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Background Pheochromocytomas and paragangliomas (PPGLs) have the highest degree of heritability among endocrine tumors. Currently, ∼40% of PPGL individuals have a genetic germline pathogenic variant and exist at least 12 different genetic syndromes related to these tumors. Pathogenic variants in the Succinate Dehydrogenase Complex Subunit B (SDHB) gene account for about 10% of PPGL cases. Moreover, SDHB pathogenic variants are the most well-established risk factor to predict metastatic disease (40%-50% of cases). Germline SDHB large deletions are very rare worldwide, but SDHB exon 1 deletion has been reported in patients with PPGLs from Portugal and Spain. Indeed, a putative founder effect for SDHB exon 1 deletion was suggested in PPGL patients from Iberian Peninsula. Aim To investigate a putative founder effect for SDHB exon 1 deletion. Methods Eighteen unrelated Brazilian patients with germline heterozygous SDHB pathogenic variants were included. Additionally, two unrelated individuals with SDHB exon 1 complete deletion from Argentina were studied. SDHB pathogenic variants were investigated by automated SAGER sequencing, multiplex ligation-dependent probe amplification (SALSA MLPA Probemix P226 SDH) and/or high-throughput sequencing. Five SDHB flanking microsatellite markers at chromosome 1p (D1S2697, GATA29A05, D1S2826, D1S2644, and D1S199) were used to investigate if patients carrying this deletion have a common origin. Haplotypes were reconstructed using the PHASE algorithm (v. 2.1). A control group comprising 26 unrelated Brazilian individuals was also studied. Results Among 18 Brazilian patients with germline SDHB pathogenic variants, heterozygous SDHB exon 1 complete deletion was identified in 6 of them (33% of the cases). The remaining 12 patients presented intragenic SDHB pathogenic variants without hotspot location. All Brazilian index patients with SDHB exon 1 deletion presented with paraganglioma, located mostly in the abdomen (4 abdominal; one thoracic; two head and neck and one colonic). Median age was 31.5 years and metastatic disease occurred in 3 (50%) of them. Haplotype analysis showed that 4 apparently unrelated Brazilian patients (4 out of 6 cases, 67%) shared a common allele (SDHB-GATA29A05-D1S2826-D1S2644-D1S199 | SDHB-186-130-213-102), which was not seen in chromosomes without the SDHB exon 1 deletion (p= 0.01). The two cases from Argentina did not have this haplotype, suggesting that SDHB exon 1 deletion in Argentina have a different origin. Conclusion SDHB exon 1 complete deletion was the most frequent SDHB defect in our cohort. Our findings indicate a founder effect for SDHB exon 1 complete deletion in Brazilian patients with paraganglioma. Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6 Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes include bilateral hyperplasia and unilateral PA, typically aldosterone-producing adenomas. Adrenal venous (AV) sampling (AVS) is a key step to define PA subtype and guide PA management. According current PA guidelines, most PA patients should undergo AVS, which is a challenging procedure, especially in terms of successfully cannulating the right AV. The aim of this study was to report a single tertiary center experience with AVS in PA patients. We retrospectively evaluated 84 AVS from 1984 to 2019. Sequential AVS was performed by an experienced interventional radiologist. AV and inferior vena cava (IVC) samples were obtained under cosyntropin continuous infusion. Successful catheterization was defined by a selectivity index [SI= AV/IVC cortisol (C) concentrations] ≥5. Unilateral disease was defined by a lateralization index [LI= aldosterone (A)/C ratio in the dominant AV divided by A/C in the non-dominant AV] ≥4. The relative aldosterone secretion index (RASI= A/C ratio in AV divided by A/C in IVC) was calculated in each side. A RASI

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin cells. At least 30% of PPGL patients have hereditary predisposition. PPGLs in children are more often hereditary, multiple and extra-adrenal. To date, more than 14 tumor-susceptibility genes have been reported: Cluster 1 or hypoxic (VHL, SDHB, SDHD, SDHC, SDHA, SDHAF2, FH, ENGL1 and HIF2A) and cluster 2 (RET, NF1, TMEM127 and MAX). The aim of this study was to evaluate clinical and molecular aspects of a Brazilian cohort of pediatric patients with PPGLs. Out of 262 patients with PPGLs, 26 (9 %) were diagnosed before 19 yrs of age (16 males and 10 females), with a median age of 14.5 yrs (range, 4 to 18). Genetic investigation was performed in 19 patients: 14 by automated Sanger sequencing (VHL, SDHB, SDHD and RET genes) and 5 by a custom next-generation sequencing (NGS) panel including all genes previously associated with germline mutations in PPGLs. Median tumor size was 5.5 cm (1.7 to 16). Pheochromocytomas (PHEOs), paragangliomas (PGLs) or both were diagnosed in 46%, 31% and 23% of the patients, respectively. Bilateral PHEOs were diagnosed in 61% of the cases, most of them asynchronous (75%). Genetic diagnosis was confirmed in 14 out of 19 (74%) patients and all variants were found in heterozygous state: 8 VHL missense mutations from 6 kindreds (p.R167W in 2 kindreds, p.R167Q in one and p.G114S in 3); 3 SDHB mutations (p.C98Y, c.201-2A>G and p.L180L); 2 SDHD mutations (p.Y144_H145del and p.Q121*); and one RET mutation (p.C634R). All 8 VHL patients had bilateral PHEOs and 3 of them had also abdominal PGLs. All patients with SDHB mutations had abdominal PGLs. Two patients with SDHD mutation had head and neck paraganglioma (one of them had unilateral PHEO). Genetic investigation by NGS Panel was negative in all 5 cases: 2 malignant PPGLs (one PHEO and one PGL) and 3 PHEOs. Four out of 26 (15%) pediatric PPGLs were malignant: 2 with SDHB mutation and 2 with negative screening (one PHEO and one PGL). In conclusion, the majority of pediatric PPGLs (74%) were hereditary and almost exclusively caused by mutations in hypoxic genes. VHL (PHEOs) and SDHB (only PGLs) were the most frequent affected genes in this cohort of pediatric PPGLs. Support: CAPES grant to Petenuci J.

Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). PA subtypes include aldosterone-producing adenomas (APA) and bilateral adrenal hyperplasia. To date, few PA patients with bilateral adenomas have been reported, but only one case was well characterized by anatomopathological analysis and clinical outcome after adrenal sparing surgery (1). Clinical case: A 53-year-old woman was referred to investigate resistant HT and hypokalemia. (3.0 mEq/L). PA screening revealed aldosterone (A) of 37.9 ng/dL, renin (R) < 1.6 (4.4-46.1 mUI/L), A/R ratio of 24.8. Confirmatory testing confirmed PA diagnosis: seated saline infusion test (A= 83.3 ng/dL) and intravenous furosemide test (R= 3.1 mUI/L; positive test Conclusion: We herein described a very rare case of PA caused by bilateral-producing adenomas, confirmed by AVS and CYP11B2 staining after adrenal sparing surgery.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. The 2016 Endocrine Society’s Guideline for PA management recommend that patients with a positive screening undergo one or more confirmatory tests to definitively confirm or exclude the diagnosis. Confirmatory testing procedures include oral sodium loading, saline infusion test (SIT), fludrocortisone suppression, captopril test (CT) and furosemide upright test (FUT). The FUT, mainly proposed by the Japan Endocrine Society, does not have limitation in patients with severe uncontrolled hypertension and heart failure. A positive FUT is defined as a plasma renin activity (PRA)

Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT) with an estimated prevalence of 10% in referred populations and 15–20% in patients with resistant HT. Aldosterone-producing adenomas are the most common cause of unilateral PA. Primary unilateral adrenal hyperplasia (PUH) is a rare cause of PA, but is probably underestimated. PUH can be diffuse or nodular, with poorly capsulated micronodules. To date, there is a paucity of data characterizing this condition. In this study, our aim was to report the clinical and imaging features of patients with PA caused by PUH. We retrospectively evaluated clinical, imaging and histopathological data of 183 PA patients. PUH was diagnosed in 9 out of 183 patients (5%). All patients had biochemical cure of PA after unilateral adrenalectomy and anatomopathological analysis showed micronodular adrenal hyperplasia in all cases. At the diagnosis, median age was 52 yrs, ranging from 33 and 74 yrs (6 men and 3 women). Hypokalemia was reported in 63% of the cases. Aldosterone/plasmatic renin activity ratio was 123.6 (range, 52 to 379). The median duration of HT was 18 yrs (range, 1 to 52). Because of HT duration before diagnosis, only a patient had HT cure after adrenalectomy. The median follow-up was 46 months (7 to 117 months). Computed tomography (CT) accuracy to determine the lateralization was 67%. The adrenal CT findings were: normal adrenals (n= 1), bilateral hyperplasia (n= 1; right incidentaloma 1.9 cm and left PUH 1.4 cm), unilateral hyperplasia (n= 1), bilateral nodules (n= 1) and unilateral nodules (n= 5; median 1.3 cm, from 0.9 to 1.5). Adrenal venous sampling was performed in 5 patients (successful rate 80%). In the remaining cases, surgery was guided by CT. PUH was in the left adrenal in 7 out of 9 cases (78%). Hot spot somatic mutations in aldosterone-driver genes (KCNJ5, ATP1A1, ATP2B3 and CTNNB1) were excluded by Sanger automated sequencing and the presence of chimeric CYP11B1/CYP11B2 gene was ruled out by long-PCR in all cases. In conclusion, PUH prevalence in our cohort was higher than previously reported. PUH was more frequent in men and in the left adrenal. The most common CT finding was a unilateral nodule smaller than 1.5 cm. However, CT accuracy was low and AVS should be the gold standard to define lateralization. Support: CNPq (403256/2016-0) to MQA; FAPESP (2017/13394-8) to MRC.

ContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure ObjectiveTo determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.MethodsWe retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.ResultsKCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration ConclusionThe presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.