scholarly journals Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update

2020 ◽  
Vol 106 (1) ◽  
pp. e350-e364
Author(s):  
Gustavo Armaiz-Pena ◽  
Shahida K Flores ◽  
Zi-Ming Cheng ◽  
Xhingyu Zhang ◽  
Emmanuel Esquivel ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Susceptibility Gene ◽  
Causal Link ◽  
Outcome Analysis ◽  
Clinical Genetic ◽  
Germline Variants ◽  
Clinical Presentations ◽  
Transmembrane Regions ◽  
Function Integration

Abstract Purpose This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main Outcome Analysis Clinical, genetic, and functional associations were determined. Results The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

Miscellaneous vasculitides

2013 ◽  
pp. 1153-1162
Author(s):  
Richard A. Watts ◽  
Eleana Ntatsaki
Keyword(s):  
Rheumatoid Arthritis ◽  
Central Nervous System ◽  
Viral Infections ◽  
Systemic Disease ◽  
Connective Tissue Diseases ◽  
Relapsing Polychondritis ◽  
Significant Morbidity ◽  
Clinical Presentations ◽  
Systemic Rheumatic Diseases

The vasculitides are a group of relatively rare conditions with a broad spectrum of clinical presentations that can cause significant morbidity and mortality. Classification of the vasculitic syndromes is done according to the size of the vessels affected and also the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Vasculitides can be either primary or secondary to an underlying systemic disease, malignancy, or infection. This chapter covers the spectrum of the secondary vasculitides; some of the non-ANCA-associated primary vasculitides and miscellaneous types of vasculitic syndromes. Secondary vasculitis can occur in the background of systemic rheumatic diseases such as rheumatoid arthritis, spondyloarthropathies, or other connective tissue diseases. Vasculitis can also present in relation to precipitants such as drugs (propylthiouracil, hydralazine, leucotriene antagonists) or vaccines. Infection (bacterial, mycobacterial, viral, and fungal) has been associated with vasculitis either as a trigger or as a consequence of iatrogenic immunosuppression. Infection-related vasculitis can affect all types and sizes of vessels. Certain forms of vasculitis such as cryoglobulinaemia are closely associated with viral infections and more specifically with HCV infection. There are forms of vasculitis, which appear to be isolated or localized to a single organ, or site (skin, gastrointestinal, genital, and primary central nervous system vasculitis) that may be histologically similar to systemic syndromes, but have a different prognosis. Other conditions that may mimic vasculitis and miscellaneous conditions such as Cogan’s syndrome and relapsing polychondritis are also discussed.

The patient with vasculitis

2015 ◽  
Author(s):  
David Jayne
Keyword(s):  
Clinical Presentation ◽  
Renal Involvement ◽  
Disease Process ◽  
Small Vessel Vasculitis ◽  
Clinical Presentations ◽  
Severe Manifestation ◽  
Definition Of ◽  
End Stage ◽  
Autoimmune Aetiology

The definition of vasculitis syndromes relies on clinical, serological, and pathological descriptions. A number of primary syndromes are recognized, of presumed autoimmune aetiology, but vasculitis may also occur as a secondary disease process. The heterogeneity of clinical presentation, low specificity of many clinical features, and mimics of other diseases complicate vasculitis diagnosis. The kidney is the most common severe manifestation for small vessel vasculitis syndromes and the severity of renal involvement predicts end-stage renal failure risk and death. Suspicion of vasculitis is key to early diagnosis and improving outcomes of vasculitis patients.The current understanding of the classification of vasculitis syndromes is presented in this chapter along with descriptions of clinical presentations, and approaches to diagnosis.

scholarly journals Tomography patterns of lung disease in systemic sclerosis

2016 ◽  
Vol 49 (5) ◽  
pp. 316-321 ◽  
Author(s):  
Andréa de Lima Bastos ◽  
Ricardo de Amorim Corrêa ◽  
Gilda Aparecida Ferreira
Keyword(s):  
Computed Tomography ◽  
Systemic Sclerosis ◽  
Pulmonary Involvement ◽  
High Resolution Computed Tomography ◽  
Clinical Presentations ◽  
Nonspecific Interstitial Pneumonia ◽  
Pulmonary Changes ◽  
Treatment Responses ◽  
Lung Impairment

Abstract Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed), Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses.

scholarly journals PDS Is a New Susceptibility Gene to Autoimmune Thyroid Diseases: Association and Linkage Study

2003 ◽  
Vol 88 (5) ◽  
pp. 2274-2280 ◽  
Author(s):  
Hassen Hadj Kacem ◽  
Ahmed Rebai ◽  
Noureddine Kaffel ◽  
Saber Masmoudi ◽  
Mohamed Abid ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Transmembrane Protein ◽  
Susceptibility Gene ◽  
Association Test ◽  
Lod Score ◽  
Autoimmune Thyroid ◽  
The Family ◽  
Family Based ◽  
Idiopathic Myxedema ◽  
Pds Gene

