bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary Macronodular Adrenal Hyperplasia Associated With Autosomal Dominant ARMC5 Mutation
Authors: Kerut Sarah Elizabeth , Subauste Angela 
Published: May 2021

Abstract
Background: Primary macronodular adrenal hyperplasia (PMAH) is an uncommon cause of Cushing’s syndrome. In some cases, this is an inherited disorder due to a mutation in the armadillo repeat-containing 5 (ARMC5) gene. Clinical Case: A 43-year-old African American woman presented to clinic with weight gain, worsening type 2 diabetes mellitus, and symptomatic hypertensive cardiomyopathy. Physical exam was significant for central obesity, bilateral supraclavicular fat pads, acanthosis nigricans and wide striae over the abdomen. Her serum cortisol was 13.8 mcg/dL after 1 mg of dexamethasone (n&lt;1.8 mcg/dL), urinary cortisol was 180 mcg in 24 hours (n=3.5–45 mcg/24h) and two midnight salivary cortisol tests were 227 and 118 ng/dL (n&lt;100 ng/dL). Her ACTH was 2.4 pg/mL (n=7.2–63.3 pg/mL). Computed tomography (CT) of the abdomen showed nodularity, diffuse thickening and low-density (&lt;10 Hounsfield units) of the bilateral adrenal glands. She underwent bilateral adrenalectomy for a diagnosis of PMAH. Pathology showed nodular adrenocortical hyperplasia; the right and left adrenal glands measured 75 grams and 68 grams, respectively. She was started on hydrocortisone and fludrocortisone postoperatively. Over the following two years, she had a 68-pound weight loss, an 86% reduction in her daily insulin requirement and a 10% improvement in her left ventricular ejection fraction. Approximately two years later, the patient’s brother was referred for bilateral macronodular hyperplasia incidentally discovered on a CT of the abdomen. He had a history of hypertension and type 2 diabetes mellitus with cushingoid features on exam. His serum cortisol was 20.7 mcg/dL after 1 mg of dexamethasone, urinary cortisol was 65.1 mcg in 24 hours, two midnight salivary cortisol tests were 232 and 404 ng/dL and ACTH was 2.0 pg/mL. Upon obtaining further family history, the patients reported clinical features of Cushing’s syndrome in their paternal grandmother but denied features in either parent. The second patient had genetic testing which showed a mutation in the ARMC5 gene, c.1777C&gt;T, p.R593W, a mutation previously described. Due to clinical signs of Cushing’s syndrome, he underwent bilateral adrenalectomy in which pathology showed right and left nodular adrenocortical hyperplasia measuring 110 and 73 grams, respectively. He is doing well postoperatively. The patients recently reported their aunt was diagnosed with PMAH and mild Cushing’s syndrome. She had a unilateral adrenalectomy of the larger adrenal gland and is doing well postoperatively. Conclusion: In some cases, Cushing’s syndrome is an inherited disorder. Autosomal dominant mutations in the ARMC5 gene are occasionally seen in PMAH, which causes less than 2% of endogenous Cushing’s syndrome. For all patients diagnosed with PMAH, clinicians should consider screening their family members with a dexamethasone suppression test.
Rare Case of Huge Adrenocortical Carcinoma in Surprisingly Asymptomatic Patient
Authors: AlJedaani Samia Mohammad , Al-Obaydi Sarah , Shah Aesha , Fan Chris , Manni Andrea 
Published: May 2021

