OBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela

OBJECTIVES: To evaluate the safety and long-term efficacy of computed tomography-guided percutaneous ethanol ablation for benign primary and secondary hyperfunctioning adrenal disorders. METHOD: We retrospectively evaluated the long-term results of nine patients treated with computed tomography-guided percutaneous ethanol ablation: eight subjects who presented with primary adrenal disorders, such as pheochromocytoma, primary macronodular adrenal hyperplasia and aldosterone-producing adenoma, and one subject with Cushing disease refractory to conventional treatment. Eleven sessions were performed for the nine patients. The patient data were reviewed for the clinical outcome and procedure-related complications over ten years. RESULTS: Patients with aldosterone-producing adenoma had clinical improvement: symptoms recurred in one case 96 months after ethanol ablation, and the other patient was still in remission 110 months later. All patients with pheochromocytoma had clinical improvement but were eventually submitted to surgery for complete remission. No significant clinical improvement was seen in patients with hypercortisolism due to primary macronodular adrenal hyperplasia or Cushing disease. Major complications were seen in five of the eleven procedures and included cardiovascular instability and myocardial infarction. Minor complications attributed to sedation were seen in two patients. CONCLUSION: Computed tomography-guided ethanol ablation does not appear to be suitable for the long-term treatment of hyperfunctioning adrenal disorders and is not without risks.

A ocorrência de carcinomas adrenocorticais metacrônicos é raramente relatada. Descrevemos o caso de uma criança portadora de tumor adrenocortical virilizante metacrônico que, apesar das inúmeras metástases, apresentou uma longa sobrevida (15 anos). Analisamos nesse tumor a expressão gênica de IGF2, IGF1R e FGFR4 e avaliamos a presença da mutação germinativa R337H no p53 e mutação somática no gene CTNNB1. O gene IGF2 foi hiperexpresso nos tumores adrenocorticais esquerdo (Weiss 5) e direito (Weiss 7). Os níveis de expressão de IGF1R foram maiores no tumor direito. Hiperexpressão do gene FGFR4 também foi observada no tumor adrenocortical direito. Esse paciente é portador da mutação germinativa R337H no p53, e perda de heterozigose (LOH) foi observada em ambos os tumores. Não foram encontradas mutações no gene CTNNB1 nos tumores. Em conclusão, demonstramos neste caso a hiperexpressão de vias moleculares de crescimento, que são mecanismos previamente relacionados à tumorigênese adrenocortical. Além disso, não encontramos mutações somáticas no gene CTNNB1, que é um marcador molecular de mau prognóstico em adultos e poderia estar relacionado à longa sobrevida desse paciente.

The occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient.

A tumorigênese adrenal é um fenômeno complexo, que envolve múltiplas alterações genéticas. Uma melhor compreensão dos mecanismos que levam ao desenvolvimento dos tumores adrenocorticais possibilitaria não só a identificação precoce dos casos de má evolução, mas também o desenvolvimento de novas estratégias terapêuticas. Embora nos últimos anos tenham surgido vários estudos sobre a tumorigênese adrenocortical, o processo permanece em grande parte desconhecido. A maior parte dos trabalhos disponíveis estudou apenas um ou poucos genes. Por se tratar de um fenômeno complexo, técnicas que avaliam múltiplos, como os microarrays, possivelmente possibilitarão o entendimento de aspectos que até o momento são desconhecidos. Nesta revisão, tentamos resumir de forma abrangente os principais trabalhos científicos produzidos nos últimos anos a respeito do processo de tumorigênese adrenocortical.

The adrenocortical tumorigenesis is a complex process, which involves multiple genetic changes. A better knowledge on the mechanisms involved in tumor development would enable an early identification of malignant disease and also lead to the development of new treatment strategies. Althought in the recent years a large amount of data was produced, the exact mechanisms that lead to adrenocortical tumor development remains poorly understood. Most of the studies produced were based on the candidate-gene strategy, which has its own limitations. A genome-wide approach, such as microarrays, will surely shed some light into the mechanisms responsible for adrenocortical tumorigenesis. In this review, we summarize the most recent data available on this complex process.