Ectopic Adrenocorticotropic Hormone Production Research Articles

Difficult Diagnosis and Management of Concealed Cushing.

Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat. A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day. ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

Neuroendocrine tumor of thymus with ectopic production of adrenocorticotropic hormone in a 13-year-old child. Case report, 5-year follow-up

Neuroendocrine tumor of thymus with ectopic production of adrenocorticotropic hormone in a 13-year-old child. Case report, 5-year follow-up

Ectopic Cushing’s Syndrome as the First Presenting Sign of Small Cell Lung Carcinoma

A 67-year-old man with a history of hypertension, hyperlipidemia, coronary artery disease, and former smoking presented with fatigue, lower extremity edema, and a new tremor over the course of one month. Workup was notable for hypokalemia, metabolic alkalosis, and extremely elevated adrenocorticotropic hormone (ACTH) and cortisol levels. He was ultimately diagnosed with ectopic Cushing’s syndrome (CS) secondary to new metastatic small cell lung carcinoma. About 5-10% of CS cases are caused by ectopic ACTH production. The most commonly implicated malignancies are small cell lung cancer (SCLC) and neuroendocrine tumors, with SCLC accounting for up to three-fourths of cases. ACTH production is a poor prognostic sign in SCLC, associated with more extensive disease and decreased response to first-line treatment. Tumor-associated ACTH production is often so rapid that patients do not have time to develop classic Cushingoid physical exam findings, instead presenting with acute-onset hyperglycemia, pseudohyperaldosteronism, and generalized weakness. Prompt diagnosis and treatment are essential to improve outcomes.

Ectopic-Adrenocorticotropic Hormone secretion in adolescents and young adult patients with neuroendocrine neoplasm: a challenge for clinical and social management

Well and poorly differentiated neuroendocrine neoplasms (NENs) may be associated with an ectopic production of Adrenocorticotropic Hormone (ACTH) [1] that leads to a paraneoplastic Cushing Syndrome (CS). This heterogeneous clinical pattern is the result of a hypercortisolism [2] due to an uncontrolled and continuous hyperstimulation of the adrenal cortex, which escapes the negative feedback of the Hypothalamus-Hypophysis axis [3]. Among NENs, ectopic-ACTH secretion (EAS) has been historically associated with small-cell lung cancers (SCLCs), but the improvement of the knowledge and diagnostic techniques led to a broadening of the causes also to NENs with different morphologies and from other sites [4]. According to the previous published data, EAS by gastro-entero-pancreatic (GEP) NENs occurs in almost 13% of cases. Irrespective of the NENs site of origin and the biology (which means morphology and proliferation index), the CS may represent a life-threatening condition for the patients due the consequences of the mineralocorticoid effect of persistent high levels of cortisol. These patients may experience a plethora of different symptoms which includes diffuse oedema, overweight/obesity of the trunk and striae rubrae, but also severe hypokalemia and hypertension, that represent medical emergencies and tumor fatal consequences even without a progression disease [1]. EAS may initially occur with non-specific clinical manifestations, as psychiatric complaints, recurrent orthopedic issues, sexual and reproductive disfunctions [3] that are not easily related to a tumoral cause and lead the patient presents to many specialists before being referred to an endocrinology / oncology Center. For all these reasons, CS diagnosis is often delayed. In a very small pool of cases [5], EAS may occur in the peculiar category of the adolescents and young adults (AYA) patients, worldwide defined as the cancerpopulation between 15 and 39 years of age [6]. Generally, the cancer diagnosis in AYA population is delayed, on one hand due to the sense of invulnerability and the minimizing of the symptoms of AYA patients and, on the other, the trend of the providers to a low suspicion of cancer in AYA population. Therefore, the features of the AYA category together with the equivocal clinical patterns of CS may lead to a delay of the diagnosis and management of EAS by extra-pituitary NENs [3, 7]. Here we reported the case of a NEN AYA patient with CS by EAS and a review of the literature on this topic in this peculiar population.