Abstract
Introduction: Adrenal Carcinoma (AC) is a rare endocrine malignancy of the adrenal glands. It can affect up to 3–10% of the human population. It is common in children as secondary malignancies or as a manifestation of a tumor syndrome. Typically patients with AC start to become symptomatic after extensive tumor development- 10–13 cm. The presentation of AC includes signs of hormone excess. The most common hormone in excess is cortisol. Thus individuals with AC typically present with symptoms of hypercortisolism or Cushing’s Syndrome. In chronic cases the high concentration of glucocorticoids can start stimulating aldosterone receptors causing hypertension and hypokalemia. Furthermore, patients with AC also have symptoms of tumor growth, such as abdominal pain, flank pain, and early satiety. Currently prognostic factors for AC are undefined. AC generally has a poor prognosis as a majority of patients are diagnosed during advanced stage of disease (stage IV). Furthermore, it was found that patients with stage IV disease had a survival of less than one year. Currently the only curative treatment is complete tumor resection. Medical management with chemotherapy can be utilized in cases of extensive metastasis and poor prognosis. A common chemotherapeutic agent is mitotane, which is a steroidogenesis inhibitor. Case Presentation:Patient is a 19 year old female, who initially presented to her primary care provider’s (PCP) office for an annual wellness visit during August 2020. She was subsequently discovered to have elevated blood pressure. At this time she was not symptomatic. She was advised on lifestyle modifications. She was also stopped on her birth control medication. Furthermore, she later presented to her PCP with continued elevated blood pressure, still not symptomatic. In an outpatient cardiology office, she presented with blood pressures in the 200s/100s range and a new murmur. She was sent to the ED for evaluation (11/2020). On her presentation to the ED, she still did not have any symptoms. She also denied any fatigue or unintentional weight changes. Her only concern was mild edema in the lower legs after standing for extended periods of time. Her medical history was insignificant. Her family history was significant for her paternal essential HTN diagnosed in the early 20s. Laboratory evaluation revealed unremarkable electrolyte levels and CBC. Furthermore, her TSH level was also normal. A chest ray revealed multiple pulmonary nodules ranging from 3–5 mm. A renal ultrasound revealed a large mass in the RUQ (16.9x9.6x12 cm). She was also found to have mildly elevated cortisol levels at 22.9, suppressed ACTH levels, and normal levels of aldosterone and metanephrines. Subsequent CT imaging and biopsy revealed adrenal carcinoma with extensive metastasis to the lungs and liver. Patient was referred to Oncology service to start Chemotherapy.
Severe Cyclical Hypercortisolism Due to Metastatic Neuroendocrine Cancer Initially Diagnosed as Colon Cancer
Authors: Liu John Chen , Patel Richa , Gundluru Rajani , Parimi Joseph Theressa Nehu , Gusov Timur , Naha Sowjanya , Syed Hasan 
Published: May 2021

Abstract
Case Description: A 65 year-old male with initial diagnosis of metastatic colon cancer based on liver biopsy presented for evaluation of severe hypercortisolism with 24-hour urinary free cortisol (UFC) of 1184 mcg/day after presenting to his Oncologist in December 2019 requesting evaluation for muscle weakness and weight gain. On re-evaluation in March, his cortisol had dramatically improved with 24-hr UFC of 120 mcg/day and ACTH of 84 pg/mL and had resolved with 24-hr UFC of 32.6 mcg/day by May.
A 2 cm pancreatic lesion was noted during cancer staging; a second opinion was obtained on the liver biopsy which was interpreted as metastatic neuroendocrine tumor, possibly of pancreatic origin. The patient was started on FOLFINIRNOX in December 2019. This was transitioned to carboplatin and etoposide after the revised diagnosis and was continued through May with regression of liver lesions on followup imaging. A 68 Ga-DOTATATE PET CT confirmed uptake in the pancreas, retroperitoneal lymph nodes, and thyroid. A thyroid ultrasound was obtained which did not meet FNA criteria.
Given the chronologic association between cortisol levels and chemotherapy response we were suspicious for ectopic Cushing’s syndrome due to metastatic neuroendocrine cancer and the patient was followed for recurrence. In September, the patient endorsed leg weakness and hyperglycemia and was found to have a 24-hr UFC of 4731 mcg/day and an 8 am cortisol of 102 mcg/dL.
The patient developed severe hypokalemia requiring admission and was restarted on chemotherapy with moderate improvement in cortisol levels and symptoms. Given the degree of cortisol elevation, we recommended bilateral adrenalectomy, for which the patient established care at a more specialized center.
Discussion: Ectopic Cushing’s syndrome is an uncommon variety of ACTH-dependent Cushing’s syndrome caused by CRH or ACTH-producing tumors. The more aggressive form is associated with small-cell lung cancer while the chronic form is associated with indolent tumors.
Cyclical Cushing’s syndrome is a rare cause of hypercortisolism characterized by cyclical variations in cortisol levels. The pathophysiology of the cyclical variation is unclear. About half of cases are caused by pituitary corticotrophs but up to 26% can be attributed to ectopic ACTH production, typically due to indolent tumors rather than aggressive malignancies.
We present a case of cyclical hypercortisolism with an initial diagnosis of colon cancer. On further review, the cyclical hypercortisolism was likely associated with chemotherapy response. Reevaluation of surgical pathology was consistent with metastatic neuroendocrine cancer, the likely source of ectopic ACTH.
Our case highlights the importance of maintaining a broad differential when considering cases of cyclical cortisol elevation, including consideration of concurrent chemotherapy for seemingly unrelated malignancies.
Severe Hyponatremia With Partial Hypoadrenalism in Acute Porphyria
Authors: Marcus-Perlman Yonit , Lahav Meir , Shefer Gabi , Stern Naftali , Greenman Yona 
Published: May 2021

