Fungal infections can affect the adrenal glands, causing primary adrenal insufficiency (PAI). Although endemic to South America, paracoccidioidomycosis (PCM), which can lead to PAI, has gained global ...relevance with the increase in international travel and migration.
The present report describes 3 patients with PAI caused by PCM.
Patients in cases 1 and 2 both reported indisposition, asthenia, nausea, hyperpigmentation of the skin, hypotension, and weight loss. Complementary exams confirmed PAI due to PCM. Case 1 was serologically diagnosed. In contrast, the definitive diagnosis of case 2 was only reached by computed tomography (CT)-guided adrenal biopsy after negative serologies for PCM. Case 3, with diabetes mellitus, had a history of asthenia, nausea and weight loss after persistent sinusitis. Initially, serologic results were negative for PCM and the patient's CT-guided biopsy resulted in insufficient tissue to obtain a definitive diagnosis. Contrary to the initial hypothesis of invasive aspergillosis, since the only etiological evidence for the patient's clinical condition were positive serologies for Aspergillus fumigatus, histopathologic examination of the specimen provided by a left adrenalectomy finally confirmed PCM as the etiology for PAI in this case as well.
The 3 cases illustrate the necessity to investigate PAI whenever there are suspicious clinical findings. They also show that fungal infections should be considered among the diagnostic hypotheses during the etiological investigation of PAI. Finally, they teach us that definitive diagnosis of PCM may require direct visualization of the pathogen.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introdução: O hiperaldosteronismo primário (HP) é a causa mais comum de hipertensão arterial sistêmica (HAS) secundária, com prevalência de até 21% em pacientes com HAS resistente. Na última década, ...foram feitos consideráveis avanços na compreensão da patogênese do HP. Variantes patogênicas somáticas nos genes de canais iônicos KCNJ5, CACNA1D, ATP1A1 e ATP2B3, envolvidos na manutenção da homeostase iônica intracelular, foram descritas em 38%, 9,3%, 5,3% e 1,7% dos tumores, respectivamente. Variantes patogênicas somáticas no gene CTNNB1, fundamental para o desenvolvimento do córtex da suprarrenal, foram também identificadas em aproximadamente 5% dos aldosteronomas. Mais recentemente, uma variante germinativa no gene CACNA1H, que codifica a subunidade Alfa1H do canal de cálcio Cav 3.2, foi identificada em um paciente com aldosteronoma. Objetivos: O objetivo geral desse projeto foi investigar as bases genéticas do HP causado por aldosteronoma. Os objetivos específicos foram: 1) Investigar variantes patogênicas somáticas nos genes KCNJ5, ATP1A1, ATP2B3 e CTNNB1 em aldosteronomas de indivíduos com HP; 2) Sequenciar o exoma (pareado sangue e tumor) dos casos de HP causados por aldosteronoma, negativos para variantes nos genes citados acima; 3) Correlacionar o genótipo com os parâmetros clínicos e hormonais dos pacientes com aldosteronomas. Métodos: As regiões hot-spot dos genes KCNJ5, ATP1A1, ATP2B3 e CTNNB1 foram sequenciadas por Sanger em 62 tumores 56% mulheres; mediana de idade ao diagnóstico 50 anos (variação, 20 a 68). Pacientes sem variantes patogênicas somáticas nos genes descritos acima foram submetidos a genotipagem do exoma (pareado sangue e tecido) por sequenciamento paralelo em larga escala (HiSeq 2500, Illumina). Variantes germinativas raras (MAF < 0,01% no 1000 genomes, ExAC, gnomAD e AbraOM) em genes codificadores de canais iônicos ou associados a hiperplasia adrenal foram selecionadas para segregação familial. Resultados: Variantes patogênicas somáticas em heterozigose foram encontradas em 34 de 62 (54,8%) aldosteronomas. As variantes identificadas nos genes KCNJ5, ATP1A1, ATP2B3 e CTNNB1 eram previamente conhecidas. Variantes patogênicas no KCNJ5 foram detectadas em 28 de 62 (45,2%) aldosteronomas. Duas variantes recorrentes foram encontradas: p.Gly151Arg em 13 de 28 (46%) e p.Leu168Arg em 14 de 28 (50%) tumores. A variante patogênica p.Glu145Gln do KCNJ5 foi identificada em um (4%) aldosteronoma. Adicionalmente, a variante patogênica p.Leu104Arg do ATP1A1 foi detectada em 2 (3,2%) aldosteronomas; a variante patogênica p.Leu425_Val426del do ATP2B3 em um (1,6%) caso e a variante patogênica p.Ser45Pro do CTNNB1 em 2 (3,2%) aldosteronomas. Uma nova variante