Genetic mutation screening in an Italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients

To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up

Time course of risk factors associated with mortality of 1260 critically ill patients with COVID-19 admitted to 24 Italian intensive care units

94noopenPurpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19). Methods: In this retrospective–prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome. Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55–69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 122 [89–175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO2/FiO2, driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil–lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO2/FiO2, respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values. Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid–base derangement, coagulation impairment, or systemic inflammation were associated with patient survival.openZanella A.; Florio G.; Antonelli M.; Bellani G.; Berselli A.; Bove T.; Cabrini L.; Carlesso E.; Castelli G.P.; Cecconi M.; Citerio G.; Coloretti I.; Corti D.; Dalla Corte F.; De Robertis E.; Foti G.; Fumagalli R.; Girardis M.; Giudici R.; Guiotto L.; Langer T.; Mirabella L.; Pasero D.; Protti A.; Ranieri M.V.; Rona R.; Scudeller L.; Severgnini P.; Spadaro S.; Stocchetti N.; Vigano M.; Pesenti A.; Grasselli G.; Aspesi M.; Baccanelli F.; Bassi F.; Bet A.; Biagioni E.; Biondo A.; Bonenti C.; Bottino N.; Brazzi L.; Buquicchio I.; Busani S.; Calini A.; Calligaro P.; Cantatore L.P.; Carelli S.; Carsetti A.; Cavallini S.; Cimicchi G.; Coppadoro A.; Dall'Ara L.; Di Gravio V.; Erba M.; Evasi G.; Facchini A.; Fanelli V.; Feliciotti G.; Fusarini C.F.; Ferraro G.; Gagliardi G.; Garberi R.; Gay H.; Giacche L.; Grieco D.; Guzzardella A.; Longhini F.; Manzan A.; Maraggia D.; Milani A.; Mischi A.; Montalto C.; Mormina S.; Noseda V.; Paleari C.; Pedeferri M.; Pezzi A.; Pizzilli G.; Pozzi M.; Properzi P.; Rauseo M.; Russotto V.; Saccarelli L.; Servillo G.; Spano S.; Tagliabue P.; Tonetti T.; Tullo L.; Vetrugno L.; Vivona L.; Volta C.A.; Zambelli V.; Zanoni A.Zanella, A.; Florio, G.; Antonelli, M.; Bellani, G.; Berselli, A.; Bove, T.; Cabrini, L.; Carlesso, E.; Castelli, G. P.; Cecconi, M.; Citerio, G.; Coloretti, I.; Corti, D.; Dalla Corte, F.; De Robertis, E.; Foti, G.; Fumagalli, R.; Girardis, M.; Giudici, R.; Guiotto, L.; Langer, T.; Mirabella, L.; Pasero, D.; Protti, A.; Ranieri, M. V.; Rona, R.; Scudeller, L.; Severgnini, P.; Spadaro, S.; Stocchetti, N.; Vigano, M.; Pesenti, A.; Grasselli, G.; Aspesi, M.; Baccanelli, F.; Bassi, F.; Bet, A.; Biagioni, E.; Biondo, A.; Bonenti, C.; Bottino, N.; Brazzi, L.; Buquicchio, I.; Busani, S.; Calini, A.; Calligaro, P.; Cantatore, L. P.; Carelli, S.; Carsetti, A.; Cavallini, S.; Cimicchi, G.; Coppadoro, A.; Dall'Ara, L.; Di Gravio, V.; Erba, M.; Evasi, G.; Facchini, A.; Fanelli, V.; Feliciotti, G.; Fusarini, C. F.; Ferraro, G.; Gagliardi, G.; Garberi, R.; Gay, H.; Giacche, L.; Grieco, D.; Guzzardella, A.; Longhini, F.; Manzan, A.; Maraggia, D.; Milani, A.; Mischi, A.; Montalto, C.; Mormina, S.; Noseda, V.; Paleari, C.; Pedeferri, M.; Pezzi, A.; Pizzilli, G.; Pozzi, M.; Properzi, P.; Rauseo, M.; Russotto, V.; Saccarelli, L.; Servillo, G.; Spano, S.; Tagliabue, P.; Tonetti, T.; Tullo, L.; Vetrugno, L.; Vivona, L.; Volta, C. A.; Zambelli, V.; Zanoni, A

