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Constantine A Stratakis - One of the best experts on this subject based on the ideXlab platform.
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OR24-06 USP8 Genetic Variants May Contribute to the Development of Bilateral Adrenal Hyperplasia and ACTH-Independent Cushing Syndrome
Journal of the Endocrine Society, 2020Co-Authors: Nikolaos Settas, Eva Kassi, Anna Angelousi, Fabio R. Faucz, Constantine A StratakisAbstract:Abstract Background: Bilateral adrenocortical hyperplasias (BAHs), including primary pigmented nodular adrenocortical disease (PPNAD), isolated micronodular adrenocortical disease (iMAD) and primary macronodular adrenocortical hyperplasia (PMAH), are rare causes of ACTH-independent Cushing Syndrome (CS). PPNAD and iMAD usually present in children or adolescents as multiple small (<1cm), cortisol-producing adrenocortical nodules. On the other hand, PMAH is most frequently identified in older patients with multiple large adrenal nodules. Most patients with PPNAD have PRKAR1A mutations whereas patients with PMAH may harbor variants in other genes (ARMC5, MC2R, GNAS, APC, MEN1). Even though several genes have been associated with ACTH-independent CS, there are still cases that the genetic cause has not been elucidated. Clinical cases: Herein, we present two unrelated patients with ACTH-independent CS that harbor USP8 gene variants. USP8 is mainly known for being mutated in Cushing disease but as a deubiquitinase it may be involved into the Wnt/β-Catenin signaling pathway. The first patient was diagnosed with BAH on prenatal ultrasound (26 gestational week) and subsequently required bilateral adrenalectomy for CS as she had virilization, hirsutism, hypertension and cardiac hypertrophy 9 weeks old. Adrenalectomy revealed that she had iMAD. She also presented with hemihypertrophy of the right leg, labia and mild newborn hypoglycemia, however she was negative for Beckwith-Wiedemann mutation. Gene analysis of PRKAR1A did not reveal any mutations. After whole exome sequencing (WES), we found a novel heterozygous USP8 variant (c.1387_1393delinsT, p.Ala463_Ile465delinsPhe) at germline level and loss of heterozygosity (LOH) at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in both of her adrenals compared to a control tissue. The second case is a 59-year old female with osteoporosis who failed to suppress cortisol levels after low dose dexamethasone administration. MRI revealed an adenoma on the right adrenal (2.6cm). She underwent right adrenalectomy and was found to have PMAH. We performed WES in germline level and we detected a novel heterozygous missense USP8 variant (c.287A>G, p.Lys96Arg) that is present also at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in her adrenal tumor compared to the control tissue. No LOH was identified. Conclusion: This is the first report of the association of USP8 in ACTH-independent CS and the preliminary findings support UPS8 involvement in the development of adrenocortical disease. We are currently performing further in vitro studies to evaluate the effect of these two USP8 variants into the canonical Wnt pathway which is commonly involved in adrenocortical disorders.
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Cushing Syndrome old and new genes
Best Practice & Research Clinical Endocrinology & Metabolism, 2020Co-Authors: Christina Tatsi, Chelsi Flippo, Constantine A StratakisAbstract:Cushing Syndrome (CS) describes the signs and symptoms caused by exogenous or endogenous hypercortisolemia. Endogenous CS is caused by either ACTH-dependent sources (pituitary or ectopic) or ACTH-independent (adrenal) hypercortisolemia. Several genes are currently known to contribute to the pathogenesis of CS. Germline gene defects, such as MEN1, AIP, PRKAR1A and others, often present in patients with pituitary or adrenal involvement as part of a genetic Syndrome. Somatic defects in genes, such as USP8, TP53, and others, are also involved in the development of pituitary or adrenal tumors in a large percentage of patients with CS, and give insight in pathways involved in pituitary or adrenal tumorigenesis.
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Cushing s Syndrome in pediatrics an update
Endocrinology and Metabolism Clinics of North America, 2018Co-Authors: Maya B Lodish, Margaret F. Keil, Constantine A StratakisAbstract:Cushing Syndrome (CS) is a multisystem disorder resulting from the prolonged exposure to excess glucocorticoids. In children, CS most commonly results from the exogenous administration of steroids and the typical presentation is height deceleration concomitant with weight gain. Endogenous and ectopic causes are rare. CS in children may be associated with distinct germline and somatic mutations. Clinical practice guidelines are available assist clinicians. Patients should be referred to multidisciplinary centers of excellence with experience in endocrinology and surgery. Early detection and treatment is essential to reduce associated acute and long-term morbidity and potential death.