p.Leu276Pro somática em heterozigose no CACNA1D foi identificada em um aldosteronoma no exoma e classificada como provavelmente patogênica. Aldosteronomas com variantes patogênicas no KCNJ5 foram diagnosticados mais frequentemente em mulheres (p= 0,047) e em idades mais jovens (p= 0,002) quando comparado com tumores sem variantes no KCNJ5. O tamanho do nódulo foi maior em aldosteronomas com variantes patogênicas no KCNJ5 (p= 0,0001). O percentual de pacientes com tempo de HAS < 5 anos foi similar nos dois grupos. A remissão pós-operatória da HAS foi observada em 50% dos pacientes com tumor contendo variante patogênica no KCNJ5, enquanto apenas 15% dos pacientes com tumor sem variante no KCNJ5 tiveram remissão da HAS (p= 0,003). Na análise multivariada, somente a presença de variante patogênica somática no KCNJ5 foi um preditor independente de remissão da HAS (p= 0,03). Após filtragem das variantes encontradas no sequenciamento exômico, quatro variantes germinativas missense em heterozigose foram consideradas deletérias em mais de 3 algoritmos de predição in silico: 1) uma nova variante (p.Pro559Thr) no gene CACNA1H, já associado ao fenótipo de HP; 2) a variante p.Arg178Cys no gene CACNA1I, que codifica a subunidade Alfa 1I do canal Cav 3.3; 3) a variante p.Glu52Ala no gene ATP13A3, que codifica uma proteína transmembrana da família de proteínas ATPase do tipo P; 4) a variante p.Tyr507Ser no gene KCNC4, que codifica o canal de potássio Kv 3.4. Conclusão: Foi caracterizado o espectro de variantes patogênicas somáticas em uma coorte brasileira de tumores corticais adrenais produtores de aldosterona, bem como o impacto das variantes no KCNJ5 na predição de remissão da HAS após adrenalectomia. Além disso, foram identificados novos genes candidatos provavelmente relacionados a patogênese do HP causado por aldosteronomas
Introduction: Primary aldosteronism (PA) is the most common form of secondary hypertension (HT), with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in 38%, 9.3%, 5.3% and 1.7% of aldosterone-producing adenomas (APAs), respectively. All these mutations lead to the activation of calcium signaling, the major trigger for aldosterone production. Additionally, somatic activating mutations in exon 3 of CTNNB1 gene, which is involved in the adrenocortical development, were identified in approximately 5% of APAs. More recently, the germline p.V1951G CACNA1H variant was described in a PA patient with an APA. Aims: To investigate the genetics of APAs. The specific aims of this study were: 1) To investigate somatic variants in KCNJ5, ATP1A1, ATP2B3 and CTNNB1 genes in APAs from PA patients; 2) To perform exome sequencing of PA patients caused by APAs without mutations in those genes already associated with PA; 3) To correlate genetic findings and clinical parameters. Methods: Hot-spot regions of KCNJ5, ATP1A1, ATP2B3 e CTNNB1 genes were sequenced by Sanger in 62 APAs 56% women; median of age at diagnosis 50 yrs (range, 20 to 68). We performed whole exome sequencing (HiSeq 2500, Illumina) in paired blood and tumor DNA samples from 10 unrelated subjects with PA caused by APAs without somatic mutations in hot-spot regions of KCNJ5, ATP1A1, ATP2B3 and CTNNB1.We searched for rare germline coding variants (MAF < 0.01% in 1000 genomes, ExAC, gnomAD and AbraOM) in ionchannel genes, which are expressed in normal adrenal tissue, or in genes previously related to adrenal hyperplasia. Results: Pathogenic somatic heterozygous variants were identified in 34 out of 62 (54.8%) APAs. KCNJ5 pathogenic variants were detected in 28 out of 62 (45.2%) APAs. Two recurrent variants were found in KCNJ5: the p.Gly151Arg in 13 out of 28 (46%) and the p.Leu168Arg in 14 out of 28 (50%) APAs. KCNJ5 pathogenic variant p.Glu145Gln was identified in one (4%) APA. In addition, the p.Leu104Arg ATP1A1 mutation was detected in two APAs (3.2%); the p.Leu425_Val426del ATP2B3 mutation in one APA (1.6%); and the p.Ser45Pro CTNNB1 mutation in two APAs (3.2%). The novel CACNA1D somatic heterozygous variant p.Leu276Pro (likely pathogenic) was identified by exome sequencing in one APA. APAs with KCNJ5 pathogenic variants were diagnosed more often in women (p= 0.047) and at younger ages (p= 0.002) when compared to APAs without KCNJ5 variants. Nodule size was larger in APAs with KCNJ5 pathogenic variants (p= 0.0001). The frequency of PA patients com HT duration < 