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1.  High Prevalence of Normal Tests Assessing Hypercortisolism in Subjects with Mild and Episodic Cushing’s Syndrome Suggests that the Paradigm for Diagnosis and Exclusion of Cushing’s Syndrome Requires Multiple Testing 
Many Endocrinologists believe that a single determination of eucortisolism or a single demonstration of appropriate suppression to dexamethasone excluded Cushing’s syndrome, except in what was previously thought to be the rare patient with episodic or periodic Cushing’s syndrome. We hypothesize that episodic Cushing’s syndrome is relatively common and a single test assessing hypercortisolism may not be sufficient to accurately rule out or diagnose Cushing’s syndrome and retrospectively examined the number of normal and abnormal tests assessing hypercortisolism performed on multiple occasions in 66 patients found to have mild and/or episodic Cushing’s syndrome compared to a similar group of 54 patients evaluated for, but determined not to have Cushing’s syndrome. We found that 65 of the 66 patients with Cushing’s syndrome had at least one normal test of cortisol status and most patients had several normal tests. The probability of having Cushing’s syndrome when one test was negative was 92 % for 23:00 h salivary cortisol, 88 % for 24-h UFC, 86 % for 24-h 17OHS, and 54 % for nighttime plasma cortisol. These results demonstrated that episodic hypercortisolism is highly prevalent in subjects with mild Cushing’s syndrome and no single test was effective in conclusively diagnosing or excluding the condition. Rather, the paradigm for the diagnosis should be a careful history and physical examination and in those patients in whom mild Cushing’s syndrome/disease is strongly suspected, multiple tests assessing hypercortisolism should be performed on subsequent occasions, especially when the patient is experiencing signs and symptoms of short-term hypercortisolism.
doi:10.1055/s-0030-1263128
PMCID: PMC2978784  PMID: 20803415
Cushing’s syndrome; episodic; periodic; urinary free cortisol; salivary cortisol; cortisol-binding globulin; 17-hydroxycorticosteroids
2.  Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study 
Objective To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing’s syndrome during treatment with glucocorticoids.
Design Cohort study.
Setting 424 UK general practices contributing to The Health Improvement Network database.
Participants People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome (n=547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing’s syndrome (n=3231) and those not prescribed systemic glucocorticoids (n=3282).
Main outcome measures Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing’s syndrome or after a randomly selected date, and association between iatrogenic Cushing’s syndrome and risk of cardiovascular events.
Results 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n=177, heart failure n=101, ischaemic stroke n=63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing’s syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing’s syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4.16 (2.98 to 5.82) when the group prescribed glucocorticoids and with iatrogenic Cushing’s syndrome was compared with the group not prescribed glucocorticoids.
Conclusion People who use glucocorticoids and exhibit iatrogenic Cushing’s syndrome should be aggressively targeted for early screening and management of cardiovascular risk factors.
doi:10.1136/bmj.e4928
PMCID: PMC3408386  PMID: 22846415
3.  Cushing's syndrome due to ectopic ACTH production by a nasal paraganglioma 
Summary
Ectopic secretion of ACTH is an infrequent cause of Cushing's syndrome. We report a case of ectopic ACTH syndrome caused by a nasal paraganglioma, a 68-year-old female with clinical features of Cushing's syndrome, serious hypokalaemia and a right paranasal sinus' lesion. Cranial magnetic resonance image showed a 46-mm mass on the right paranasal sinuses. Endocrinological investigation confirmed the diagnosis of ectopic ACTH production. Resection of the tumour normalised ACTH and cortisol secretion. The tumour was found to be a paraganglioma through microscopic analysis. On follow-up 3 months later, the patient showed nearly complete clinical recovery. Ectopic ACTH syndrome due to nasal paraganglioma is extremely uncommon, as only two other cases have been discussed in the literature.
Learning points
Ectopic Cushing's syndrome accounts for 10% of Cushing's syndrome etiologies.Most paraganglioma of the head and neck are not hormonally active.Nasal paraganglioma, especially ACTH producing, is a very rare tumour.
doi:10.1530/EDM-13-0038
PMCID: PMC3922001  PMID: 24616770
4.  A Case of Cushing Syndrome Diagnosed by Recurrent Pathologic Fractures in a Young Woman 
Journal of Bone Metabolism  2012;19(2):153-158.
