Publications by authors named "Alexander S Karageorgiadis"

7 Publications

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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

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

Growth hormone and risk for cardiac tumors in Carney complex.

Endocr Relat Cancer 2016 09 18;23(9):739-46. Epub 2016 Jul 18.

National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA

Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor.
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http://dx.doi.org/10.1530/ERC-16-0246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991637PMC
September 2016

Cholesterol Biosynthesis and Trafficking in Cortisol-Producing Lesions of the Adrenal Cortex.

J Clin Endocrinol Metab 2015 Oct 23;100(10):3660-7. Epub 2015 Jul 23.

Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.

Context: Cortisol-producing adenomas (CPAs), primary pigmented nodular adrenocortical disease (PPNAD), and primary macronodular adrenocortical hyperplasia (PMAH) cause ACTH-independent Cushing syndrome (CS). Investigation of their pathogenesis has demonstrated their integral link to the cAMP-dependent protein kinase signaling pathway.

Objective: The aim of this study was to identify differences in cholesterol biosynthesis among different CS-causing adrenocortical tumors. Because of the concomitant associations of cAMP levels with cholesterol and with steroid biosynthesis, we hypothesized that benign cortisol-producing tumors would display aberration of these pathways.

Design And Setting: Twenty-three patients with CPA, PPNAD, or PMAH who underwent adrenalectomy for CS were included in the study. Preoperative biochemical analyses were performed, and excised adrenal tissues were studied.

Main Outcome Measures: Serum, urinary hormone levels, serum lipid profiles, and anthropometric data were obtained preoperatively. Adrenal tissues were analyzed for total protein, cholesterol, and neutral sterol content by mass spectrometry and expression of HMGCR, LDLR, ABCA1, DHCR24, and STAR genes.

Results: There were differences in cholesterol content and markers of cholesterol biosynthesis and metabolism that distinguished CPAs from PMAH and PPNAD; cholesterol, lathosterol, and lathosterol/cholesterol ratio were significantly higher in CPAs. ABCA1 mRNA was lower among CPAs compared to tissues from bilateral adrenocortical hyperplasia (PMAH and PPNAD), and mRNA expression of LDL-R, DCHR24, and HMGCR tended to be higher in CPA tumor tissues.

Conclusion: CPAs displayed characteristics of "cholesterol-starved" tissues when compared to PPNAD and PMAH and appeared to have increased intrinsic cholesterol production and uptake from the periphery, as well as decreased cholesterol efflux. This has implications for a potential new way of treating these tumors.
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http://dx.doi.org/10.1210/jc.2015-2212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596036PMC
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

A gender-dependent analysis of Cushing's disease in childhood: pre- and postoperative follow-up.

Clin Endocrinol (Oxf) 2015 Jul 2;83(1):72-7. Epub 2015 Feb 2.

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

Objective: To analyse gender differences in the clinical presentation and recovery of paediatric patients with Cushing's disease (CD) after transsphenoidal surgery (TSS). Indeed, gender differences between paediatric patients with CD during presentation, after TSS and postoperative recovery have not been adequately studied.

Design: Data were obtained and retrospectively analysed from clinical reports and biochemical tests at the time of presentation, 5-9 days after TSS and at the 6 and 12 months postoperative follow-up visits to determine hypothalamic-pituitary-adrenal axis (HPAA) recovery.

Patients: Data from 102 paediatric patients (48 females, 54 males, mean age 12.9 ± 3.0) with CD who underwent TSS at the National Institute of Health (NIH) Clinical Center between 1997 and 2011.

Results: There was equal distribution of paediatric CD between males and females (53% vs 47%; n = 102, P = 0.484). Males were more likely than females to present with higher mean BMI Z-scores (2.2 ± 0.7 vs 1.9 ± 0.6, P = 0.0079), lower mean height Z-scores (-1.2 ± 1.3 vs -0.7 ± 1.1, P = 0.0467) and higher median plasma ACTH (12.2 vs 8.5 pmol/l; P = 0.0495). Females did not present more frequently with any single sign or symptom. No significant differences were found between males and females for CD cure rates 5-9 days after TSS (87.0% males vs 87.5% females, P = 1.0), long-term cure rates (86.5% vs 93.7%; n = 69; P = 0.4374) and HPAA recovery time (11.2 ± 2.5 vs 11.7 ± 2.5 months; n = 47; P = 0.1992).

Conclusions: Paediatric CD is found to have equal distribution between males and females, but male patients present with elevated BMI and potentially shorter height and higher plasma ACTH. There is no significant difference in the cure rate or HPAA recovery time after TSS between males and females.
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http://dx.doi.org/10.1111/cen.12644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342464PMC
July 2015

Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it.

J Clin Endocrinol Metab 2015 Jan;100(1):141-8

Section on Endocrinology and Genetics (A.S.K., J.B., M.F.K., C.L., M.B.L., C.A.S.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Section of Radiology and Imaging Sciences (G.Z.P., N.J.P.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pathology (M.M.Q., M.M.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Thoracic and Gastrointestinal Oncology Branch (D.S.S.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Endocrine Oncology Branch (E.K.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Randall Children's Hospital at Legacy Emanuel (M.K.H.), Children's Diabetes and Endocrine Center, Portland, Oregon 97227; Department of Pediatrics (M.R.A., L.P.K., A.E.B.), Section of Diabetes and Endocrinology, Baylor College of Medicine, Houston, Texas 77030.

Context: Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH-secreting tumors are discussed.

Setting: A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009-2014.

Patients: Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1-21), and 3 are female.

Measurements: Clinical, biochemical, radiological features, treatment, and histological findings are described.

Results: Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). PATIENTS underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor.

Conclusions: Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary.
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http://dx.doi.org/10.1210/jc.2014-2945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283025PMC
January 2015