Cushing’s disease secondary to a pancreatic Ewing Sarcoma in an 18-month-old child: a case report

Extraskeletal paediatric Ewing Sarcoma with resultant Cushing’s syndrome due to ectopic ACTH (adrenocorticotropic hormone) production is a very rare presentation with a poor prognostic outlook. This is the first pancreatic case ever reported.

Cushing Syndrome Secondary to Ectopic ACTH Production in Pregnancy: A Case Report

Ectopic adrenocorticotropic hormone production is an extremely rare cause of Cushing syndrome in pregnancy and is associated with significant morbidity. A 37-year-old multiparous woman at 32 weeks’ gestation presented with hypertension, anasarca, hypokalemia, and fetal distress requiring an urgent cesarean section. Her adrenocorticotropic hormone and cortisol levels were elevated, and high-dose dexamethasone failed to suppress them, suggesting ectopic adrenocorticotropic hormone production. Multimodality imaging did not identify a source, and she had urgent bilateral adrenalectomy for refractory severe hypercortisolism. Ectopic Cushing syndrome in pregnancy requires a high index of suspicion for diagnostic testing and prompt treatment to minimize maternal and fetal complications.

A Rare Cause of Hypokalemia: Ectopic ACTH Syndrome

The most common cause of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is a benign ACTH-producing pituitary tumour or, less frequently, ectopic ACTH production from non-pituitary tumours. Ectopic ACTH syndrome occurs more commonly in men and usually presents after 40 years. It is most commonly associated with small cell lung cancer. Although this syndrome is associated with severe hypercortisolemia, some findings of Cushing’s syndrome, such as central obesity, may not be observed due to underlying malignant diseases. In these cases, rapid metabolic disruption, anorexia, myopathy, glucose intolerance, hypokalemic alkalosis, and hyperpigmentation accompany the patients’ clinical condition. In the current case report, we aimed to emphasize that ectopic ACTH syndrome should be kept in mind in the differential diagnosis, especially in the presence of hypokalemia accompanying hypertension and proximal muscle weakness, if the patient also has progressive weight loss.

Cushing´s syndrome: high aggressiveness of low-grade tumors

Cushing´s syndrome is caused by prolonged exposition supraphysiological to endogenous or exogenous cortisol. Ectopic production of adrenocorticotropic hormone by lung carcinoid tumors is relatively rare. Most documented cases have been reported individually. This rare neoplasm low grade that may secrete adrenocorticotropin (ACTH) leading to rapid development of hypercortisolism which is the main mode of discovery, can be a real aggressive form. This report shows a high aggressiveness of this endocrine neoplasia, wich was marked on the general, morphological, bone and psychiatric level. The trivialization of clinical signs had caused the delay in diagnosis with irreparable bone consequences.

Ectopic Adrenocorticotropic Hormone Production: A Case of Neuroendocrine Cervical Small Cell Carcinoma Presenting as Cushing Syndrome

Objective: To present a case of Cushing syndrome caused by a rare, ectopic, adrenocorticotropic hormone (ACTH)-secreting neuroendocrine small cell carcinoma of the cervix. Methods: A differential diagnosis was considered in a young female with ectopic ACTH-dependent Cushing syndrome. Results: A 35-year-old female presented with multiple complications of Cushing syndrome including hypertension, diabetes mellitus, weight gain, and profound lower-extremity weakness. Serum ACTH was elevated and dexamethasone suppression testing with both 1 mg and 8 mg failed to suppress cortisol. Pituitary magnetic resonance imaging and computed tomography of the adrenals were negative. Positron emission tomography and computed tomography revealed a 5.4 × 5.3-cm hypermetabolic pelvic mass with metastases to the lungs. Cervical biopsy confirmed small cell carcinoma of the cervix. The patient underwent1 round of chemotherapy however later passed away due to septic shock and multiple organ failure. Conclusion: Neuroendocrine sma...

Spontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review

BackgroundEctopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition.Case presentationA 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing’s syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2–63.3 pg/mL), cortisol (73.1 μg/dL; 6.4–21.0 μg/dL) and 24-h urinary free cortisol (UFC) (6160 μg/day; 11.2–80.3 μg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case.ConclusionMTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.

Cushing Syndrome: Diagnostic Workup and Imaging Features, With Clinical and Pathologic Correlation.

Cushing syndrome (CS) is a constellation of clinical signs and symptoms resulting from chronic exposure to excess cortisol, either exogenous or endogenous. Exogenous CS is most commonly caused by administration of glucocorticoids. Endogenous CS is subdivided into two types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent. Cushing disease, which is caused by a pituitary adenoma, is the most common cause of ACTH-dependent CS for which pituitary MRI can be diagnostic, with bilateral inferior petrosal sinus sampling useful in equivocal cases. In ectopic ACTH production, which is usually caused by a tumor in the thorax (e.g., small cell lung carcinoma, bronchial and thymic carcinoids, or medullary thyroid carcinoma) or abdomen (e.g., gastroenteropancreatic neuroendocrine tumors or pheochromocytoma), CT, MRI, and nuclear medicine tests are used for localizing the source of ACTH. In ACTH-independent CS, which is caused by various adrenal abnormalities, adrenal protocol CT or MRI is usually diagnostic.

Severe Cushing's syndrome due to small cell prostate carcinoma: a case and review of literature.

Cushing’s syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) is associated with a variety of tumours most of which arise in the thorax or abdomen. Prostate carcinoma is a rare but important cause of rapidly progressive CS. To report a case of severe CS due to ACTH production from prostate neuroendocrine carcinoma and summarise previous published cases. A 71-year-old male presented with profound hypokalaemia, oedema and new onset hypertension. The patient reported two weeks of weight gain, muscle weakness, labile mood and insomnia. CS due to ectopic ACTH production was confirmed with failure to suppress cortisol levels following low- and high-dose dexamethasone suppression tests in the presence of a markedly elevated ACTH and a normal pituitary MRI. Computed tomography demonstrated an enlarged prostate with features of malignancy, confirmed by MRI. Subsequent prostatic biopsy confirmed neuroendocrine carcinoma of small cell type and conventional adenocarcinoma of the prostate. Adrenal steroidogenesis blockade was commenced using ketoconazole and metyrapone. Complete biochemical control of CS and evidence of disease regression on imaging occurred after four cycles of chemotherapy with carboplatin and etoposide. By the sixth cycle, the patient demonstrated radiological progression followed by recurrence of CS and died nine months after initial presentation. Prostate neuroendocrine carcinoma is a rare cause of CS that can be rapidly fatal, and early aggressive treatment of the CS is important. In CS where the cause of EAS is unable to be identified, a pelvic source should be considered and imaging of the pelvis carefully reviewed.

An Unlikely Cause of Hypokalemia

BackgroundHypokalemia is a common clinical disorder caused by a variety of different mechanisms. Although the most common causes are diuretic use and gastrointestinal losses, elevated cortisol levels can also cause hypokalemia through its effects on the renin–angiotensin–aldosterone system. Cushing's syndrome refers to this general state of hypercortisolemia, which often manifests with symptoms of generalized weakness, high blood pressure, diabetes mellitus, menstrual disorders, and psychiatric changes. This syndrome is most commonly caused by exogenous steroid use, but other etiologies have also been reported in the literature. Ectopic adrenocorticotropic hormone production by small-cell lung cancer is one rare cause of Cushing's syndrome, and may be associated with significant hypokalemia. Case ReportWe describe the case of a 62-year-old man who presented to the emergency department with weakness and hypokalemia. The patient was initially misdiagnosed with furosemide toxicity. Despite having a 30-pack-year smoking history, this patient's lack of respiratory complaints allowed him to present for medical attention twice before being diagnosed with lung cancer. It was later determined that this patient's hypokalemia was due to Cushing's syndrome caused by ectopic adrenocorticotropic hormone production from small-cell lung cancer. Why Should an Emergency Physician Be Aware of This?This case reminds emergency physicians to consider a broad differential when treating patients with hypokalemia. More importantly, it prompts emergency physicians to recognize comorbid conditions and secondary, less common etiologies in patients with repeated visits for the same complaint.