Cushing's syndrome is characterized by central obesity, fatigability, weakness, amenorrhea, hirsutism, edema, hypertension, impaired glucose tolerance, and osteoporosis due to excessive production of steroids. Cushing's syndrome is an important cause of secondary osteoporosis. Patients with Cushing's syndrome have a high incidence of osteoporotic fractures. At least, 30-50% of patients with Cushing's syndrome experience fractures, particularly in the vertebral body. And it is consistent with the 50% prevalence of osteoporosis in patients with Cushing's syndrome. However, reports of multiple pathological fractures in young patients with Cushing's syndrome are rare. Thus, we describe the case of a 26-year-old woman with Cushing's syndrome accompanied with recurrent multiple osteoporotic fractures and being treated by parathyroid hormone. Careful consideration for the possibility of Cushing's syndrome will be necessary in case of young patients with a spontaneous multiple compression fractures in spine.
doi:10.11005/jbm.2012.19.2.153
PMCID: PMC3780926  PMID: 24524047
Cushing syndrome; Osteoporotic fractures
5.  Severe hypokalemia, metabolic alkalosis and hypertension in a 54 year old male with ectopic ACTH syndrome: a case report 
Cases Journal  2009;2:6174.
Ectopic ACTH syndrome is a rare cause of Cushing’s syndrome accounting for about 15% of all cases. Small cell lung cancer and bronchial carcinoids account for about half of the cases. Malignant neoplasm has rapid and more aggressive metabolic effects. We report a 54-year-old male patient with phenotypic features of Cushing’s syndrome with severe hypokalemia, metabolic alkalosis, hypertension and altered mental status as manifestations of an ACTH-secreting small cell carcinoma from the lung. Ectopic ACTH syndrome should be highly considered in patients with hypertension and severe hypokalemic metabolic alkalosis, especially when a lung mass is discovered.
doi:10.4076/1757-1626-2-6174
PMCID: PMC2740289  PMID: 19829770
6.  Anthropometric Measures and Fasting Insulin Levels in Children Before and after Cure of Cushing syndrome 
Background & Aims
Children with Cushing syndrome present with growth delay and excess adiposity that tends to be generalized rather than centripetal. There are no prospective studies of this phenotype as it evolves before and after treatment in children. The aims of this study were to evaluate children prior to and one-year after surgical cure compared to controls and to determine fasting insulin levels and their possible association with waist circumference and waist-height ratio, pre- and post-cure of Cushing syndrome.
Methods
30 children with Cushing syndrome were evaluated prior to and one-year post-treatment and compared to 14 age and body mass index-matched controls.
Results
Only triceps skin fold z- score showed a significant difference between patients with active Cushing syndrome and controls. A positive correlation between fasting insulin levels and waist circumference z- score was found for children with Cushing syndrome; this association persisted one-year following cure.
Conclusions
Unlike adults affected with Cushing syndrome, upper arm muscle area of children with Cushing syndrome did not differ from obese children without Cushing syndrome. The persistence of a positive correlation between waist circumference and fasting insulin despite remission of Cushing syndrome suggests that children with a history of Cushing syndrome may have an increased risk for adverse long-term effects of increased abdominal fat mass.
Clinical Trial numbers: NCT00001595, NCT00001452, NCT00005927
doi:10.1016/j.clnu.2011.11.007
PMCID: PMC3319516  PMID: 22154461
Cushing; pediatric; obesity; insulin resistance; waist circumference; anthropometrics
7.  Cushing’s syndrome caused by an ACTH-producing large cell neuroendocrine carcinoma of the gallbladder 
Malignancies of the gallbladder, including neuroendocrine tumors, are uncommon, mostly found incidentally after cholecystectomy and are frequently asymptomatic in the early stages, but highly fatal. Limited data is available on adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumors specifically originating from the gallbladder. We report the clinical and radiographic findings, which included positron emission tomography and computed tomography, of a patient with a gallbladder mass who presented with Cushing’s syndrome. Subsequently, a diagnosis of ACTH-producing large cell neuroendocrine carcinoma of the gallbladder was made. Despite being rare and having a poor prognosis, hormone-producing neuroendocrine tumors should be part of the differential diagnosis in the approach of patients with Cushing’s syndrome.
doi:10.4251/wjgo.v2.i1.56
PMCID: PMC2999155  PMID: 21160818
Adrenocorticotropic hormone; Cushing’s syndrome; Neuroendocrine; Carcinoma; Gallbladder
8.  Adrenocortical carcinoma initially presenting with hypokalemia and hypertension mimicking hyperaldosteronism: a case report 
BMC Research Notes  2013;6:405.