Pheochromocytoma/paraganglioma: Diagnosis and treatment

The terms pheochromocytoma (PHEO) and paraganglioma (PGL) refer to a broad spectrum of clinical conditions that have as their common denominator the origin from a pathological (neoplastic) proliferation of neural crest cells. Clinical presentation and evolution of the disease is extremely variable in relation to several factors, such as the secretive functional characteristics of the cells involved, the primitive site of neoplastic proliferation and the tendency to form remote metastases, the presence of a genetic predisposition that may affect the expression of particular phenotypes. PHEO/PGL is sometimes a complex diagnostic and therapeutic challenge, but the main difficulty is probably the fact that it is a rare condition that is met on very few occasions by most physicians and therefore may remain unrecognized. A good knowledge of the polymorphic expressions of this disease should result in clinical suspicion, which can be confirmed or excluded reliably in most cases. Similarly, the therapeutic management of PHEO/PGL is well established in the overwhelming majority of cases, provided it is entrusted to experienced medical staff

A search for genetic variability in the human alpha-2 adrenergic receptor on chromosome 10.

On line pubblication: Gene Bank, locus AF262016

FAILURE TO REPLICATE THE ASSOCIATION OF UROMODULIN GENE VARIANT RS 13333226 WITH HYPERTENSION IN A GENERAL POPULATION STUDY

Objective: A recent GWAS study of blood pressure (BP) extremes identified a strong association with hypertension of an A/G polymorphic variant (rs13333226) of the UMOD gene encoding uromodulin, the less common G-allele being associated with lower BP. Aim of the present study was to investigate the consistency of this association in a sample of Italian general population (VOBARNO Study) characterized by repeated clinical (CLIN) and ambulatory BP (ABPM) measurements over a decade. Design and Methods: Genotyping of rs13333226 was performed using the TaqMan assay. Genotype data are available in 525 subjects (238 males, aged 50.4 ± 8.2, BMI 25.7 ± 3.8; mean ± SD) at the time of study entry (BAS) and in 429 at a second follow-up evaluation (FU), after an average of 8.7 years Hypertension was defined as BP values ≥140/90 and/or ≥125/80, respectively at CLIN and ABPM, or in presence of antihypertensive drug treatment. In addition, association of rs13333226 with renal function (eGFR, urinary albumin excretion), metabolic risk factors (cholesterol, glycemia, uric acid), cardiovascular damage (left ventricular hypertrophy, carotid intima media thickening) and cardiovascular events were also investigated. Results: Genotype distribution (AA 74%, AG 23%, GG 3%) resulted in Hardy-Weinberg equilibrium; G-allele frequency (0.14) was slightly lower than in previous reports. At univariate analysis there was a trend toward slightly higher BP values in G-allele carriers both at CLIN and ABPM measurements and at BAS and FU evaluations. The same was found when hypertension was considered as a dichotomic variable and when treated subjects were excluded from the analysis. After adjustment for age, sex and BMI, the presence of at least one copy of the G-allele was weakly associated with hypertension at FU evaluation (OR 1.69, 95%CI 1.00–2.87, p = 0.05). No significant association of rs13333226 with the other phenotypes examined was detected. Conclusion: Despite careful genotyping and BP phenotyping, we were not able to replicate, in this sample of general population, the previously described association of UMOD SNP rs13333226 G-allele with lower BP values and we found, if any, an opposite trend

Revised sequence of the alpha 1B adrenergic receptor promoter region.

GenBank sequence AY53019