Pediatric Endocrinology Inter Institute Training Program

Bethesda, MD, United States

Pediatric Endocrinology Inter Institute Training Program

Bethesda, MD, United States
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Gkourogianni A.,Pediatric Endocrinology Inter Institute Training Program | Sinaii N.,U.S. National Institutes of Health | Jackson S.H.,Minority | Karageorgiadis A.S.,Pediatric Endocrinology Inter Institute Training Program | And 7 more authors.
Pediatric Research | Year: 2017

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. © 2017 International Pediatric Research Foundation, Inc.

Almeida M.Q.,Section on Endocrinology and Genetics | Tsang K.M.,Section on Endocrinology and Genetics | Cheadle C.,Johns Hopkins University | Watkins T.,Johns Hopkins University | And 5 more authors.
Human Molecular Genetics | Year: 2011

Patients with genetic defects of the cyclic (c) adenosine-monophosphate (AMP)-signaling pathway and those with neonatal-onset multisystem inflammatory disease (NOMID) develop tumor-like lesions of the long bones. The molecular basis of this similarity is unknown. NOMID is caused by inappropriate caspase-1 activity, which in turn activates the inflammasome. The present study demonstrates that NOMID bone lesions are derived from the same osteoblast progenitor cells that form fibroblastoid tumors in mice and humans with defects that lead to increased cAMP-dependent protein kinase A (PKA) signaling. NOMID tumor cells showed high PKA activity, and an increase in their cAMP signaling led to PKA-specific activation of caspase-1. Increased PKA led to inflammation-independent activation of caspase-1 via over-expression of the proto-oncogene (and early osteoblast factor) Ets-1. In NOMID tumor cells, as in cells with defective PKA regulation, increased prostaglandin E2 (PGE2) led to increased cAMP levels and activation of Wnt signaling, like in other states of inappropriate PKA activity. Caspase-1 and PGE2 inhibition led to a decrease in cell proliferation of both NOMID and cells with abnormal PKA. These data reveal a previously unsuspected link between abnormal cAMP signaling and defective regulation of the inflammasome and suggest that caspase-1 and PGE2 inhibition may be therapeutic targets in bone lesions associated with defects of these two pathways. © The Author 2010. Published by Oxford University Press. All rights reserved.

Xekouki P.,Eunice Kennedy Shriver National Institute of Child Health and Human Development | Xekouki P.,Hippocrateion General Hospital | Pacak K.,Eunice Kennedy Shriver National Institute of Child Health and Human Development | Almeida M.,Eunice Kennedy Shriver National Institute of Child Health and Human Development | And 19 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Background: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD). Aim: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma. Patients and Methods: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298-301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors. Conclusion: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis. Copyright © 2012 by The Endocrine Society.

Almeida M.Q.,Pediatric Endocrinology Inter institute Training Program | Harran M.,Pediatric Endocrinology Inter institute Training Program | Bimpaki E.I.,Pediatric Endocrinology Inter institute Training Program | Hsiao H.-P.,Pediatric Endocrinology Inter institute Training Program | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Massive macronodular adrenocortical disease or ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a clinically and genetically heterogeneous disorder. Objective and Design: Whole-genome expression profiling and oligonucleotide array comparative genomic hybridization changes were analyzed in samples of different nodules from the same patients withAIMAH.Quantitative RT-PCRandstainingwereemployedto validate themRNAarray data. Results: Chromosomal gains were more frequent in larger nodules when compared with smaller nodulesfromthesamepatients.Amongthe 50mostoverexpressed genes,50%hadachromosomal locus that was amplified in the comparative genomic hybridization data. Although the list of most over-and underexpressed genes was similar between the nodules of different size, the gene set enrichment analysis identified different pathways associated with AIMAH that corresponded to the size; the smaller nodules were mainly enriched for metabolic pathways, whereas p53 signaling and cancer genes were enriched in larger nodules. Confirmatory studies demonstrated that BCL2, E2F1, EGF, c-KIT,MYB, PRKCA, and CTNNB1 were overexpressed in the larger nodules at messenger and/or protein levels. Chromosomal enrichment analysis showed that chromosomes 20q13 and 14q23 might be involved in progression of AIMAH from smaller to larger tumors. Conclusion: Integrated transcriptomic and genomic data for AIMAH provides supporting evidence to the hypothesis that larger adrenal lesions, in the context of this chronic, polyclonal hyperplasia, accumulate an increased number of genomic and, subsequently, transcript abnormalities. The latter shows that the disease appears to start with mainly tissue metabolic derangements, as suggested by the study of the smaller nodules, but larger lesions showed aberrant expression of oncogenic pathways. Copyright © 2011 by The Endocrine Society.

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