Aortic pulse wave velocity in children with Cushing syndrome: A window into a marker of early cardiovascular disease.

ObjectiveTo investigate early signs of cardiovascular arterial remodelling in paediatric patients with Cushing syndrome (CS) in comparison with normative values from healthy children.Study designThe metrics used to assess cardiac health were from thoracic aorta and carotid MRI. Scans were performed on 18 children with CS (mean: 12.5 ± 3.1 years, range: 6.0-16.8 years, 10 female). Pulse wave velocity (PWV), aortic distensibility (AD) and carotid intima-media thickness (cIMT), well-validated measurements of cardiac compromise, were measured from the images and compared to normative age-matched values where available.ResultsPatients with CS had significantly higher PWV compared to age-adjusted normal median control values (4.0 ± 0.7 m/s vs. 3.4 ± 0.2 m/s, respectively, P = 0.0115). PWV was positively correlated with midnight plasma cortisol (r = 0.56, P = 0.02). Internal and common cIMT were negatively correlated with ascending AD (r = -0.75, P = 0.0022, r = -0.69, P = 0.0068, respectively).ConclusionPulse wave velocity data indicate that paediatric patients with CS have early evidence of cardiovascular remodelling. The results suggest the opportunity for monitoring as these changes begin in childhood

Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene.

UnlabelledAutosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4-5.1 mmol/l), aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia.Learning pointsPHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment

Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks.

BackgroundCardiovascular (CV) complications are the most significant cause of mortality in adults with Cushing disease (CD); little is known about CV risk factors in children with CD. Measurement of lipoprotein particles by nuclear magnetic resonance (NMR) spectroscopy is a novel technology to assess CV risk. The objective of the current study is to analyze the NMR lipid profile in pediatric CD patients before and 1 year after remission.MethodsNMR lipid profile was obtained via the Vantera NMR analyzer, using frozen serum samples from 33 CD patients (mean age 13.8 ± 4.0 years) evaluated between 1997 and 2017 at the National Institutes of Health (NIH) Clinical Center (CC).ResultsGlycA (glycosylated acute-phase proteins), triglyceride-rich particles (TRLP medium and very small sizes), low-density lipoprotein (LDL) particles (LDLP total and large size), high-density lipoprotein (HDL) particles (HDLP total, medium and small sizes), total cholesterol, LDL-cholesterol, HDL-cholesterol, GlycA inflammatory biomarker, and apolipoprotein B and apolipoprotein A1 (ApoA1) concentrations showed statistically significant changes after remission of CD (p < 0.05).ConclusionIn our study population, most of the lipid variables improved post-CD remission, with the exception of HDL and ApoA1, indicating that NMR lipoprotein profile may be a helpful tool in assessing the CV risk in pediatric patients with CD

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children

Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children

Glucocorticoids are widely used for immunosuppression in autoimmune diseases. After the resolution of hypercortisolemia, the immune system recovers allowing for autoimmune diseases to manifest. Here we investigated the presence of autoimmune and related diseases that developed after cure of endogenous Cushing syndrome (CS) in children. We identified 129 children who were diagnosed and successfully treated for endogenous CS at the National Institutes of Health from 1997 until 2017, and who were followed for at least 6 months after treatment. We performed a retrospective chart review analysis to identify the presence of autoimmune or related diseases after cure. Ten children were diagnosed with a new autoimmune or related disorder after resolution of hypercortisolemia. This results in a frequency of 7.8% of our pediatric CS population. The identified patients had a shorter duration of hypercortisolemia prior to diagnosis, but did not otherwise differ from the remaining patients. The various identified diseases were: celiac disease (n=1), psoriasis (n=1), Hashimoto thyroiditis (n=1), Graves disease (n=1), optic neuritis (n=2), skin hypopigmented lesions/vitiligo (n=2), allergic rhinitis/asthma (n=1), and neuropathy responding to glucocorticoid treatment (n=1). The reported time between the treatment of CS and diagnosis of autoimmune disorder ranged from 6 to 19 months. The presence of autoimmune or related diseases might be masked by the hypercortisolemic state in endogenous CS. After resolution of hypercortisolemia, the presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise

Development of a Sensitive Microarray Immunoassay for the Quantitative Analysis of Neuropeptide Y

A direct competitive immunoassay in an antibody microarray format was developed for the sensitive detection of neuropeptide Y (NPY) and employed in the analysis of NPY in human sweat samples. This is the first demonstration that antibody microarray, as a powerful multiplex analysis tool, can be used for the sensitive determination of NPY and potentially other neuropeptides. 400 pg/mL of dibiotinylated NPY and 0.1 mg/mL spotting capture antibody were found to offer the best performance, yielding a sensitivity of 50 pg/mL and a linear dynamic range of 0.1–100 ng/mL for NPY. Evaluation of matrix effects by using artificial sweat revealed that dialysis is necessary for analyzing NPY in human sweat samples with microarray immunoassay. In a preliminary application, 50–210 pg/mL of NPY was detected in sweat samples collected with Macroduct collectors. This study indicates that antibody microarrays can be used for NPY analysis and that human sweat could be a valuable sample source for biomarker and proteomics studies, especially when noninvasive human sample collection is preferable

Circadian Plasma Cortisol Measurements Reflect Severity of Hypercortisolemia in Children with Different Etiologies of Endogenous Cushing Syndrome

BackgroundThe utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet.MethodsA retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated.ResultsPlasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them.ConclusionOur study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS

Obesity and the Diagnostic Accuracy for Primary Aldosteronism

The effects of body mass index on the diagnostic accuracy of primary aldosteronism (PA) are inconsistent and yet important considering the high prevalence and frequent co-occurrence of obesity and hypertension. The current study included 59 adult patients who underwent a stepwise evaluation for PA, using aldosterone to renin ratio for case detection and plasma aldosterone concentration after saline suppression test and/or 24-hour urinary aldosterone after oral sodium loading for case confirmation. Body mass index had a quadratic (U-shaped) correlation with plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, and plasma aldosterone concentration after saline suppression test. Among patients with a body mass index ≥30 kg/m2 , the aldosterone to renin ratio yielded lower case detection accuracy of PA. We conclude that obesity results in a nonlinear correlation with plasma aldosterone concentration, plasma renin activity, and aldosterone to renin ratio, which affects the accuracy of case detection for PA. Patients with a body mass index ≥30 kg/m2 are less accurately identified as having PA when saline suppression and/or oral salt loading tests are used for case confirmation