Autoimmune thyroid disease (AITD), including Graves’ disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, is caused by multiple genetic and environmental factors. Genes involved in immune response and/or thyroid physiology appear to influence susceptibility to disease. The PDS gene (7q31), responsible for Pendred syndrome (congenital sensorineural hearing loss and goiter), encodes a transmembrane protein known as pendrin. Pendrin is an apical porter of iodide in the thyroid. To evaluate the contribution of PDS gene in the genetic susceptibility of AITD, we examined four microsatellite markers in the gene region. Two hundred thirty-three unrelated patients (GD,141; HT, 54; primary idiopathic myxedema, 38), 15 multiplex AITD families (104 individuals/46 patients) and 154 normal controls were genotyped. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with GD (P = 10−3) and HT (P = 1.07 10−24), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test are in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). Multipoint nonparametric linkage analysis using MERLIN showed intriguing evidence for linkage with marker D7S496 in families with only GD patients [Z = 2.12, LOD = 0.81, P = 0.026]. Single-point and multipoint parametric LOD score linkage analysis was also performed. Again, the highest multipoint parametric LOD score was found for marker D7S496 (LOD = 1.23; P = 0.0086) in families segregating for GD under a dominant model. This work suggests that the PDS gene should be considered a new susceptibility gene to AITDs with varying contributions in each pathology.

scholarly journals A Ruptura do Nexo de Causalidade Diante da Contaminação pelo Vírus da COVID-19 em Vítimas de Disparos de Arma de Fogo

2021 ◽  
Vol 22 (1) ◽  
pp. 37-40
Author(s):  
Luan Paixão Rampinelli
Keyword(s):  
Criminal Law ◽  
Causal Link ◽  
De Se ◽  
Causal Nexus

ResumoO trabalho em epígrafe busca a análise detida da ocorrência ou não da ruptura do nexo de causalidade em morte decorrente de contaminação pelo vírus da COVID-19 em casos de vítimas de disparos de arma de fogo. Trata-se de estudo de notável importância para a seara do Direito Penal, uma vez ser notória a existência de debates sobre a existência do nexo de causalidade em casos específicos. Partindo-se deste pressuposto se torna imperiosa a interpretação, ainda que de forma crítica, das teorias adotadas pelo Código Penal sobre o nexo causal, perquirindo se a regra ou se a exceção deve ser adotada na situação fática ora analisada. O estudo, para tanto, analisa as interpretações doutrinárias e jurisprudenciais em hipóteses semelhantes sobre o nexo de causalidade em vítimas de disparos de arma de fogo. Por fim, concluída a análise das questões mencionadas se tornou inconteste a necessidade de se aferir, na hipótese em tela, se há ou não a ruptura do nexo de causalidade, interferindo na própria tipificação do delito, seja na modalidade consumada, seja na modalidade tentada a depender da ruptura ou não do nexo causal. Palavras-chave: Nexo Causal. COVID-19. Concausas. AbstractThis study aims to analyze the occurrence or not of the rupture of the causal link in death from contamination by the virus of COVID-19 in cases of firearm shots victims. This is a study of notable importance in criminal law, since there are notorious debates about the existence of a causal link in specific cases. Based on this assumption, it is imperative to analyze, albeit in a critical way, the theories adopted by the criminal law on the causal link, investigating whether the rule or the exception should be adopted in the factual situation here analyzed. The study, therefore, analyzes the doctrinal and jurisprudential interpretations in similar hypotheses about the causal link in firearm shots victims. Finally, after the analysis of the aforementioned issues was completed, the need to assess, in the hypothesis, whether or not there is a rupture of the causal link, interfering in the classification of the crime, whether in the consummated or in the attempted modality, to depend on the rupture or not of the causal nexus. Keywords: Causal Link; COVID-19; Concauses.

scholarly journals The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Annamaria Landolfi ◽  
Paolo Barone ◽  
Roberto Erro
Keyword(s):  
Movement Disorders ◽  
Neurodevelopmental Disorders ◽  
Transmembrane Protein ◽  
Brain Disorders ◽  
Hemiplegic Migraine ◽  
Causative Gene ◽  
Paroxysmal Kinesigenic Dyskinesia ◽  
Infantile Epilepsy ◽  
Biallelic Mutations

Mutations in the PRRT2 (proline-rich transmembrane protein 2) gene have been identified as the main cause of an expanding spectrum of disorders, including paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy, which places this gene at the border between epilepsy and movement disorders. The clinical spectrum has largely expanded to include episodic ataxia, hemiplegic migraine, and complex neurodevelopmental disorders in cases with biallelic mutations. Prior to the discovery of PRRT2 as the causative gene for this spectrum of disorders, the sensitivity of paroxysmal kinesigenic dyskinesia to anticonvulsant drugs regulating ion channel function as well as the co-occurrence of epilepsy in some patients or families fostered the hypothesis this could represent a channelopathy. However, recent evidence implicates PRRT2 in synapse functioning, which disproves the “channel hypothesis” (although PRRT2 modulates ion channels at the presynaptic level), and justifies the classification of these conditions as synaptopathies, an emerging rubric of brain disorders. This review aims to provide an update of the clinical and pathophysiologic features of PRRT2-associated disorders.

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