Abstract
Background: Hyponatremia is the most common electrolyte-abnormality in hospitalized-patients, it increases likelihood of hospital death up-to 50% when serum Na&lt;120mEq/L. Syndrome of inappropriate ADH secretion (SIADH) is the most common cause of hyponatremia in hospital inpatients. Clinical Case: 29 years-old woman, hospitalized several times due to severe hyponatremia of 103mEq/L; Admissions were accompanied by severe abdominal-pain and vomiting. She complained of severe premenstrual syndrome with severe abdominal pain and was hospitalized twice after intrauterine insemination. She was euvolemic and due to high urinary-sodium was diagnosed with SIADH. Brain MRI, chest x-ray, thyroid-function test, and 1-mcg ACTH-test were normal. Insulin Tolerance Test for hypoadrenalism was abnormal with cortisol levels of 14.2mcg/dl and 40mg/dl glucose. She was instructed to take strong analgesics and prednisone during attacks, this did not prevent hyponatremia. Finally, due to recurrent abdominal pain, porphyria workup was done and was positive. There are 30 case-reports of porphyria and SIADH. Porphyrias are a group of 8 inherited metabolic-disorders of heme biosynthesis, often classified as hepatic or erythropoietic according to the organ in which heme precursors accumulate. Acute intermitted porphyria is estimated in ~1/75000 people of European descend, yet clinical disease is seen in ~10% of carriers. Attacks present with severe abdominal-pain, nausea, vomiting, constipation, occasionally excretion of red colored urine and signs of increased sympathetic activity. Hyponatremia due to SIADH develops in 40% of patients and can lead to convulsions. Porphyria can exacerbate by several drugs, infectious processes, alcohol, and menstruation-induced hormonal-changes. Diagnosis is made by excess of urine porphobilinogen and 5-aminolaevulinic-acid. Treatment should include avoidance of precipitating factors and hemein infusions. Conclusions: SIADH is considered responsible for the hyponatremia seen in porphyria patients. Our patient showed an abnormal cortisol response to Insulin induced hypoglycemia, in accordance to (1) that demonstrated decreased output of cortisol and metabolites in porphyria patients secondary to decreased hemoproteins, as p450 cytochromes. Importantly, levels of endogenous hormones, particularly progesterone, can trigger an attack especially in luteal phase and in clomiphene citrate administration.1. Pozo et al Orphanet Journal of Rare Diseases 2014
Surgically Treated Resistant Hypertension Due to Bilateral Adrenal Hyperplasia
Authors: Ganesan Kavitha , Sallar Anthony Selase , James Deirdre 
Published: May 2021

Abstract
Background: Treatment resistant hypertension (TRH) may affect about 15% of patients with hypertension. While primary hyperaldosteronism is a known etiology of TRH, clinicians must consider the possibility of elevations of other adrenal hormones. Early identification of an etiology may prevent or delay the onset of complications. Case Report: Endocrinology was consulted on a 46 years-old man for evaluation of TRH. His past medical history is significant for TRH, nonischemic cardiomyopathy, congestive heart failure (Ejection Fraction 45–50%), and chronic kidney disease. Physical examination was unremarkable except for a blood pressure of 193/124 mmHg while on furosemide, isosorbide mononitrate, hydralazine, carvedilol, spironolactone, and clonidine. Chart review revealed mild hypokalemia. Computed tomography (CT) of the abdomen without contrast showed bilateral enlarged nodular adrenal glands with an increase in size over the last three years (left adrenal gland: 6.3 cm, right adrenal gland: 5.6 cm). Initial workup showed normal free plasma metanephrine, normetanephrine, aldosterone renin ratio, 17-hydroxyprogesterone, and undetectable random adrenocorticotropic hormone (ACTH) with random cortisol of 29 mcg/dl. Subsequent evaluation revealed elevated deoxycorticosterone (3030 ng/dL), 11-deoxycorticosterone (42 ng/d) and 18-Hydroxycorticosterone (640 ng/dL). He subsequently developed Cushing’s syndrome and diabetes mellitus. The patient underwent laparoscopic left adrenalectomy and subtotal right adrenalectomy. Pathology showed macro-nodular adrenal cortical hyperplasia. He was started on hydrocortisone for postoperative adrenal insufficiency. On his most recent follow-up, his blood pressure was well controlled on bumetanide, carvedilol, metolazone, and nifedipine. (Hydralazine, isosorbide mononitrate, spironolactone, and clonidine were stopped). After surgery, Corticosterone (92.10 ng/dL), 11-Deoxycorticosterone (&lt;5.00 ng/dL) and ACTH(9 pg/mL) normalized. Conclusion: Determining the etiology of TRH should not be stopped after ruling out the “usual suspects” since malignant hypertension with end-organ dysfunction can develop, if not appropriately treated. In our patient, TRH was due to elevated 18-Hydroxycorticosterone (precursor of aldosterone), which improved after adrenalectomy.
Testosterone Use and Adrenal Hemorrhage
Authors: Sattar Moin U , Mahali Priyanka L , Chamorro-Pareja Natalia , Suda Nisha , Bloomgarden Noah 
Published: May 2021

