MARIA ADELAIDE ALBERGARIA PEREIRA
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
3 resultados
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- ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia(2014) ALENCAR, Guilherme Asmar; LERARIO, Antonio Marcondes; NISHI, Mirian Yumie; MARIANI, Beatriz Marinho de Paula; ALMEIDA, Madson Queiroz; TREMBLAY, Johanne; HAMET, Pavel; BOURDEAU, Isabelle; ZERBINI, Maria Claudia Nogueira; PEREIRA, Maria Adelaide Albergaria; GOMES, Gilberto Carlos; ROCHA, Manoel de Souza; CHAMBO, Jose Luis; LACROIX, Andre; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresContext: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. Objective: The aim of the present study was to identify the gene responsible for familial PMAH. Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.
conferenceObject Inherited Autosomal Dominant Mutations in ARMC5 Gene a Frequent Cause of Primary Macronodular Adrenal Hyperplasia(2014) ALENCAR, Guilherme Asmar; LERARIO, Antonio M.; NISHI, Mirian Yumie; MARIANI, Beatriz M. P.; ALMEIDA, Madson Q.; TREMBLAY, Johanne; HAMET, Pavel; BOURDEAU, Isabelle; ZERBINI, Maria Claudia N.; PEREIRA, Maria Adelaide Albergaria; GOMES, Gilberto Carlos; ROCHA, Manoel Souza; CHAMBO, Jose Luiz; LACROIX, Andre; MENDONCA, Berenice B.; FRAGOSO, Maria Candida Barisson Villares- Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors(2018) KRAUSS, Tobias; FERRARA, Alfonso Massimiliano; LINKS, Thera P.; WELLNER, Ulrich; BANCOSS, Irina; KVACHENYUK, Andrey; HERAS, Karim Villar Gomez de las; YUKINA, Marina Y.; PETROV, Roman; BULLIVANT, Garrett; DUECKER, Laura von; JADHAV, Swati; PLOECKINGER, Ursula; WELIN, Staffan; SCHALIN-JANTTI, Camilla; GIMM, Oliver; PFEIFER, Marija; NGEOW, Joanne; HASSE-LAZAR, Kornelia; SANSO, Gabriela; QI, Xiaoping; UGURLU, M. Umit; DIAZ, Rene E.; WOHLLK, Nelson; PECZKOWSKA, Mariola; ABERLE, Jens; JR, Delmar M. Lourenco; PEREIRA, Maria A. A.; V, Maria C. B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.; VIOLANTE, Alice H. D.; OUIDUTE, Ana R. P.; ZHANG, Zhewei; RECASENS, Monica; DIAZ, Luis Robles; KUNAVISARUT, Tada; WANNACHALEE, Taweesak; SIRINVARAVONG, Sirinart; JONASCH, Eric; GROZINSKY-GLASBERG, Simona; FRAENKEL, Merav; BELTSEVICH, Dmitry; I, Viacheslav Egorov; BAUSCH, Dirk; SCHOTT, Matthias; TILING, Nikolaus; PENNELLI, Gianmaria; ZSCHIEDRICH, Stefan; DAERR, Roland; RUF, Juri; DENECKE, Timm; LINK, Karl-Heinrich; ZOVATO, Stefania; DOBSCHUETZ, Ernst von; YAREMCHUK, Svetlana; AMTHAUER, Holger; MAKAY, Ozer; PATOCS, Attila; WALZ, Martin K.; HUBER, Tobias B.; SEUFERT, Jochen; HELLMAN, Per; EKATERINA, Raymond H.; KUCHINSKAYA, Ekaterina; SCHIAVI, Francesca; MALINOC, Angelica; REISCH, Nicole; JARZAB, Barbara; BARONTINI, Marta; JANUSZEWICZ, Andrzej; SHAH, Nalini; YOUNG JR., William F.; OPOCHER, Giuseppe; ENG, Charis; NEUMANN, Hartmut P. H.; BAUSCH, BirkePancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were >= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off >= 2.8 cm, 44% and 91% for TVDT cut-off of <= 24 months). In 117 of 273 patients, PanNETs > 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs < 2.8 cm vs >= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.