5 yrs was similar in both groups. HT remission was observed in 50% of patients with APAs harboring KCNJ5 pathogenic variants, whereas only 15% of patients with APAs without KCNJ5 pathogenic variants had HT remission (p= 0.003). In multivariate analysis, only the presence of a KCNJ5 pathogenic variant was an independent predictor of HT remission (p= 0.03). After exome sequencing analysis, four germline missense heterozygous variants predicted to be pathogenic in >=3 in silico tools were selected: 1) the novel p.Pro559Thr variant in CACNA1H gene, previously associated with PA phenotype; 2) the p.Arg178Cys variant in CACNA1I gene, which encodes the Alpha 1I subunit of Cav 3.3 channel; 3) the p.Glu52Ala variant in ATP13A3 gene, which is a member of the P-type ATPase family of membrane transport proteins; and 4) the p.Tyr507Ser variant in KCNC4 gene, which encodes the voltage-gated potassium channel Kv 3.4. Conclusion: We have characterized the spectrum of somatic pathogenic variants in a Brazilian cohort of APAs, and evaluated the impact of KCNJ5 somatic pathogenic variants in predicting HT remission after adrenalectomy. In addition, we identified potential novel gene candidates in the pathogenesis of PA caused by APAs
Abstract
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 <1 was defined as contralateral suppression (CS). In patients with unsuccessful AV catheterization (mostly right AV) or undetermined LI (3-4), CS was used to indicate adrenalectomy. The biochemical cure of PA after adrenalectomy was defined as the gold standard parameter to confirm unilateral disease. Successful bilateral AV catheterization was achieved in 75% of the cases. After 2015, the use of intra-procedural rapid cortisol assay improved angiographer experience and increased AVS successful rate from 52 to 80%. LI revealed unilateral and bilateral aldosterone excess in 68 and 32% of the cases, respectively. A LI ≥4 had a sensitivity of 100% and specificity of 98% to define unilateral PA among patients with successful catheterization. In addition, RASI in the non-dominant AV was significantly lower in unilateral PA according the LI when compared to bilateral cases 0.12 (0.03 to 1.18) vs. 1.1 (0.04 to 4.56), p= 0.0001. RASI in the non-dominant AV was inversely correlated with LI (r= -0.81, p= 0.0001). A CS index ≤0.5 had a high sensitivity (90%) and specificity (94%) to define unilateral aldosterone excess. In conclusion, the LI is the most valuable parameter in AVS for PA subtyping. Additionally, CS (cut-off of 0.5) is very useful to define lateralization and can be used in cases of borderline LI or unsuccessful AV catheterization.CAPES Grant to Freitas TC.
OBJECTIVEFungal infections can affect the adrenal glands, causing primary adrenal insufficiency (PAI). Although endemic to South America, paracoccidioidomycosis (PCM), which can lead to PAI, has ...gained global relevance with the increase in international travel and migration. METHODSThe present report describes 3 patients with PAI caused by PCM. RESULTSPatients in cases 1 and 2 both reported indisposition, asthenia, nausea, hyperpigmentation of the skin, hypotension, and weight loss. Complementary exams confirmed PAI due to PCM. Case 1 was serologically diagnosed. In contrast, the definitive diagnosis of case 2 was only reached by computed tomography (CT)-guided adrenal biopsy after negative serologies for PCM. Case 3, with diabetes mellitus, had a history of asthenia, nausea and weight loss after persistent sinusitis. Initially, serologic results were negative for PCM and the patient's CT-guided biopsy resulted in insufficient tissue to obtain a definitive diagnosis. Contrary to the initial hypothesis of invasive aspergillosis, since the only etiological evidence for the patient's clinical condition were positive serologies for Aspergillus fumigatus, histopathologic examination of the specimen provided by a left adrenalectomy finally confirmed PCM as the etiology for PAI in this case as well. CONCLUSIONThe 3 cases illustrate the necessity to investigate PAI whenever there are suspicious clinical findings. They also show that fungal infections should be considered among the diagnostic hypotheses during the etiological investigation of PAI. Finally, they teach us that definitive diagnosis of PCM may require direct visualization of the pathogen.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP