Publications by authors named "Elena Belyavskaya"

36 Publications

Liver findings in patients with Carney complex, germline PRKAR1A pathogenic variants, and link to cardiac myxomas.

Endocr Relat Cancer 2020 06;27(6):355-360

Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.
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http://dx.doi.org/10.1530/ERC-19-0517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486872PMC
June 2020

Computerized Analysis of Brain MRI Parameter Dynamics in Young Patients With Cushing Syndrome-A Case-Control Study.

J Clin Endocrinol Metab 2020 05;105(5)

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Background: Young patients with Cushing Syndrome (CS) may develop cognitive and behavioral alterations during disease course.

Methods: To investigate the effects of CS on the brain, we analyzed consecutive MRI scans of patients with (n = 29) versus without CS (n = 8). Multiple brain compartments were processed for total and gray/white matter (GM/WM) volumes and intensities, and cortical volume, thickness, and surface area. Dynamics (last/baseline scans ratio per parameter) were analyzed versus cortisol levels and CS status (persistent, resolved, and non-CS).

Results: Twenty-four-hour urinary free cortisol (24hUFC) measurements had inverse correlation with the intensity of subcortical GM structures and of the corpus callosum, and with the cerebral WM intensity. 24hUFC dynamics had negative correlation with volume dynamics of multiple cerebral and cerebellar structures. Patients with persistent CS had less of an increase in cortical thickness and WM intensity, and less of a decrease in WM volume compared with patients with resolution of CS. Patients with resolution of their CS had less of an increase in subcortical GM and cerebral WM volumes, but a greater increase in cortical thickness of frontal lobe versus controls.

Conclusion: Changes in WM/GM consistency, intensity, and homogeneity in patients with CS may correlate with CS clinical consequences better than volume dynamics alone.
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http://dx.doi.org/10.1210/clinem/dgz303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089850PMC
May 2020

Somatic Gene Mutation in a Nonsyndromic Metastatic Large Cell Calcifying Sertoli Cell Tumor.

J Endocr Soc 2019 Jul 10;3(7):1375-1382. Epub 2019 May 10.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1% of all testicular neoplasms. Almost 40% of patients with LCCSCTs will present in the context of an inherited tumor predisposition condition, such as Carney complex (CNC) or Peutz-Jeghers syndrome. We report the case of a 42-year-old man who had presented with a right testicular mass, and was diagnosed with metastatic LCCSCT. The patient underwent radical orchiectomy, achieving initial remission of his disease. However, lymph node and hepatic metastases were identified. He received chemotherapy without response, and he died of complications of his disease 4 years after the initial diagnosis. Genetic analysis of the tumor and a lymph node metastasis identified a somatic frameshift mutation in the gene (c.319delG, p.E107fs*22). The mutation was predicted to result in premature termination of the PRKAR1A protein and, thus, not be expressed at the protein level, consistent with other nonsense mutations. The patient was extensively screened for signs of CNC, but he had no stigmata of the complex. To the best of our knowledge, the present report is the first of a somatic mutation in the gene shown to be associated with a seemingly sporadic case of LCCSCT. Somatic mutations are rare in sporadic tumors, and it is unknown whether this mutation was causative of LCCSCT in our patient who did not have CNC, or contributed to the malignancy of the tumor, which might have been caused by additional mutations.
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http://dx.doi.org/10.1210/js.2019-00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608558PMC
July 2019

A novel mutation in the glucocorticoid receptor gene as a cause of severe glucocorticoid resistance complicated by hypertensive encephalopathy.

J Hypertens 2019 07;37(7):1475-1481

Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

Background: Glucocorticoid resistance syndrome (GRS) is caused by mutations of the glucocorticoid receptor (coded by the NR3C1 gene) and presents with signs of mineralocorticoid and/or androgen excess.

Patient: A female patient presented at the age of almost 3 years with hypertensive and hypoglycemic seizure. She was diagnosed with GRS and was treated with antihypertensive medications and dexamethasone. She was later found to have MRI findings of punctuate microinfarcts at the basal ganglia, left thalamus and pons, possibly associated with uncontrolled hypertension. Increase of the dexamethasone dose up to 14 mg/day resulted in sufficient control of her symptoms.

Results: Two mutations in the NR3C1 gene were identified: a novel mutation in exon 2 (p.E198X), and a previously described mutation in exon 8 (p.R714Q).

Conclusion: GRS may present with life-threatening complications; this is the first report of hypertensive encephalopathy in association with GRS. Successful management of patients might require high doses of dexamethasone to control blood pressure.
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http://dx.doi.org/10.1097/HJH.0000000000002048DOI Listing
July 2019

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

Pediatr Res 2019 09 21;86(3):375-381. Epub 2019 May 21.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, USA.

Background: Cardiovascular (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.

Methods: NMR 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).

Results: GlycA (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).

Conclusion: In 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.
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http://dx.doi.org/10.1038/s41390-019-0438-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702083PMC
September 2019

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

Endocrinol Diabetes Metab 2019 Apr 15;2(2):e00054. Epub 2019 Jan 15.

Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health Bethesda Maryland.

Objective: To investigate early signs of cardiovascular arterial remodelling in paediatric patients with Cushing syndrome (CS) in comparison with normative values from healthy children.

Study Design: The 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.

Results: Patients 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,  = 0.0115). PWV was positively correlated with midnight plasma cortisol ( = 0.56,  = 0.02). Internal and common cIMT were negatively correlated with ascending AD ( = -0.75,  = 0.0022,  = -0.69,  = 0.0068, respectively).

Conclusion: Pulse 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.
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http://dx.doi.org/10.1002/edm2.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458483PMC
April 2019

Optical Imaging Technology: A Useful Tool to Identify Remission in Cushing Disease After Surgery.

Horm Metab Res 2019 Feb 2;51(2):120-126. Epub 2019 Jan 2.

Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3-6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p<0.001). All patients that were followed up for up to 12 months showed the same decrease from preoperative values and they remained in remission from CD. We conclude that MSI can be used for the evaluation of remission from CD, at least in the immediate post-operative period and up to one year after surgery. The use of this technology can supplement biochemical and other testing for the evaluation of the various treatment modalities available for patients with CD.
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http://dx.doi.org/10.1055/a-0801-8917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753582PMC
February 2019

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

Horm Metab Res 2018 Apr 19;50(4):290-295. Epub 2018 Feb 19.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA.

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.
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http://dx.doi.org/10.1055/s-0044-101144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341463PMC
April 2018

Postoperative Diabetes Insipidus and Hyponatremia in Children after Transsphenoidal Surgery for Adrenocorticotropin Hormone and Growth Hormone Secreting Adenomas.

J Pediatr 2018 04 1;195:169-174.e1. Epub 2018 Feb 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD. Electronic address:

Objectives: To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas.

Study Design: We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Results: Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P < .001), or invasion 4 of 15 (P = .022) of the PP. Sixty patients developed hyponatremia, 19 because of SIADH, 39 to hypotonic fluids and 2 to cerebral salt wasting syndrome. Patients with SIADH were placed on fluid restriction; 1 received salt tablets.

Conclusions: Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain.

Trial Registration: ClinicalTrials.gov: NCT00001595 and NCT00060541.
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http://dx.doi.org/10.1016/j.jpeds.2017.11.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869073PMC
April 2018

Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome.

Pediatr Res 2018 02 6;83(2):431-437. Epub 2017 Dec 6.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

BackgroundHypercortisolemia results in changes of the immune system and elevated infection risk, but data on the WBC changes in pediatric Cushing syndrome (CS) are not known. We describe the changes of the WBC lineages in pediatric endogenous hypercortisolemia, their associations with the markers of disease severity, and the presence of infections.MethodsWe identified 197 children with endogenous CS. Clinical and biochemical data were recorded. Sixty-six children with similar age and gender, and normocortisolemia served as controls.ResultsThe absolute lymphocyte count of CS patients was significantly lower than that of controls, while the total WBC and the absolute neutrophil counts were significantly higher. These changes correlated with several markers of CS severity and improved after resolution of hypercortisolemia. Infections were identified in 35 patients (17.8%), and their presence correlated to elevated serum morning cortisol, midnight cortisol, and urinary free cortisol levels, as well as with the decrease in absolute lymphocyte count.ConclusionsChildren with endogenous CS have abnormal WBC counts, which correlate with the severity of CS, and normalize after cure. Infections are common in this population; clinicians should be aware of this complication of CS and have low threshold in diagnosis and treating infections in CS.
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http://dx.doi.org/10.1038/pr.2017.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866174PMC
February 2018

Failure to Thrive in the Context of Carney Complex.

Horm Res Paediatr 2018 21;89(1):38-46. Epub 2017 Nov 21.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Background/aims: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT).

Methods: A retrospective case series of pediatric patients with CNC presenting with FTT.

Results: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease.

Conclusion: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.
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http://dx.doi.org/10.1159/000484690DOI Listing
October 2018

Management of primary aldosteronism in patients with adrenal hemorrhage following adrenal vein sampling: A brief review with illustrative cases.

J Clin Hypertens (Greenwich) 2017 Dec 9;19(12):1372-1376. Epub 2017 Sep 9.

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

The authors describe the clinical investigation of two cases of primary aldosteronism with adrenal hemorrhage (AH) following adrenal vein sampling. A literature review was conducted regarding the medical management of primary aldosteronism in patients with AH following adrenal vein sampling. Guidelines on the management of primary aldosteronism with AH following adrenal vein sampling are lacking. The two patients were followed with serial imaging to document resolution of AH and treated medically with excellent blood pressure response. Resolution of AH was achieved, but a repeat adrenal vein sampling was deferred given the increased morbidity risk associated with a repeat procedure.
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http://dx.doi.org/10.1111/jch.13059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722684PMC
December 2017

Obesity and the diagnostic accuracy for primary aldosteronism.

J Clin Hypertens (Greenwich) 2017 Aug 13;19(8):790-797. Epub 2017 Jun 13.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

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/m , 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/m are less accurately identified as having PA when saline suppression and/or oral salt loading tests are used for case confirmation.
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http://dx.doi.org/10.1111/jch.13041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602533PMC
August 2017

3D Volumetric Measurements of GH Secreting Adenomas Correlate with Baseline Pituitary Function, Initial Surgery Success Rate, and Disease Control.

Horm Metab Res 2017 Jun 4;49(6):440-445. Epub 2017 May 4.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

There is scarce data on the clinical utility of volume measurement for growth hormone (GH)-secreting pituitary adenomas. The current study objective was to assess the association between pituitary adenoma volumes and baseline endocrine evaluation, initial surgical success rate, and disease control among patients with acromegaly. A retrospective cohort study was conducted at a clinical research center including patients with acromegaly due to GH-secreting pituitary adenomas. Baseline hormonal evaluation and adenoma characteristics according to MRI were collected. Volumetric measurements of pituitary adenomas were performed using a semi-automated lesion segmentation and tumor-volume assessment tools. Rates of post-operative medical treatment, radiation therapy, and re-operation were gathered from the patients' medical records. Twenty seven patients (11 females) were included, median age 21.0 years (interquartile range 29 years, range 3-61 years). Patients harboring adenomas with a volume <2 000 mm had higher chance to achieve disease remission [94.1% (n=16) vs. 50.0% (n=4), p<0.05]. Adenoma volumes positively correlated with baseline plasma GH levels before and after oral glucose administration, and with plasma IGF-I and PRL levels. Adenoma volume had negative correlation with morning plasma cortisol levels. Finally, patients harboring larger adenomas required 2nd surgery and/or medical treatment more often compared with subjects with smaller adenomas. Accurate 3D volume measurement of GH-secreting pituitary adenomas may be used for the prediction of initial surgery success and for disease control rates among patients with a GH-secreting pituitary adenomas and performs better than standard size assessments.
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http://dx.doi.org/10.1055/s-0043-107245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309337PMC
June 2017

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

Horm Res Paediatr 2017 21;87(5):295-300. Epub 2017 Apr 21.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Background: The 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.

Methods: A 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.

Results: Plasma 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.

Conclusion: Our study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.
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http://dx.doi.org/10.1159/000464463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506540PMC
March 2018

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

Pediatr Res 2017 Aug 17;82(2):272-277. Epub 2017 May 17.

Section on Endocrinology and Genetics, Developmental Endocrinology Branch, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1038/pr.2017.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552413PMC
August 2017

Coagulation Profile in Patients with Different Etiologies for Cushing Syndrome: A Prospective Observational Study.

Horm Metab Res 2017 May 22;49(5):365-371. Epub 2017 Feb 22.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Previous studies reported a higher prevalence of venous-thromboembolic events among patients with Cushing disease (CD) compared to those with ACTH-independent Cushing syndrome (CS) from adrenal sources. The objective of the current study was to evaluate the coagulation profile of patients with CS from different etiologies. A prospective observational study was conducted at a clinical research center. The study included adult patients admitted for evaluation of suspected CS (n=85), that were divided into 3 groups: CD (n=22), ACTH-independent CS from an adrenal tumor/hyperplasia (adrenal CS, n=21), and a control group consisting of subjects with negative screening for CS (rule-out CS, n=42). Coagulation profiles were drawn before and 8.5±4.3 months after surgery (trans-sphenoidal or adrenalectomy, n=18), and included fibrinogen, Factor VIII (FVIII), von Willebrand factor antigen (vWF:Ag), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (ATIII), Protein C (PC), Protein S (PS), α2-antiplasmin (α2AP), and aPTT measurements. Patients with CD had higher baseline mean cortisol levels, ATIII activity and vWF:Ag levels compared with adrenal CS. Differences in ATIII activity and vWF:Ag levels remained even after controlling for BMI, and ATIII after also controlling for 24-h urinary free cortisol collections. Our study showed for the first time the differences in coagulation profiles between various etiologies of CS. We assume that the higher cortisol burden among CD patients may explain the differences found in the coagulation profile as well as the higher risk for VTE compared with primary adrenal CS patients.
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http://dx.doi.org/10.1055/s-0043-100113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533628PMC
May 2017

Hair cortisol in the evaluation of Cushing syndrome.

Endocrine 2017 Apr 13;56(1):164-174. Epub 2017 Feb 13.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.

Purpose: Hair cortisol evaluation has been used to help detect patients with suspected Cushing syndrome. Our goal was to correlate segmental hair cortisol with biochemical testing in patients with Cushing syndrome and controls. This study was a prospective analysis of hair cortisol in confirmed Cushing syndrome cases over 16 months.

Methods: Thirty-six subjects (26.5 ± 18.9 years, 75% female, and 75% Caucasian) were analyzed by diurnal serum cortisol, 24 h urinary free cortisol corrected for body surface area (UFC/BSA), and 24 h urinary 17-hydroxysteroids corrected for creatinine (17OHS/Cr). Thirty patients were diagnosed with Cushing syndrome, and six were defined as controls. 3-cm hair samples nearest to the scalp, cut into 1-cm segments (proximal, medial, and distal), were analyzed for cortisol by enzyme immunoassay and measured as pmol cortisol/g dry hair. Hair cortisol levels were compared with laboratory testing done within previous 2 months of the evaluation.

Results: Proximal hair cortisol was higher in Cushing syndrome patients (266.6 ± 738.4 pmol/g) than control patients (38.9 ± 25.3 pmol/g) (p = 0.003). Proximal hair cortisol was highest of all segments in 25/36 (69%) patients. Among all subjects, proximal hair cortisol was strongly correlated with UFC/BSA (r = 0.5, p = 0.005), midnight serum cortisol (r = 0.4, p = 0.03), and 17OHS/Cr, which trended towards significance (r = 0.3, p = 0.06).

Conclusions: Among the three examined hair segments, proximal hair contained the highest cortisol levels and correlated the most with the initial biochemical tests for Cushing syndrome in our study. Further studies are needed to validate proximal hair cortisol in the diagnostic workup for Cushing syndrome.
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http://dx.doi.org/10.1007/s12020-017-1231-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437744PMC
April 2017

Case 1: Poor Growth With Presence of a Pituitary Lesion in an 11-year-old Boy.

Pediatr Rev 2017 Jan;38(1):44-45

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1542/pir.2014-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343498PMC
January 2017

Sporadic melanotic schwannoma with overlapping features of melanocytoma bearing a GNA11 mutation in an adolescent girl.

Pediatr Blood Cancer 2017 06 24;64(6). Epub 2016 Dec 24.

Section on Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

Melanotic schwannoma (MS) is a soft tissue neoplasm that shares histologic features with melanocytic tumors and schwannomas. A type of MS, called psammomatous MS (PMS), is associated with Carney complex (CNC), which is caused by PRKAR1A mutations. Other pigmented neoplasms, such as uveal melanomas and melanocytomas (MCs), are associated with genetic defects in other genes including GNA11. We report an adolescent female with a large sporadic mesenteric MS with complex histologic findings reminiscent of both PMS and MC. The lesion carried a mutation of the GNA11 gene. We conclude that sporadic MSs may occur rarely in adolescents without CNC; MSs may also be associated with somatic GNA11 mutations.
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http://dx.doi.org/10.1002/pbc.26400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309823PMC
June 2017

Spontaneously Resolving Hyperreninemic Hypertension Caused by Accessory Renal Artery Stenosis in a 13-Year-Old Girl: A Case Report.

J Clin Hypertens (Greenwich) 2017 01 15;19(1):100-102. Epub 2016 Aug 15.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

The authors describe the clinical investigation and progress of a 13-year-old girl diagnosed with hypertension 4 years prior to her admission. A thorough history was taken and physical examination performed. Laboratory analysis and relevant radiological evaluation were obtained in order to determine the etiology for suspected secondary hypertension, and later to differentiate between the possible causes of hyperreninemic hypertension. The patient had an accessory left renal artery, presumptively leading to renin secretion by the underperfused kidney. The patient was treated medically with spontaneous resolution of her hypertension and near normalization of plasma renin activity. On repeat imaging, the artery was not demonstrated. The authors concluded that the diagnosis of hyperreninemic hypertension in young ages should prompt investigation for the etiology. However, cautious observation is a valid option that might lead to spontaneous resolution.
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http://dx.doi.org/10.1111/jch.12893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341473PMC
January 2017

Coagulation Profile Dynamics in Pediatric Patients with Cushing Syndrome: A Prospective, Observational Comparative Study.

J Pediatr 2016 10 2;177:227-231. Epub 2016 Aug 2.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Objective: To evaluate the association between Cushing syndrome and hypercoagulability in children.

Study Design: A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 ± 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with18 normocortisolemic children, 13.7 ± 3.6 years.

Results: At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL ± 84 vs 99 ± 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 ± 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic α2-antiplasmin, 96 ± 17% vs 82 ± 26%, P = .015. After surgery, antifibrinolytic α2-antiplasmin levels decreased to 82 ± 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 ± 41% vs 84 ± 25%, P < .001), protein S (94 ± 19% vs 74 ± 19%, P = .001), and antithrombin III (96 ± 18% vs 77 ± 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004.

Conclusion: Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome.

Trial Registration: ClinicalTrials.gov:NCT00001595.
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http://dx.doi.org/10.1016/j.jpeds.2016.06.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298225PMC
October 2016

Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene.

Endocrinol Diabetes Metab Case Rep 2016 7;2016:150104. Epub 2016 Jan 7.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, BG 10-CRC, Room 1-3216, 10 Center Drive, Bethesda, Maryland, 20814, USA; Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baltimore, Maryland, 21287, USA; Suburban Hospital, Bethesda, Maryland, 20814, USA.

Unlabelled: Autosomal 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 Points: PHA1 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.
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http://dx.doi.org/10.1530/EDM-15-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722246PMC
January 2016

Facial Plethora: Modern Technology for Quantifying an Ancient Clinical Sign and Its Use in Cushing Syndrome.

J Clin Endocrinol Metab 2015 Oct 24;100(10):3928-33. Epub 2015 Aug 24.

Section on Analytical and Functional Biophotonics (A.A., Y.A., F.A.C., V.C., A.A.A., A.G.), and Program on Developmental Endocrinology and Genetics (M.B.L., E.G, M.K., E.B., C.L., C.A.S.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Research Center, National Institutes of Health, Bethesda, Maryland 20892; and George Washington University Department of System Engineering (T.A.M.), Washington, DC 20052.

Context: Facial plethora is a clinical sign described since ancient times for a variety of diseases. In the 19th century, it was linked to increased blood volume or flow, but this has never been proven. Facial plethora is also one of the earliest described clinical features of Cushing's syndrome (CS).

Objective: This study aimed to quantify facial plethora changes in CS as an early assessment of cure after surgery using noninvasive near-infrared multispectral imaging (MSI).

Design: The longitudinal cohort study was initiated in August 2012 and completed in August 2014.

Setting: Clinical research hospital, National Institutes of Health.

Patients: Thirty-four of the 38 patients who received surgical treatment for CS under protocol 97CH0076 during this period were included.

Intervention(s): MSI was performed on the right cheek of patients before surgery and 4.9 ± 3.1 days afterward.

Main Outcome Measure(s): Average blood volume fraction as measured by MSI and serum cortisol.

Results: All but four of the 28 patients (86%) who were assessed as cured by postoperative plasma cortisol measurements of < 3 μg/dL showed a decrease in blood volume fraction (17.7 ± 0.03 vs 15.8 ± 0.03%; P = .0019), whereas an increase was seen in patients with persistent CS (18.5 ± 0.03 vs 21.4 ± 0.04%; P = .0017). Change in blood volume fraction before and after surgery was correlated with postoperative cortisol (rs = 0.58; P = .0003).

Conclusions: Clinical data obtained from 34 patients indicate that a decrease in facial plethora after surgery, as evidenced by a decrease in blood volume fraction, is correlated with CS outcome. This novel technology for the first time identified a physiological mechanism associated with an ancient clinical sign. Furthermore, as a proof of principle, MSI is a promising early marker of cure in patients with CS that complements biochemical and clinical data.
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http://dx.doi.org/10.1210/jc.2015-2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596033PMC
October 2015

Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.

Eur J Endocrinol 2015 06;172(6):803-11

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Building 10-CRC, Room 9D42, 10 Center Drive, MSC, 1103, Bethesda, Maryland 20892, USA

Objective: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification.

Design: This study is a case series.

Methods: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.

Results: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype.

Conclusions: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.
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http://dx.doi.org/10.1530/EJE-14-1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428149PMC
June 2015

Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.

J Clin Endocrinol Metab 2015 May 19;100(5):E710-9. Epub 2015 Feb 19.

Section on Endocrinology and Genetics (P.X., E.S., S.A.M., P.M., M.R., N.R., M.d.L.L.S., C.L., E.B., M.L., C.A.S.), Program on Developmental Endocrinology and Genetics, Section on Medical Neuroendocrinology (P.B., A.G.), Program in Reproductive and Adult Endocrinology, Section on Molecular Dysmorphology (C.A.W., A.C.), Program in Developmental Endocrinology and Genetics, Microscopy and Imaging Core (L.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Laboratory of Pathology (A.G., M.Q., K.P.), National Cancer Institute, and Biostatistics and Clinical Epidemiology Service (D.K.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology (C.M.), University of Connecticut Health Center, Farmington, Connecticut 06030; Genomic Medicine Institute (J.M., C.E.), Cleveland Clinic, Cleveland, Ohio 44195; Department of Biochemistry and Molecular Biology (L.J.M.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; and Department of Molecular Medicine (P.B.), Institute of Virology, Slovak Academy of Sciences, 833 06 Bratislava, Slovakia.

Context: Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported.

Design: We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages.

Results: No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx-deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex.

Conclusion: The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation.
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http://dx.doi.org/10.1210/jc.2014-4297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422891PMC
May 2015

Post-operative growth is different in various forms of pediatric Cushing's syndrome.

Endocr Relat Cancer 2014 25;21(6):L27-31. Epub 2014 Sep 25.

Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN)Bethesda, MarylandUSAPediatric Endocrinology Inter-Institute Training ProgramEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)Bethesda, Maryland, 20892USADepartment of Pediatric EndocrinologyGeorgetown University School of Medicine3800 Reservoir Road, Washington, District of Columbia, 20007USABiostatistics and Clinical Epidemiology ServiceNational Institutes of Health Clinical CenterBethesda, Maryland, 20982USADepartment of RadiologyNational Institutes of Health Clinical CenterBethesda, Maryland, 20892USA Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN)Bethesda, MarylandUSAPediatric Endocrinology Inter-Institute Training ProgramEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)Bethesda, Maryland, 20892USADepartment of Pediatric EndocrinologyGeorgetown University School of Medicine3800 Reservoir Road, Washington, District of Columbia, 20007USABiostatistics and Clinical Epidemiology ServiceNational Institutes of Health Clinical CenterBethesda, Maryland, 20982USADepartment of RadiologyNational Institutes of Health Clinical CenterBethesda, Maryland, 20892USA.

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http://dx.doi.org/10.1530/ERC-14-0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209309PMC
June 2015

Death in pediatric Cushing syndrome is uncommon but still occurs.

Eur J Pediatr 2015 Apr 23;174(4):501-7. Epub 2014 Sep 23.

Section on Endocrinology and Genetics and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA,

Unlabelled: Cushing syndrome (CS) in children is rare. Delayed diagnosis and treatment of CS may be associated with increased morbidity and, unfortunately, mortality. We performed a retrospective review of all patients with CS under the age of 18 years referred to the National Institutes of Health (NIH) from 1998 to 2013 in order to describe deceased patients among cases of pediatric CS referred to the National Institutes of Health (NIH). The deaths of four children (three females and one male), aged 7.5-15.5 years (mean age 11.2 years) with length of disease 2-4 years, were recorded among 160 (2.5 %) children seen at or referred to the NIH over the last 15 years. All died at different institutions, prior to coming to the NIH (two) or after leaving NIH (two). Presenting symptoms included increasing weight and decreasing height gain, facial plethora, dorsocervical fat pad (webbed neck), striae, headache, vision disturbances, and depression and other mood or behavior changes; there were no differences between how these patients presented and the others in our cohort. The causes of CS in the deceased patients were also not different, in fact, they spanned the entire spectrum of CS: pituitary disease (one), ectopic corticotropin production (one), and primary adrenal hyperplasia (one). In one patient, the cause of CS could not be verified. Three died of sepsis and one due to residual disease and complications of the primary tumor.

Conclusions: Despite the advances in early diagnosis and treatment of pediatric CS, a 2.5 % mortality rate was identified in a large cohort of patients with this condition referred to an experienced, tertiary care referral center (although these deaths occurred elsewhere). Pediatricians need to recognize the possibility of death, primarily due to sepsis, in a patient with pediatric CS and treat accordingly.
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http://dx.doi.org/10.1007/s00431-014-2427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370787PMC
April 2015

Reninoma presenting in pregnancy.

J Clin Endocrinol Metab 2014 Aug 21;99(8):2625-6. Epub 2014 May 21.

Diabetes, Endocrinology, and Obesity Branch (T.D.-C.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland 20814; Section on Endocrinology and Genetics (S.B.A., M.R., G.Z.P., C.L., E.B., C.A.S.), Program on Developmental Endocrinology and Genetics and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver, National Institute of Child Health & Human Development, NIH, Bethesda, Maryland 20814; Division of Endocrinology, Diabetes & Nutrition (K.M.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Mid-Atlantic Nephrology Associates, P.A. (E.B.), Baltimore, Maryland 21117; and Laboratory of Diagnostic Pathology (M.M.), National Cancer Institute, NIH, Bethesda, Maryland 20814.

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http://dx.doi.org/10.1210/jc.2014-1730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121021PMC
August 2014