Clinical and morphological characteristic of ACTH producing tumors of various localization and the ectopic Cushing’s syndrome

Background: Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is a type hypercorticism caused by ectopic production of ACTH and/or its precursors by neuroendocrine tumors (NET) of various localization, such as lung and thymus carcinoids, less frequently those of pancreas and gastrointestinal tract, medullary thyroid cancer, pheochromocytoma, small cell lung cancer, as well as some other tumor types. The wide spectrum of tumors associated with the ectopic ACTH syndrome (EAS) makes their diagnosis and treatment a complicated issue. Materials and methods : The study was done with surgical and diagnostic biopsy samples from 60 patients who had tumors with EAS, 36 (60%) of them being bronchopulmonary carcinoids, 10 (16.7%) thymus carcinoids, 5 (8.3%) pancreatic NETs, 3 (5%) medullary thyroid cancers, 3 (5%) NETs of unknown primary localization, and NET of appendix, cecum and pheochromocytoma (one case of each, i.e. 1.7%, 1.7%, 1.7%). There were 38 female and 22 male patients (1.72:1), with their mean age of 39 ± 14 years (range, 16 to 77 years). We analyzed their clinical data, as well as the results of morphological and immunohistochemical examination of the tumors. Results : According to the World Health Organization classification (2015), typical carcinoids (TC) of the lung were found in 77.8% (28/36) of the bronchopulmonary tumors. 22.2% (8/36) of the bronchopulmonary tumors and all thymus tumors (100%, n = 10) were classified as atypical carcinoids (ATC). Four pancreatic NETs were classified as Grade 2 (G2), 1 as G3, and NETs of the cecum and appendix as G1 and G2, respectively. At present, 29 (48%) patients are living with no relapse (mean age 39 ± 13.5 years), whereas 22 (37%) of patients developed a relapse (mean age 35 ± 13 years), and 15 (25%) of them died, regardless of the age of the patients The history of the disease was not traced in 4 cases. 5-year relapse-free survival of patients with TC of the lung was 85.7% (24/28), of those with ATC 25% (2/8), with ATC of the thymus and medullary thyroid cancer 0%. Mortality from to TC of the lung for the entire follow-up period was 3.6% (1/28), to ATC 12.5% (1/8), to ATC of the thymus and for medullary thyroid cancer 62.5% and 100%, respectively. The patients with NET of the cecum, appendix and pheochromocytoma are alive without progression for 4, 5 and 6 years, respectively. Therefore, the lowest 5-year survival of patients with EAS was observed in medullary thyroid cancer, pancreatic NET and thymus carcinoids: in 100% (3/3), 75% (3/4), and 57.1% (4/7), respectively. Conclusion: The most unfavorable prognostic factors in the EAS are the localization of tumors in the thymus, pancreas and thyroid gland. This indicates the necessity of a differentiated treatment approaches to patients with this syndrome.

Frequency of Cushing\u2019s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center

Cushing’s syndrome due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions has occasionally been described. We retrospectively reviewed all 164 cases of Cushing’s syndrome and 77 cases of pheochromocytomas during 10 years. Of all cases with Cushing’s syndrome, only two cases (1.2 %) were due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions (one case of pheochromocytoma and one case of adrenal medullary hyperplasia). Of all pheochromocytomas only the above-mentioned case (1.3 %) also gave rise to an ectopic adrenocorticotropic hormone syndrome. The clinical presentation of adrenocorticotropic hormone-secreting pheochromocytoma and adrenal medullary hyperplasia can be anything from mild to dramatic. These are rare conditions important to bear in mind in the workup of a patient with Cushing’s syndrome or with pheochromocytoma. The identification of ectopic adrenocorticotropic hormone secretion from adrenal medullary lesions can be life-saving.

Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome.

Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin.

Bilateral inferior petrosal sinus sampling using vasopressin

Context:Anatomical localization of pituitary adenoma can be challenging in adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, and bilateral inferior petrosal sinus sampling (BIPSS) is considered gold standard in this regard. Stimulation using corticotrophin-releasing hormone (CRH) improves the sensitivity of BIPSS, however, same is not easily available in India. Therefore, we undertook this study of BIPPS using vasopressin as agent for stimulation owing to its ability to stimulate V3 receptors present on corticotrophs.Aims:To study the tumor localization and lateralization in difficult to localize cases of ACTH-dependent Cushing's syndrome by bilateral inferior petrosal sinus sampling using vasopressin for corticotroph stimulation.Settings and Design:Prospective observational study.Subjects and Methods:Six patients (5 females) meeting inclusion criteria underwent BIPSS using vasopressin for stimulation.Results:All six patients had nonsuppressible overnight and low dose dexamethasone suppression test with elevated plasma ACTH levels suggestive of ACTH-dependent Cushing's syndrome. High dose dexamethasone suppression test showed suppressible cortisol in two cases, and microadenoma was seen in two patients on magnetic resonance imaging pituitary. Contrast enhanced computed tomography of the abdomen showed left adrenal hyperplasia in one case and anterior mediastinal mass with bilateral adrenal hyperplasia another. Using BIPSS four patients were classified as having Cushing's disease that was confirmed histopathologically following surgery. Of the remaining two, one had primary pigmented nodular adrenocortical disease, and another had thymic carcinoid with ectopic ACTH production as the cause of Cushing's syndrome. No serious adverse events were noted.Conclusions:Vasopressin may be used instead of CRH and desmopressin for stimulation in BIPSS.

Ectopic Adrenocorticotropin Production in a Patient with Lung Cancer: A Case Report

Ectopic Adrenocorticotropin Production in a Patient with Lung Cancer: A Case Report

Biochemical Testing in Patients with Neuroendocrine Tumors.

Neuroendocrine tumors are usually slow-growing tumors. Many of these are capable of secreting peptide hormones or biogenic amines that may lead to endocrine syndromes. Nonfunctioning tumors can either secrete no hormones at all, or secrete hormones not giving rise to endocrine symptoms, such as chromogranin A, chromogranin B or pancreatic polypeptide. Chromogranin A is produced by the majority of endocrine tumors, both functioning and nonfunctioning, and is the best available marker for diagnosis, follow-up and treatment monitoring of patients with differentiated neuroendocrine tumors. Examples of endocrine syndromes are classical carcinoid syndrome caused by serotonin (measured in the urine as its metabolite 5-HIAA), insulinoma syndrome caused by insulin or proinsulin, Zollinger-Ellison syndrome resulting from gastrin secretion, glucagonoma syndrome caused by glucagon, WDHA syndrome caused by vasoactive intestinal peptide, or Cushing's syndrome resulting from ectopic production of adrenocorticotropic hormone or corticotropin-releasing hormone. In case there is uncertainty about the diagnosis, specific tests can be applied, such as the secretin test for diagnosis of gastrinomas and the 72-hour fast for diagnosis of an insulinoma. In patients with suspicion of an inherited syndrome, such as multiple endocrine neoplasia (MEN) 1 and MEN2 syndromes, genetic testing is indicated.

Death in pediatric Cushing syndrome is uncommon but still occurs.

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 18years 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 7.5-15.5years (mean age 11.2years) with length of disease 2-4years, were recorded among 160 (2.5%) children seen at or referred to the NIH over the last 15years. 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. 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.