Ikerpárban előforduló örökletes phaeochromocytoma

Absztrakt A phaeochromocytoma a katecholamin-termelő mellékvesevelő neuroendokrin sejtjeinek daganata. Az extraadrenalisan elhelyezkedő phaeochromocytomákat paragangliomának nevezzük. A phaeochromocytomák nagy része sporadikusan fordul elő, de mintegy 25–30%-uk genetikai eredetű, örökletes forma. Az örökletes phaeochromocytoma-paraganglioma szindrómák incidenciája folyamatosan növekszik. Ez egyrészt az egyre szélesebb körben elterjedő genetikai vizsgálatokkal, valamint az újabb gének felfedezésével függ össze. A középkorú nőbetegnél végzett komputertomográfia során derült fény kétoldali mellékvese-nagyobbodásra. A kiegészítő képalkotó vizsgálatok, a vizeletkatecholamin- és szérum-chromogranin-A-eredmények kétoldali phaeochromocytoma jelenlétét erősítették meg. A beteg egypetéjű ikertestvérénél is hasonló, hormonálisan aktív kétoldali phaeochromocytoma igazolódott, ezért felmerült öröklődő, familiáris phaeochromocytoma lehetősége. Ennek igazolására genetikai vizsgálat történt, ami a nemrégiben felismert transzmembrán protein 127 tumorszuppresszor gén mutációját igazolta. A kivizsgálást követően mindkét betegnél mellékvese-megtartó műtétre került sor, amely során a nagyobb daganatot tartalmazó mellékvesét teljes egészében reszekálták, míg az ellenkező oldalon a mellékvese velőállományát eltávolítva mellékvesekéregállományt hagytak vissza. A műtétet követően mindkét betegnél a vizeletkatecholamin- és szérum-chromogranin-A-szintek normalizálódtak. A mellékvesekéreg-megtartó műtét ellenére az egyik betegnél mellékvesekéreg-elégtelenség alakult ki, ami miatt tartós glükokortikoidpótlásra szorul. Az eset különlegességét az adja, hogy az áttekintett irodalomban és a rendelkezésre álló nemzetközi phaeochromocytoma-regiszterekben sem egypetéjű, sem kétpetéjű ikerpárról a szerzők nem találtak említést. Az egész családra kiterjesztett genetikai vizsgálat során 4 generáción keresztül sikerült igazolni a mutáns gén jelenlétét. Orv. Hetil., 2016, 157(33), 1326–1330. | Abstract Phaeochromocytoma is a tumor of the catecholamine-producing cells of the adrenal gland. Extraadrenal phaeochromocytomas are frequently called paragangliomas. The majority of phaeochromocytomas are sporadic, however, about 25-30% are caused by genetic mutation. These tumor are frequently referred as hereditary phaeochromocytomas/paragangliomas. Their incidence increases continuously which can be attributed to availability of genetic examination and to the discovery of novel genes. The 47-year-old female patient underwent abdominal computed tomography which revealed bilateral adrenal gland enlargement. Abdominal magnetic resonance imaging, the 131-I- metaiodobenzylguanidine scintigraphy, urinary catecholamines and serum chomogranin A measurements confirmed the diagnosis of bilateral phaeochromocytomas. The genetically identical twin sister of the patient was also diagnosed with hormonally active bilateral phaechromocytoma, suggesting the genetic origin of phaeochromocytoma. Mutation screening confirmed a germline mutation of the transmembrane protein 127 tumorsupressor gene in both patients. Both patients underwent cortical-sparing adrenalectomy. The adrenal gland with the larger tumor was totally resected, while in the opposite side only the tumor was resected and a small part of the cortex was saved. After the operation urinary catecholamines and serum chromogranin A returned to normal in both patients. Adrenocortical deficiency was absent in the first patient, but her sister developed adrenal insufficiency requiring glucocorticoid replacement. To the best of the authors’ knowledge phaeochromocytoma affecting twins has never been described earlier. Genetic examination performed in siblings confirmed the presence of the mutant gene through four generations. Orv. Hetil., 2016, 157(33), 1326–1330

Biokémiai markerek jelentősége a neuroendokrin daganatok felismeresében és a betegek követésében

Circulating markers of neuroendocrine tumours are useful tools in the diagnosis of these tumours. Laboratory tests for general biomarkers have acceptable sensitivity for the recognition of neuroendocrine tumours as these biologically active proteins are typically synthesized by all types of neuroendocrine cells. Measurement of chromogranin A is widely used not only in the diagnosis of neuroendocrine tumours but it may predict the prognosis of the diseases and the effect of the antitumor therapy. It is also a useful tool for the detection of residual tumours. Neurendocrine tumours represent a heterogeneous group of tumours with the ability to secrete several hormones and, therefore, measurement of these hormones can also serve as neuroendocrine cell type-specific markers in routine clinical practice. In this review the authors summarize the significance of tumour markers in the diagnosis of neuroendocrine tumours as well as in the management and follow-up of patients with this disease. Orv. Hetil., 2014, 155(45), 1775-1782

Új módszertani lehetőségek és ezek alkalmazása a hormonális rendszer daganatainak genetikai kivizsgálásában

The technical developments leading to revolution in clinical genetic testing offer new approaches for patients with cancer. From one mutation or one gene approach the scale of genetic testing moved to whole exome or whole genome scale. It is well known that many tumours are genetically determined ans they are part of familial tumour syndromes. In addition, some mutations indicate specific molecular targeted therapies. Although sampling and sample preparation are different for testing germline and somatic mutations, the technical background of the analysis is the same. The aim of clinical genetic testing is to identify patients who are carriers of disease-causing mutations or to test tumour tissue for the presence of genetic alterations which may be targets for therapeutic approaches. In this review the authors summarize novel possibilities offered by next-generation sequencing in clinical genetic testing of patients with endocrine tumours. In addition, the authors review recent guidelines on technical and ethical issues related to these novel methods. Orv. Hetil., 2015, 156(51), 2063-2069

