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Background: Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations., Methods: Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs., Results: If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression <40%) were applied, a sensitivity of 88% (CI, 61%-98%) and a specificity of 97% (CI, 90%-100%) were observed. An improved cutoff for plasma NMN 180 minutes after clonidine was established at 80% of the age-related upper limit of normal, resulting in a sensitivity of 94% and a specificity of 97%. False-negative CST results occurred in 2 patients with small PPGL., Conclusions: This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity.

Objective: Hypertension and symptoms of catecholamine excess are features of pheochromocytomas and paragangliomas (PPGLs). This prospective observational cohort study assessed whether differences in presenting features in patients tested for PPGLs might assist establishing likelihood of disease., Design and Methods: Patients were tested for PPGLs because of signs and symptoms, an incidental mass on imaging or routine surveillance due to previous history or hereditary risk. Patients with (n = 245) compared to without (n = 1820) PPGLs were identified on follow-up. Differences in presenting features were then examined to assess the probability of disease and relationships to catecholamine excess., Results: Hyperhidrosis, palpitations, pallor, tremor and nausea were 30-90% more prevalent (P < 0.001) among patients with than without PPGLs, whereas headache, flushing and other symptoms showed little or no differences. Although heart rates were higher (P < 0.0001) in patients with than without PPGLs, blood pressures were not higher and were positively correlated to BMI, which was lower (P < 0.0001) in patients with than without PPGLs. From these differences in clinical features, a score system was established that indicated a 5.8-fold higher probability of PPGLs in patients with high than low scores. Higher scores among patients with PPGLs were associated, independently of tumor size, with higher biochemical indices of catecholamine excess., Conclusions: This study identifies a complex of five signs and symptoms combined with lower BMI and elevated heart rate as key features in patients with PPGLs. Prevalences of these features, which reflect variable tumoral catecholamine production, may be used to triage patients according to likelihood of disease.

Objective: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1)., Design: We performed genetic analysis of known tumor predisposition genes, including NF1 , using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced., Methods: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing., Results: Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified., Conclusions: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients., (© 2018 European Society of Endocrinology.)

Pheochromocytomas in pregnancy are rare but potentially lethal. Even rarer is the combination of pheochromocytoma in pregnancy with subsequent development of ectopic Cushing's syndrome. We report a 36-year-old woman, previously diagnosed with essential hypertension, who developed severe hypertension in pregnancy complicated by insulin-dependent gestational diabetes. A cesarean section was performed at 32 weeks following a hypertensive crisis after routine administration of betamethasone. Postnatal persistence of signs and symptoms of catecholamine excess led to the diagnosis of a left adrenal pheochromocytoma. Between diagnosis and planned tumor removal, the patient developed signs and symptoms of Cushing's syndrome (facial edema and hirsutism, myopathy and fatigue). Biochemical testing confirmed hypercortisolism with extremely elevated levels of plasma adrenocorticotropin, urinary cortisol and multiple steroids of a plasma panel that were all normal at previous testing. The previously noradrenergic tumor also started producing epinephrine. Histopathological examination confirmed the pheochromocytoma, which was also immunohistochemically positive for adrenocorticotropin. Full post-surgical recovery was sustained with normal blood pressure and biochemical findings after one year. This report not only underlines the chameleon behavior of pheochromocytoma but also illustrates its potential for a metamorphosing presentation. Corticosteroid administration in pregnancy requires a cautious approach in patients with hypertension.

Context: Most patients with adrenal incidentaloma have nonfunctional lesions that do not require treatment, while others have functional or malignant tumors that require intervention. The plasma steroid metabolome may be useful to assess therapeutic need. Objective: This work aimed to establish the utility of plasma steroid profiling combined with metanephrines and adrenal tumor size for the differential diagnosis of patients with adrenal incidentaloma. Methods: This retrospective cross-sectional study, which took place at 7 European tertiarycare centers, comprised 577 patients with adrenal incidentaloma, including 19, 77, 65, 104 and 312 respective patients with adrenocortical carcinoma (ACC), pheochromocytoma (PHEO), primary aldosteronism (PA), autonomous cortisol secretion (ACS), and nonfunctional adrenal incidentaloma (NFAI). Mesaures of diagnostic performance were assessed (with [95% CIs]) for discriminating different subgroups of patients with adrenal incidentaloma. Results: Patients with ACC were characterized by elevated plasma concentrations of 11-deoxycortisol, 11-deoxycorticosterone, 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone-sulfate, whereas patients with PA had elevations of aldosterone, 18-oxocortisol, and 18-hydroxycortisol. A selection of those 8 steroids, combined with 3 others (cortisol, corticosterone, and dehydroepiandrosterone) and plasma metanephrines, proved optimal for identifying patients with ACC, PA, and PHEO at respective sensitivities of 83.3% (66.1%-100%), 90.8% (83.7%-97.8%), and 94.8% (89.8%-99.8%); and specificities of 98.0% (96.9%-99.2%), 92.0% (89.6%-94.3%), and 98.6% (97.6%-99.6%). With the addition of tumor size, discrimination improved further, particularly for ACC (100% [100%-100%] sensitivity, 99.5% [98.9%-100%] specificity). In contrast, discrimination of ACS and NFAI remained suboptimal (70%-71% sensitivity, 89%-90% specificity). Conclusion: Among patients with adrenal incidentaloma, the combination of plasma steroid metabolomics with routinely available plasma free metanephrines and data from imaging studies may facilitate the identification of almost all clinically relevant adrenal tumors. [ABSTRACT FROM AUTHOR]

Abstract Background Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites. Graphical abstract Unlabelled Image Highlights • LC-MS/MS plasma and urinary catecholamine metabolite measurements in 590 subjects. • Reference intervals optimized using publically available data for 2,056 patients. • Age-specific upper cut-offs are important for plasma free normetanephrine. • Sex is the most practical variable to consider for cut-offs for urinary metabolites. • Presence or absence of hypertension is of lesser importance for reference intervals. [ABSTRACT FROM AUTHOR]