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neonatal Cushing Syndrome a rare but potentially devastating disease
Clinics in Perinatology, 2017Co-Authors: Christina Tatsi, Constantine A StratakisAbstract:Neonatal Cushing Syndrome (CS) is most commonly caused by exogenous administration of glucocorticoids and rarely by endogenous hypercortisolemia. CS owing to adrenal lesions is the most common cause of endogenous CS in neonates and infants, and adrenocortical tumors (ACTs) represent most cases. Many ACTs develop in the context of a TP53 gene mutation, which causes Li-Fraumeni Syndrome. More rarely, neonatal CS presents as part of other Syndromes such as McCune-Albright Syndrome or Beckwith-Wiedemann Syndrome. Management usually includes resection of the primary tumor with or without additional medical treatment, but manifestations may persist after resolution of hypercortisolemia.
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diagnosis and clinical genetics of Cushing Syndrome in pediatrics
Endocrinology and Metabolism Clinics of North America, 2016Co-Authors: Constantine A StratakisAbstract:Endogenous Cushing Syndrome (CS) in pediatrics is rare; it may be caused by tumors that produce corticotropin in the pituitary gland or elsewhere, tumors that produce corticotropin-releasing hormone anywhere, and adrenocortical masses that produce cortisol. Adrenocortical cancer is a rare cause of CS in children but should be excluded first. CS in children is often caused by germline or somatic mutations with implications for patient prognosis and for their families. CS should be recognized early in children; otherwise, it can lead to significant morbidity and mortality. Patients with suspected CS should be referred to specialized clinical centers for workup.
Lynnette K Nieman - One of the best experts on this subject based on the ideXlab platform.
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Diagnosis of Cushing's Syndrome in the Modern Era.
Endocrinology and metabolism clinics of North America, 2018Co-Authors: Lynnette K NiemanAbstract:Four challenges complicate the evaluation for Cushing Syndrome. These challenges include increasing global prevalence of obesity and diabetes; increasing use of exogenous glucocorticoids, which cause a Cushing Syndrome phenotype; the confusion caused by nonpathologic hypercortisolism not associated with Cushing Syndrome, which may present with symptoms consistent with Cushing Syndrome; and difficulty identifying pathologic hypercortisolism when it is extremely mild or cyclic or in renal failure, incidental adrenal masses, and pregnancy. Careful choice of screening tests, consideration of confounding conditions, and repeated testing when the results are ambiguous improve the accuracy of diagnosis.
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iatrogenic Cushing Syndrome after epidural triamcinolone injections in an hiv type 1 infected patient receiving therapy with ritonavir lopinavir
Clinical Infectious Diseases, 2008Co-Authors: Roshan Ramanathan, Lynnette K Nieman, Alice K Pau, Kristin H Busse, Marina Zemskova, Richard Kwan, Jean H Hammer, Joann M Mican, Frank MaldarelliAbstract:We report the first case of a human immunodeficiency virus type 1 (HIV-1)-infected individual receiving combination antiretroviral therapy, which included ritonavir, who developed Cushing Syndrome with profound complications after epidural triamcinolone injections. This case highlights the potential of ritonavir interactions even with local injections of a corticosteroid.
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cortisolemic indices predict severe infections in Cushing Syndrome due to ectopic production of adrenocorticotropin
The Journal of Clinical Endocrinology and Metabolism, 2000Co-Authors: Nicholas J Sarlis, Stephen J Chanock, Lynnette K NiemanAbstract:Because high circulating levels of glucocorticoids impair immunity and predispose to infections, we evaluated whether indices of cortisol (F) production could predict infections in patients with Cushing Syndrome (CS) caused by ectopic production of ACTH (EA). Charts of 54 consecutive patients with untreated EA, without underlying diagnosis of small cell carcinoma of the lung, were reviewed, and types of infections, white blood cell (WBC) count, fever, as well as the glucocorticoid indices [0800 h F, daily urine F excretion (UFC), and daily urine 17-hydroxysteroid/g creatinine excretion (17OHS)], were recorded. Thirty-five patients had no or clinically mild infection; the remaining 19 patients had severe, systemic infection (n = 13) and/or sepsis (n = 6), including either bacterial or opportunistic pathogens or both (73.7%, 42.1%, and 13.8%, respectively). The latter group of patients had significantly higher indices of hypercortisolism (F, UFC, and 17OHS) than those with mild or no infections, but these i...
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Corticotropin-secreting carcinoid tumors of the thymus: diagnostic unreliability of thymic venous sampling.