Az ösztrogénmetabolom biológiai és klinikai jelentősége lokális folyamatokban

Absztrakt: Az ösztrogénhormonok fiziológiai szerepe sok tekintetben ismert. Meglehetősen kevés információ áll azonban rendelkezésre az ösztron és az ösztradiol lebontása során képződő vegyületek szerepéről a különböző, ösztrogénhatással összefüggésbe hozott kórképekben. A kutatások intenzív érdeklődésének középpontjában jelenleg a két ösztrogénhormon mellett tizenhárom extragonadális metabolit áll. A képződő metabolitok protektív vagy éppen proinflammatorikus és/vagy proonkogén hatással rendelkeznek. A szisztémás keringésben mért metabolitszintek nem mutatnak összefüggést a lokálisan megjelenő metabolitokéval, ennek a jövőben diagnosztikai jelentősége lehet. A jelen tanulmány célja a perifériás szövetekben az extragonadális metabolommal kapcsolatos irodalmi források átfogó áttekintése, valamint felhívni a figyelmet a perifériás szövetek ösztrogénhomeosztázisának szerepére, az ösztrogénmetabolom igazolt, valamint a klasszikus hormonhatásoktól eltérő biológiai aktivitására, egyes kórfolyamatokban azonosított klinikai jelentőségére. Ezek az ismeretek a lokálisan determinált kórfolyamatok megértését, korai diagnosztikáját a későbbiekben a metabolomika eszköztárával jelentősen segíthetik. Orv Hetil. 2017; 158(24): 929–937. | Abstract: Considerable knowledge has been gathered on the physiological role of estrogens. However, fairly little information is available on the role of compounds produced in the breakdown process of estrone and estradiol wich may play a role in various diseases associated with estrogen impact. To date, approximately 15 extragonadal estrogen-related compounds have been identified. These metabolites may exert protective, or, instead, pro-inflammatory and/or pro-oncogenic activity in a tissue-specific manner. Systemic and local estrogen metabolite levels are not necesserily correlated, which may promote the diagnostic significance of the locally produced estrogen metabolites in the future. The aim of the present study is a bibliographic review of the extragonadal metabolome in peripheral tissues, and to highlight the role of the peripheral tissue homeostasis of estrogens as well as the non-hormonal biological activity and clinical significance of the estrogen metabolome. Orv Hetil. 2017; 158(24): 929–937

Analytical performance of ngs-based molecular genetic tests used in the diagnostic workflow of pheochromocytoma/paraganglioma

Next Generation Sequencing (NGS)-based methods are high-throughput and cost-effective molecular genetic diagnostic tools. Targeted gene panel and whole exome sequencing (WES) are applied in clinical practice for assessing mutations of pheochromocytoma/paraganglioma (PPGL) associated genes, but the best strategy is debated. Germline mutations of at the least 18 PPGL genes are present in approximately 20–40% of patients, thus molecular genetic testing is recommended in all cases. We aimed to evaluate the analytical and clinical performances of NGS methods for mutation detection of PPGL-associated genes. WES (three different library preparation and bioinformatics workflows) and an in-house, hybridization based gene panel (endocrine-onco-gene-panel- ENDOGENE) was evaluated on 37 (20 WES and 17 ENDOGENE) samples with known variants. After optimization of the bioinformatic workflow, 61 additional samples were tested prospectively. All clinically relevant variants were validated with Sanger sequencing. Target capture of PPGL genes differed markedly between WES platforms and genes tested. All known variants were correctly identified by all methods, but methods of library preparations, sequencing platforms and bioinformatical settings significantly affected the diagnostic accuracy. The ENDOGENE panel identified several pathogenic mutations and unusual genotype–phenotype associations suggesting that the whole panel should be used for identification of genetic susceptibility of PPGL

Looking beyond linear regression and Bland-Altman plots: a comparison of the clinical performance of 25-hydroxyvitamin D tests.

BACKGROUND: The systematic evaluation of the clinical concordance of various 25-hydroxyvitamin D (25OHD) testing methods is presented. The need for this approach is raised by the discrepancies in the analytical performance of the available assays. METHODS: The analytical and clinical performance of six automated 25OHD assays and an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was investigated. Leftover serum samples (n=162, SA: n=114) were analyzed and all 21 assay combinations were evaluated. The utility of Cohen's kappa values was assessed by transforming them into minimum percentage agreement (MPA). McNemar's hypothesis test was employed for testing the symmetry of the disagreeing classification outcomes within each method pair. RESULTS: Depending on the assay method, the ratio of results classified as positive (<20 ng/mL) was 13.5%-40.0%. The percentage agreement (PA) was 74.1%-92.6%. Compared to other methods, significantly more hypovitaminosis cases were delivered by DiaSorin Liaison(R) 25 OH vitamin D Total (DL) and significantly fewer by IDS-iSYS 25-Hydroxy Vitamin DS (II). The strongest clinical concordance was exerted by II vs. LC-MS/MS. The kappa-derived MPA showed close similarity to the PA scores. McNemar's tests confirmed the asymmetry of the disagreement in the classification in 14 method combinations. CONCLUSIONS: The presented approach allows the prediction of the clinical consequences of a 25OHD method transfer. Differences in the clinical classification of assay results are likely encountered when transferring to a new method, even between assays standardized according to the Vitamin D Standardization Program (VDSP) Reference Method Procedure (RMP)