a casuistic report of 226 cases, the authors propose a classification of venous emergencies, including acute deep thrombo-phlebites (with their anatomo-clinical and topographical varieties), the complications of varicose disease, venous traumatism and anorectal venous thrombosis. The authors touch on problems associated with clinical and paraclinical diagnosis, prophylaxis and active surgical therapy, respectively thrombectomy, ligation of the long saphenofemoral junction, the treatment of varico-phlebitis and urgent traumatic lesions, the thrombectomy and radical cure of haemorrhoids. The coupling of any of these affections presents a potential of great seriousness, sometimes a major vital risk which necessitates immediate therapeutic intervention. The classification of the idea of "venous emergency" in comparison with that of "arterial emergency", is outlined, and the authors mention that a surgical treatment in these affections is to be preferred.
Assuntos
Extremidades/irrigação sanguínea , Doenças Vasculares/terapia , Veias , Emergências , Hemorroidas/complicações , Humanos , Complicações Intraoperatórias/terapia , Tromboflebite/terapia , Varizes/terapia , Doenças Vasculares/diagnóstico , Veias/lesõesRESUMO
An obese female patient aged 47 with a personal and familial history of recurrent venous thrombosis, who developed a coumarin-induced skin necrosis is presented. Laboratory investigations, performed three months after the acute event and in absence of coumarin therapy, emphasized a decreased anticoagulant activity of her plasma protein C (50% of the normal). These results as well as the high incidence of thrombotic disease in her relatives point to a familial heterozygous protein C deficiency. The antithrombotic role of the protein C system and the mechanism of coumarin induced necrosis of the skin are briefly discussed.