Radiology, 1992Co-Authors: John L. Doppman, Harvey I. Pass, Donald L. Miller, Gordon B. Cutler, G. Jaffe, Lynnette K Nieman, George P Chrousos, Richard Chang, Jeffrey A. NortonAbstract:Three patients with Cushing Syndrome due to ectopic production of corticotropin underwent total thymectomy on the basis of elevated concentrations of corticotropin in selective samples from thymic veins but in the absence of a radiographically detectible thymic mass. In one patient, radiologic examination demonstrated hyperplasia of neuroendocrine cells staining positively for corticotropin throughout the thymus but no discrete mass. This patient had complete remission after total thymectomy. The other two patients had no evidence of an intrathymic source of corticotropin, and both had persistent Cushing Syndrome. Elevated levels of corticotropin in thymic vein samples may reflect corticotropin production by pulmonary bronchial carcinoid tumors, mediastinal metastases, thymic carcinoids, or diffuse hyperplasia of intrathymic neuroendocrine elements. In the absence of a demonstrable intrathymic mass, corticotropin gradients in thymic veins do not reliably indicate a thymic source of corticotropin and shoul...
George P Chrousos - One of the best experts on this subject based on the ideXlab platform.
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Factitious Cushing Syndrome.
The Journal of clinical endocrinology and metabolism, 1996Co-Authors: Giovanni Cizza, John L. Doppman, George P Chrousos, L K Nieman, M D Passaro, F S Czerwiec, Gordon B. CutlerAbstract:There have been few reports of factitious Cushing Syndrome. To characterize the clinical and laboratory features leading to this unusual diagnosis, we describe 6 patients (5 women, 1 man), ages 31-44, identified retrospectively among 860 patients evaluated for hypercortisolism at the National Institutes of Health Clinical Center. All six patients had multiple surgeries unrelated to Cushing Syndrome and a history of depression or anxiety. Four patients had close contact with the medical profession, three a history of drug abuse, and three had undergone previous treatment for Cushing Syndrome. The physical features of Cushing Syndrome were variable and not helpful in the differential diagnosis with endogenous Cushing Syndrome. Four patients had striking variability in urine-free cortisol (UFC) and 17-hydroxysteroid (17-OHCS) values from low to high. Adrenal computed tomography, performed in two patients, showed small adrenal glands (n = 1) or a left-sided mass (n = 1), and adrenal magnetic resonance imaging...
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Decreased Delta-Sleep and Plasma Delta-Sleep-Inducing Peptide in Patients with Cushing Syndrome
Neuroendocrinology, 1994Co-Authors: Theodore C. Friedman, Diego Garcia-borreguero, Donna Hardwick, Cecilia N. Akuete, Charles N. Barker, Jack A. Yanovski, Lorah D Dorn, John L. Doppman, George P ChrousosAbstract:To evaluate the sleep disturbances of patients with Cushing Syndrome and to examine the relationship between the sleep disturbances and plasma levels of delta-sleep-inducing peptide-like immunoreactiv
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posterior subcapsular cataract in endogenous Cushing Syndrome an uncommon manifestation
Investigative Ophthalmology & Visual Science, 1993Co-Authors: Evrydiki A Bouzas, George Mastorakos, Mark H Scott, Theodore C. Friedman, George P Chrousos, Muriel I KaiserkupferAbstract:PURPOSE: Posterior subcapsular cataract is a well-known complication of longstanding glucocorticoid therapy (exogenous Cushing Syndrome). The purpose of this study was to examine the effect of chronic endogenous hypercortisolism (endogenous Cushing Syndrome) on the human lens. METHODS: Sixty consecutive patients (8 to 67 years of age, 46 females, 14 males) with endogenous Cushing Syndrome were studied. The exposure to cortisol was estimated based on the duration of the disease and measurements of the 24-hour urine free cortisol excretion. Complete ocular examination included biomicroscopy of the lens after dilation. RESULTS: Duration from the onset of endogenous Cushing Syndrome ranged from 1 to 20 years (mean +/- SD, 5.5 +/- 3.7). Urine free cortisol excretion ranged from 250 to 3065 micrograms/24 hr (mean +/- SD, 693 +/- 547; normal values, 20 to 90 micrograms/24 hr). Only two of the 60 patients (3.3%) had posterior subcapsular cataract. This low prevalence contrasts to the high prevalence attributed to glucocorticoid therapy with grossly equivalent total dosage of glucocorticoids. CONCLUSION: It was concluded that posterior subcapsular cataract is an infrequent complication of endogenous hypercortisolism compared to exogenous Cushing Syndrome. Because the total exposure to endogenous glucocorticoids was not lower than that of exogenous glucocorticoid therapy, a potential explanation for this difference might be the exposure of the lens to the natural (cortisol) rather than a synthetic glucocorticoid or pharmacokinetic differences of glucocorticoids between the two forms of Cushing Syndrome.
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Corticotropin-secreting carcinoid tumors of the thymus: diagnostic unreliability of thymic venous sampling.