Background
Adrenocortical carcinoma is a rare malignancy and rare cause of Cushing’s syndrome.
Case presentation
A 65-year-old seemingly well male patient was referred to our clinic under the suspicion of hyperaldosteronism due to hypertension combined with hypokalemia. However, his serum aldosterone and plasma renin activity were within normal limits. Instead, Cushing’s syndrome was diagnosed by elevated urine free cortisol and a non-suppressible dexamethasone test. Abdominal computed tomography showed a 7.8 × 4.8 cm mass lesion at the right adrenal gland with liver invasion. Etomidate infusion was performed to reduce his cortisol level before the patient received a right adrenalectomy and liver wedge resection. The pathology report showed adrenocortical carcinoma with liver and lymph node metastasis. According to the European Network for the Study of Adrenal Tumors (ENSAT) staging system, the tumor was classified as T4N1M1, stage IV. Recurrent hypercortisolism was found shortly after surgery. The patient died of Fournier’s gangrene with septic shock on the 59th day after diagnosis.
Conclusions
We report a case of rapidly progressive stage IV adrenocortical carcinoma with initial presentations of hypokaelmia and hypertension, mimicking hyperaldosteronism.
doi:10.1186/1756-0500-6-405
PMCID: PMC3852253  PMID: 24103295
Adrenocortical carcinoma; Cushing’s syndrome; Hyperaldosteronism
9.  Cushing’s Syndrome: All variants, detection, and treatment 
Synopsis
Cushing’s syndrome is caused by prolonged exposure to excess glucocorticoids. Diagnosis of Cushing’s syndrome involves a step-wise approach and establishing the cause can be challenging in some cases. Hypertension is present in about 80% of patients with Cushing’s syndrome and can lead to significant morbidity and mortality. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension including a functional mineralocorticoid excess state, up-regulation of the renin angiotensin system and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment for Cushing’s syndrome. Anti-glucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery, and in cases where surgery is contraindicated or has not led to cure.
doi:10.1016/j.ecl.2011.01.006
PMCID: PMC3095520  PMID: 21565673
Cushing’s syndrome; hypertension; glucocorticoids; ectopic ACTH secretion; 11-beta hydroxysteroid dehydrogenase; hypercortisolemia
10.  Two diagnoses become one? Rare case report of anorexia nervosa and Cushing’s syndrome 
Hypothalamic-pituitary-adrenal axis impairment in anorexia nervosa is marked by hypercortisolemia, and psychiatric disorders occur in the majority of patients with Cushing’s syndrome. Here we report a patient diagnosed with anorexia nervosa who also developed Cushing’s syndrome. A 26-year-old female had been treated for anorexia nervosa since she was 17 years old, and also developed depression and paranoid schizophrenia. She was admitted to the Department of Endocrinology, Metabolism, and Internal Medicine with a preliminary diagnosis of Cushing’s syndrome. Computed tomography revealed a 27 mm left adrenal tumor, and she underwent laparoscopic adrenalectomy. She was admitted to hospital 6 months after this procedure, at which time she did not report any eating or mood disorder. This is a rare case report of a patient with anorexia nervosa in whom Cushing’s syndrome was subsequently diagnosed. Diagnostic difficulties were caused by the signs and symptoms presenting in the course of both disorders, ie, hypercortisolemia, osteoporosis, secondary amenorrhea, striae, hypokalemia, muscle weakness, and depression.
doi:10.2147/NDT.S40398
PMCID: PMC3621711  PMID: 23579693
anorexia nervosa; Cushing’s syndrome; adrenalectomy; osteoporosis
11.  Watchful waiting for some children with a mediastinal mass: the potential role for 18 F-fluorodeoxyglucose positron emission tomography: a case report and review of the literature 
BMC Pediatrics  2013;13:103.
Background
Benign hyperplastic thymus is a rare but important differential diagnosis of anterior mediastinal lesions. Histological and radiological criteria are used to distinguish this benign condition from other malignant diseases but have their limitations, and biopsy of mediastinal masses can be risky. We report for the first time the diagnostic value of fluorodeoxyglucose 18 F positron emission tomography for patients with incidentally identified anterior mediastinal masses to avoid biopsy in some cases.
Case presentation
A 2 year old girl presented with new onset of emesis and constipation leading to the incidental discovery of an anterior mediastinal mass on radiograph. Chest computed tomography revealed cystic components within the mass concerning for a malignancy. Biopsy of the lesion and bone marrow aspiration and biopsy were negative but there was concern that the mediastinal biopsy may have missed the malignant component of the lesion. Hence, a positron emission tomography scan was obtained that showed mild homogeneous fluorodeoxyglucose 18 F avidity within the mass similar to that of normal thymus. The diagnosis of benign hyperplastic thymus was made.
Conclusion
The differential diagnosis of an incidentally found anterior mediastinal mass includes malignancy, but benign lesions such as benign hyperplastic thymus must also be considered, particularly when the complete blood count and biochemical profile are normal. Fluorodeoxyglucose 18 F positron emission tomography can help guide a clinician’s decision for further interventions and treatment.
doi:10.1186/1471-2431-13-103
PMCID: PMC3717068  PMID: 23841990
Mediastinal disease; Mediastinum; Positron-emission tomography; Thymus hyperplasia
12.  Carcinoid tumours of the thymus. 
Thorax  1994;49(4):357-360.
BACKGROUND--Carcinoid tumours of the thymus are rare. The clinical manifestations, radiographic findings, and cytological features of eight histopathologically verified thymic carcinoid tumours have been assessed. METHODS--One hundred and sixty two patients of mean age 52 (range 31-68) years with malignant mediastinal tumours were reviewed retrospectively and eight cases of thymic carcinoid were identified. Four of the eight patients were diagnosed by percutaneous ultrasound guided fine needle aspiration biopsy via a parasternal approach. RESULTS--Two patients had Cushing's syndrome at presentation and four had symptoms and signs secondary to mediastinal compression. Two were asymptomatic. Local extension of the tumour to pleura, pericardium, great vessels, phrenic nerve or regional lymph nodes, or both, were found in seven patients. Only one had the tumour confined to the thymus at diagnosis. Distant metastases were found in two patients, one to both lungs and the other in the iliac bone. Local recurrence or distant metastases developed 15-60 months after surgery in four of the five patients who underwent radical resection of the thymic tumour. Three patients died at 17 months, 34 months, and 10 years after diagnosis. The other five patients are alive at 9-51 months. CONCLUSION--Thymic carcinoid is a slow growing tumour with a poor prognosis because of its tendency to local and distant spread. Cytological examination of samples obtained by ultrasound guided fine needle aspiration may provide a useful method for diagnosis in selected patients.
Images
PMCID: PMC475370  PMID: 8202907
13.  Mediastinal neoplasms in patients with Graves disease: a possible link between sustained hyperthyroidism and thymic neoplasia? 
Thyroid Research  2012;5:5.
Background
Anterior mediastinal masses are a rare but well documented finding in Graves disease. The vast majority of these lesions represents benign thymic hypertrophy and regress after treatment of the hyperthyroidism. A small percentage of these cases however represent neoplastic/malignant diseases which require further treatment.
Cases
12 year old boy with one year history of refractory Graves disease was found to have an anterior mediastinal mass and underwent curative thyroidectomy for sustained hyperthyroidism. Cervical lymphadenopathy was detected during the procedure and biopsy was obtained. A 23 year old woman who presented with a one month history of hyperthyroid symptoms, was diagnosed with Graves disease and also was found to have an anterior mediastinal mass on imaging. Biopsy of the anterior mediastinal mass was obtained and subsequently the patient underwent robotic thymectomy. Histologic examination and immunophenotyping of the cervical lymph node in a 12 year old boy revealed neoplastic proliferation of T lymphoblasts diagnostic of T lymphoblastic leukemia/lymphoma. Examination of the anterior mediastinal mass biopsy in the 23 year old woman revealed type B1 thymoma which was confirmed after examination of the subsequent robotic thymectomy specimen.
Conclusion
This is the first reported case of T cell lymphoblastic lymphoma and the third reported case of thymoma associated with sustained hyperthyroidism due to Graves disease. These cases indicate that an anterior mediastinal mass in a patient with active Graves disease may be due to a neoplastic cause, which may require definitive treatment. Caution should be exercised when dismissing a mediastinal mass as benign thymic hyperplasia in patients with active Graves disease.
doi:10.1186/1756-6614-5-5
PMCID: PMC3411457  PMID: 22824515
Graves disease; Hyperthyroidism; Thymoma; T Lymphoblastic leukemia/lymphoma; Thymic hyperplasia
14.  P36 - Severe Osteoporosis in Cushing’s Syndrome 
Cushing’s syndrome is characterised by a series of clinical manifestations due to hypersecretion of cortisol. These include: arterial hypertension, diabetes mellitus (DM), asthenia, amenorrhea, osteoporosis and pathological fractures. We describe the case of a 70-year-old woman with Cushing’s syndrome with right adrenal adenoma, vertebral compression fractures (VCFs) and severe secondary osteoporosis. This patient had been diagnosed with Cushing’s syndrome in May 2008, three years after the onset of arterial hypertension and type II DM, treated with insulin; in July 2008, she underwent right adrenalectomy and replacement therapy with cortisone acetate, 37.5 mg/day, in association with a multiple drug regimen for hypertension and DM; she also had an at least 10-year history of dorso-lumbar pain with multiple disc protrusions. As part of a series of investigations for Cushing’s syndrome the patient underwent femoral bone mineral densitometry, recording a T-score <−3, radiographic examination of the dorso-lumbar spine, which revealed collapse of the superior endplate of D7 and a wedge fracture of D8. At the endocrinology centre of reference for Cushing’s syndrome, she began treatment with alendronate 70 mg/day without undergoing blood chemistry tests of bone metabolism and without calcium and vitamin D supplementation. At the end of August 2009, she experienced worsening spinal pain due to a new severe fracture of D9, which was confirmed on MRI as a recent fracture. At the end of December 2009 she received kyphoplasty of D9, antiresorptive therapy and a CAMP-C35 brace.
In January 2010 she was admitted to the specialist rehabilitation unit for functional recovery, in view of her comorbidities, and bone disease investigation, with collection of history relating to osteoporosis risk factors. First- and second-level blood chemistry analyses revealed the presence of iron-deficiency anaemia, mild chronic renal insufficiency, and secondary hyerparathyroidism (PTH 101ng/ml); spinal radiography revealed severe VCFs of D7, D8 and D9, treated with kyphoplasty; the patient was also assessed using the VAS for pain, the FIM to evaluate independence in activities of daily living, and the SF-36 to investigate quality of life. The alendronate treatment was suspended and the patient was given cholecalciferol 300,000 IU, administered as an oral bolus, followed by a maintenance dose of 800 IU/day. When PTH values had returned to normal, she began treatment with teriparatide 20 mcg/day s.c. (therapeutic plan in compliance with Note 79 issued by the AIFA - Italian Drug Agency).
In conclusion, this case underlines the importance of a correct diagnostic and therapeutic approach in patients with severe osteoporosis. Over time, we will evaluate the efficacy of the treatment in preventing new fractures and the whether the use of a bone anabolic agent might be the correct choice also in order to control pain and improve quality of life. There are no reports in the literature of patients with Cushing’s syndrome treated with teriparatide.
PMCID: PMC3213844
15.  Functioning Adrenocortical Tumors in Children-Secretory Behavior 
Objective: Adrenocortical tumors are rare childhood neoplasms. More than 95% are functional and present with virilization, Cushing’s syndrome, hypertension, or hyperestrogenism. The objective of this paper is to present the clinical, laboratory and pathological findings of this rare disease and to highlight the secretory behavior of these tumors.
Methods: Clinical and laboratory data of seven Iranian children and adolescents aged between 2 and 16 years with functioning adrenocortical tumors are presented. Five patients had virilization and two had Cushing’s syndrome at the time of diagnosis. In all subjects, the tumors were removed successfully by open surgery, during which a blood sample was drawn from the corresponding adrenal vein for hormonal evaluation.
Results: Peripheral blood evaluation revealed that in addition to the dominant hormone (testosterone in the cases presenting with virilization and cortisol in those with Cushing’s syndrome), significant amounts of other hormones were secreted from these tumors. Adrenal vein evaluation revealed that testosterone, dehydroepiandrosterone sulfate, estradiol, ?17(OH) progesterone, and cortisol were directly released from the tumor. The tumors weighed between 36-103 grams. The patients have since been followed for 5 to 20 years, and there have been no signs or symptoms of relapse in any of the patients.
Conclusions: The study shows that functioning adrenocortical tumors should be considered in children and adolescents presenting with hyperandrogenism, Cushing’s syndrome, or hyperestrogenism. A diagnosis of a functioning adrenocortical tumor requires surgical removal as early as possible to prevent the untoward effects of virilization or corticosteroid excess. Evaluation of adrenal vein hormones showed that the steroids are secreted directly from the tumor and peripheral conversion has little contribution to the serum levels.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.835
PMCID: PMC3628389  PMID: 23367496
Adrenocortical tumors; child; virilism; feminization; Cushing’s syndrome
16.  Five cases of cyclical Cushing's syndrome. 
Reported cases of cyclical Cushing's syndrome are rare. Of 14 successive patients with Cushing's syndrome nine collected sequential urine samples for the estimation of cortisol:creatinine ratio. Five had cyclical Cushing's syndrome while two had considerable variation in urinary cortisol excretion without a cyclical pattern being established. Two of the five patients with a cyclical syndrome had paradoxical responses to dexamethasone. In only one patient with a cyclical pattern did the cortisol:creatinine ratio fall after treatment with bromocriptine or cyproheptadine, or both. The high incidence of the cyclical form of Cushing's syndrome has important clinical implications. A high index of suspicion of the syndrome is required in patients with symptoms or signs of Cushing's syndrome but with normal cortisol values, in patients with fluctuating cortisol values, and in patients with anomalous responses to dexamethasone. Because of possible variations in steroidogenesis the results of drug studies in Cushing's syndrome must be interpreted cautiously.
PMCID: PMC1418075  PMID: 2998540
17.  Topical-steroid-induced iatrogenic Cushing syndrome in the pediatric age group: A rare case report 
Cushing syndrome, a systemic disorder, is the result of abnormally high blood level of cortisol or other glucocorticoids. The most common cause of Cushing syndrome is prolonged exogenous administration of glucocorticoid hormones. Prolonged use of topical corticosteroids, particularly in children, may cause Cushing syndrome and suppression of the hypothalamopituitory-adrenal axis, which is less common than that of oral or parenteral route. However, iatrogenic Cushing syndrome in the infantile age group due to topical steroid is very rare and only a few patients have been reported to date in the literature. Here we report a case of iatrogenic Cushing syndrome due to topical steroid application in a 5-month-old female child admitted to the hospital for repeated episodes of fever and cough.
doi:10.4103/2230-8210.119593
PMCID: PMC3830325  PMID: 24251179
Hypothalamopituitory axis; İatrogenic Cushing's syndrome; topical corticosteroid
18.  "Osler's phenomenon": misdiagnosing Cushing's syndrome 
Postgraduate Medical Journal  2003;79(936):594-596.
Four cases of Cushing's syndrome are described that were associated with deteriorating morbidity because of the considerable delay from first presentation to a secondary care physician to eventual diagnosis. The clinical diagnosis was delayed in all the four patients, although they had symptoms and signs that were missed by a number of primary and secondary care physicians. Trans-sphenoidal surgery resulted in biochemical cure as well as improvement in the accompanying co-morbidity.
Although still rare, the prevalence of Cushing's syndrome is increasing. Increasing clinical awareness and the use of appropriate screening tests should facilitate earlier diagnosis with reduced morbidity and mortality. Although the syndrome is named after Harvey Cushing, Sir William Osler was probably the first to describe it. Therefore, in deference to Osler's contribution to Cushing's syndrome and the work of Harvey Cushing, it is suggested that to the list of the other eponymous conditions of Osler-Weber-Rendu and Osler's nodes, should be added the delay or misdiagnosis of Cushing's syndrome—"Osler's phenomenon".
doi:10.1136/pmj.79.936.594
PMCID: PMC1742858  PMID: 14612605
19.  Pathogenesis of hepatic steatosis: The link between hypercortisolism and non-alcoholic fatty liver disease 
Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing’s syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing’s syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing’s syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing’s syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.
doi:10.3748/wjg.v19.i40.6735
PMCID: PMC3812473  PMID: 24187449
Nonalcoholic fatty liver disease; Cushing’s syndrome; Hypercotisolism
20.  Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: a case report and review of the literature 
Diagnostic Pathology  2010;5:56.
Background
Cushing's Syndrome (CS) which is caused by isolated Corticotropin-releasing hormone (CRH) production, rather than adrenocorticotropin (ACTH) production, is extremely rare.
Methods
We describe the clinical presentation, course, laboratory values and pathologic findings of a patient with isolated ectopic CRH causing CS. We review the literature of the types of tumors associated with this unusual syndrome and the behavior of these tumors by endocrine testing.
Results
A 56 year old woman presented with clinical and laboratory features consistent with ACTH-dependent CS. Pituitary imaging was normal and cortisol did not suppress with a high dose dexamethasone test, consistent with a diagnosis of ectopic ACTH. CT imaging did not reveal any discrete lung lesions but there were mediastinal and abdominal lymphadenopathy and multiple liver lesions suspicious for metastatic disease. Laboratory testing was positive for elevated serum carcinoembryonic antigen and the neuroendocrine marker chromogranin A. Serum markers of carcinoid, medullary thyroid carcinoma, and pheochromocytoma were in the normal range. Because the primary tumor could not be identified by imaging, biopsy of the presumed metastatic liver lesions was performed. Immunohistochemistry was consistent with a neuroendocrine tumor, specifically small cell carcinoma. Immunostaining for ACTH was negative but was strongly positive for CRH and laboratory testing revealed a plasma CRH of 10 pg/ml (normal 0 to 10 pg/ml) which should have been suppressed in the presence of high cortisol.
Conclusions
This case illustrates the importance of considering the ectopic production of CRH in the differential diagnosis for presentations of ACTH-dependent Cushing's Syndrome.
doi:10.1186/1746-1596-5-56
PMCID: PMC2942804  PMID: 20807418
21.  Nonseminomatous germ cell tumor with seizure disorder and mental retardation 
We report a case of a patient who presented with anterior mediastinal mass, seizure disorder, and mental retardation. Computerized tomography–guided fine-needle aspiration biopsy of the mass showed nonseminomatous germ cell tumor. Chromosomal analysis showed XXY karyotype. A diagnosis of Klinefelter syndrome and mediastinal germ cell tumor was made.
doi:10.4103/0970-2113.56351
PMCID: PMC2876702  PMID: 20531999
Klinefelter syndrome; nonseminomatous germ cell tumor; Mediastinal germ cell tumors
22.  Adrenocortical oncocytic neoplasm presenting with Cushing's syndrome: a case report 
Introduction
Oncocytic neoplasms occur in several organs and are most commonly found in the thyroid, kidneys and salivary glands. Oncocytic neoplasms of the adrenal cortex are extremely rare and are usually non-functioning.
Case presentation
We report the case of an adrenocortical oncocytic neoplasm with uncertain malignant potential in a 31-year-old man with Cushing's syndrome. The patient had been operated on following diagnosis of a 7 cm adrenal mass. Following surgery, the Cushing's syndrome resolved. The patient is still alive with no metastases one year after the surgery.
Conclusion
Adrenocortical oncocytic neoplasms must be considered in the differential diagnosis of both functioning and non-functioning adrenal masses.
doi:10.1186/1752-1947-2-228
PMCID: PMC2481265  PMID: 18620603
23.  Disease-specific quality of life evaluation and its determinants in Cushing’s syndrome: what have we learnt? 
Pituitary  2013;17:187-195.
Cushing’s syndrome (CS) has a considerable negative impact on patient health-related quality of life (HRQoL). Two disease-specific instruments (the CushingQoL and the Tuebingen CD-25 questionnaire) are now available to assess the impact of the disease and its treatment on HRQoL. The purpose of this review was to summarize the characteristics of the studies which have used these two instruments to date and summarize their findings regarding (a) the determinants of disease-specific HRQoL in patients with CS and (b) the impact of treatment for CS on disease-specific HRQoL. A total of 7 studies were identified, 5 with the CushingQoL and 2 with the Tuebingen CD-25. Most were observational studies, though the CushingQoL had been used in one randomized clinical trial. In terms of clinical factors, there was some evidence for an association between UFC levels and disease-specific HRQoL, though the presence and strength of the association varied between studies. There was also some evidence that a more recent diagnosis of CS could lead to poorer HRQoL, and that length of time with adrenal insufficiency may also affect HRQoL. There was no evidence for an impact on disease-specific HRQoL of etiology or of the clinical signs and symptoms associated with CS, such as bruising, rubor, and fat deposits. One factor which did have a significant negative effect on HRQoL was the presence of depression. No clear picture emerged as to the effect of demographic variables such as age and gender on HRQoL scores, though there was some evidence for poorer HRQoL in female patients. As regards treatment, the two interventions studied to date (transsphenoidal surgery and pasireotide) both showed significant gains in HRQoL, with moderate to large effect sizes. This type of review is useful in summarizing knowledge to date and suggesting future research directions.
doi:10.1007/s11102-013-0484-2
PMCID: PMC3942630  PMID: 23564339
Quality of life; Cushing syndrome; Treatment for Cushing’s syndrome; Factors related to HRQoL
24.  Adrenocorticotropic Hormone-Independent Cushing Syndrome with Bilateral Cortisol-Secreting Adenomas 
Endocrinology and Metabolism  2013;28(2):133-137.
A 48-year-old woman was incidentally found to have bilateral adrenal masses, 2.8 cm in diameter on the right, and 2.3 cm and 1.7 cm in diameter on the left, by abdominal computed tomography. The patient had a medical history of hypertension, which was not being controlled by carvedilol, at a dose of 25 mg daily. She presented with signs and symptoms that suggested Cushing Syndrome. We diagnosed adrenocorticotropic hormone (ACTH)-independent Cushing Syndrome based on the results of basal and dynamic hormone tests. Adrenal vein sampling (AVS) was performed to localize a functioning adrenal cortical mass. AVS results were consistent with hypersecretion of cortisol from both adrenal glands, with a cortisol lateralization ratio of 1.1. Upon bilateral laparoscopic adrenalectomy, bilateral ACTH-independent adrenal adenomas were found. The patient's signs and symptoms of Cushing Syndrome improved after surgery just as the blood pressure was normalized. After surgery, the patient was started on glucocorticoid and mineralocorticoid replacement therapy.
doi:10.3803/EnM.2013.28.2.133
PMCID: PMC3811713  PMID: 24396667
Adrenal vein sampling; Bilateral cortisol-secreting adenomas; Cushing Syndrome
25.  Mapping CushingQoL Scores onto SF-6D Utility Values in Patients with Cushing’s Syndrome 
The Patient  2013;6(2):103-111.
Objectives
To construct a prediction model of preference-adjusted health status (SF-6D) for Cushing’s syndrome using a disease-specific health-related quality of life (HRQOL) measure (CushingQoL).
Methods
Data were obtained from the original multicenter, multinational study to validate the CushingQoL questionnaire. HRQOL was measured using the CushingQoL and the SF-36 questionnaires. SF-6D scores were calculated from responses on the SF-36. Sociodemographic and clinical data were also collected. Various predictive models were tested and the final one was selected on the basis of four criteria: explanatory power, consistency of estimated coefficients, normality of prediction errors, and parsimony.
Results
For the mapping analysis, data were available from 116 of the 125 patients included in the original validation study. Mean (SD) age was 45.3 (13.1) years and the sample was predominantly (83 %) female. Patients had a mean (SD) CushingQoL score of 52.9 (21.9), whereas the SF-6D (derived from SF-36) was skewed towards better health with a mean of 0.71 (median 0.74) on a scale of −0.704 to 1. Of the various models tested, a model which included the intercept (0.61), CushingQoL overall score, level one in CushingQoL item 2 (always have pain preventing me from leading a normal life), and level one in CushingQoL item 10 (my illness always affects my everyday activities) best met the four criteria for model selection. The model had an adjusted R2 of 0.60 and a root mean square error of 0.084.
Conclusions
Although the mapping function finally selected appears to be able to accurately map CushingQoL scores onto SF-6D outcomes at the group level, further testing is required to validate the model in independent patient samples.
doi:10.1007/s40271-013-0010-7
PMCID: PMC3663200  PMID: 23549927

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