Radiology, 1992Co-Authors: John L. Doppman, Harvey I. Pass, Donald L. Miller, Gordon B. Cutler, G. Jaffe, Lynnette K Nieman, George P Chrousos, Richard Chang, Jeffrey A. NortonAbstract:Three patients with Cushing Syndrome due to ectopic production of corticotropin underwent total thymectomy on the basis of elevated concentrations of corticotropin in selective samples from thymic veins but in the absence of a radiographically detectible thymic mass. In one patient, radiologic examination demonstrated hyperplasia of neuroendocrine cells staining positively for corticotropin throughout the thymus but no discrete mass. This patient had complete remission after total thymectomy. The other two patients had no evidence of an intrathymic source of corticotropin, and both had persistent Cushing Syndrome. Elevated levels of corticotropin in thymic vein samples may reflect corticotropin production by pulmonary bronchial carcinoid tumors, mediastinal metastases, thymic carcinoids, or diffuse hyperplasia of intrathymic neuroendocrine elements. In the absence of a demonstrable intrathymic mass, corticotropin gradients in thymic veins do not reliably indicate a thymic source of corticotropin and shoul...
John L. Doppman - One of the best experts on this subject based on the ideXlab platform.
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Factitious Cushing Syndrome.
The Journal of clinical endocrinology and metabolism, 1996Co-Authors: Giovanni Cizza, John L. Doppman, George P Chrousos, L K Nieman, M D Passaro, F S Czerwiec, Gordon B. CutlerAbstract:There have been few reports of factitious Cushing Syndrome. To characterize the clinical and laboratory features leading to this unusual diagnosis, we describe 6 patients (5 women, 1 man), ages 31-44, identified retrospectively among 860 patients evaluated for hypercortisolism at the National Institutes of Health Clinical Center. All six patients had multiple surgeries unrelated to Cushing Syndrome and a history of depression or anxiety. Four patients had close contact with the medical profession, three a history of drug abuse, and three had undergone previous treatment for Cushing Syndrome. The physical features of Cushing Syndrome were variable and not helpful in the differential diagnosis with endogenous Cushing Syndrome. Four patients had striking variability in urine-free cortisol (UFC) and 17-hydroxysteroid (17-OHCS) values from low to high. Adrenal computed tomography, performed in two patients, showed small adrenal glands (n = 1) or a left-sided mass (n = 1), and adrenal magnetic resonance imaging...
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Decreased Delta-Sleep and Plasma Delta-Sleep-Inducing Peptide in Patients with Cushing Syndrome
Neuroendocrinology, 1994Co-Authors: Theodore C. Friedman, Diego Garcia-borreguero, Donna Hardwick, Cecilia N. Akuete, Charles N. Barker, Jack A. Yanovski, Lorah D Dorn, John L. Doppman, George P ChrousosAbstract:To evaluate the sleep disturbances of patients with Cushing Syndrome and to examine the relationship between the sleep disturbances and plasma levels of delta-sleep-inducing peptide-like immunoreactiv
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Corticotropin-secreting carcinoid tumors of the thymus: diagnostic unreliability of thymic venous sampling.
Radiology, 1992Co-Authors: John L. Doppman, Harvey I. Pass, Donald L. Miller, Gordon B. Cutler, G. Jaffe, Lynnette K Nieman, George P Chrousos, Richard Chang, Jeffrey A. NortonAbstract:Three patients with Cushing Syndrome due to ectopic production of corticotropin underwent total thymectomy on the basis of elevated concentrations of corticotropin in selective samples from thymic veins but in the absence of a radiographically detectible thymic mass. In one patient, radiologic examination demonstrated hyperplasia of neuroendocrine cells staining positively for corticotropin throughout the thymus but no discrete mass. This patient had complete remission after total thymectomy. The other two patients had no evidence of an intrathymic source of corticotropin, and both had persistent Cushing Syndrome. Elevated levels of corticotropin in thymic vein samples may reflect corticotropin production by pulmonary bronchial carcinoid tumors, mediastinal metastases, thymic carcinoids, or diffuse hyperplasia of intrathymic neuroendocrine elements. In the absence of a demonstrable intrathymic mass, corticotropin gradients in thymic veins do not reliably indicate a thymic source of corticotropin and shoul...
Frank Maldarelli - One of the best experts on this subject based on the ideXlab platform.
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iatrogenic Cushing Syndrome after epidural triamcinolone injections in an hiv type 1 infected patient receiving therapy with ritonavir lopinavir
Clinical Infectious Diseases, 2008Co-Authors: Roshan Ramanathan, Lynnette K Nieman, Alice K Pau, Kristin H Busse, Marina Zemskova, Richard Kwan, Jean H Hammer, Joann M Mican, Frank MaldarelliAbstract:We report the first case of a human immunodeficiency virus type 1 (HIV-1)-infected individual receiving combination antiretroviral therapy, which included ritonavir, who developed Cushing Syndrome with profound complications after epidural triamcinolone injections. This case highlights the potential of ritonavir interactions even with local injections of a corticosteroid.