Abstract
Background: Testosterone supplementation has been associated with a variety of side effects, such as polycythemia, and can potentially increase the risk of cardiovascular disease. Testosterone use has also been associated with increased thrombotic events, especially in patients with underlying hypercoagulable state. Clinical Case: A 57-year-old man presented with abdominal pain and distention. He had history of previous intramuscular (IM) and oral testosterone use for ten years. For 8 weeks prior to initial presentation, he reported using weekly IM 500mg Testosterone injections. Computed Tomography (CT) of the abdomen and pelvis revealed multiple thrombi of the portal, splenic, superior mesenteric and inferior mesenteric veins. He was started on Warfarin and discharged home. A few weeks later, he presented with similar symptoms with labs now showing an International Normalized Ratio (INR) of 10.2. Repeat CT was significant for presence of bilateral adrenal hemorrhage, measuring 2.9cm on the right and 2.4cm on the left, which were not seen on previous imaging done one week prior. During the hospital course, he was found to be hypotensive with low platelet count so Intravenous Immunoglobulin therapy was initiated for suspected catastrophic antiphospholipid syndrome (CAPS). Morning cortisol was 5.82 ug/dL (6.2–29.0) so this critically-ill patient was started on stress dose hydrocortisone, which was subsequently tapered to physiological dose after clinical improvement. Cosyntropin stimulation test was performed after withholding the prior dose of hydrocortisone. The baseline cortisol was 0.88 ug/dL (6.20–29.00ug/dL), after administration of 250mcg of Cosyntropin 30- and 60-minute cortisol levels were 1.5 ug/dL (4.3–22.4ug/dL) and 1.6 ug/dL (4.3–22.4ug/dL) respectively. Baseline ACTH of 121.0 pg/mL (7.2–63.3pg/mL), consistent with primary adrenal insufficiency. Dehydroepiandrosterone Sulfate (DHEA-S) level was 15.7 ug/dL (80.0–560.0ug/dL). Hypercoagulability workup was significant for the presence of lupus anticoagulant and antibodies positive for heparin induced thrombocytopenia, so patient was diagnosed with Antiphospholipid syndrome. Conclusion: This is a case of hypercoagulability in a patient with history of anabolic steroid misuse who developed extensive intraabdominal venous thrombosis, adrenal hemorrhage, and primary adrenal insufficiency. Adrenal vein thrombosis and hemorrhage can be life threatening sequalae of testosterone misuse and should be considered in the differential for patients with history of testosterone misuse and adrenal insufficiency.
The Development of Hypogonadotropic Hypogonadism After Starting Low Dose Mifepristone for Cushing’s Syndrome
Authors: Rowell Jennifer Voigt 
Published: May 2021

Abstract
Background: Mifepristone is an antiprogesterone that has been studied in females and has shown central effects including suppressing LH surges. There is a paucity of information about how it effects males. Clinical Case: 65-year-old male with bilateral adrenal macronodular hyperplasia noted on a past surveillance CT scan presented to endocrinology. He had a history of coronary artery disease, type 2 diabetes, obesity, and treated sleep apnea. He had progressively worsening abdominal weight gain, supraclavicular fat pads, thin bruising skin, and hypertension. He had several abnormal 1 mg overnight dexamethasone suppression tests (ACTH 3 & &lt;1 pg/ml and cortisol 10 ug/dL & 11.1 ug/dL). He had several abnormal midnight salivary cortisol tests (109 ng/dL, 147ng/dL, and 152 ng/dL, reference &lt;100 ng/dL). He elected to have medical treatment for his Cushing’s Syndrome after worsening hypertension and several episodes of hypertensive urgency. He was deemed a non-surgical candidate. He was started on mifepristone 300 mg/day and spironolactone 12.5 mg/day given eGFR 47 mL/min/1.73sq m. His mifepristone dose was dropped to 300 mg every other day after he had several episodes of orthostatic hypotension, nausea, and hot flashes. On lower dose mifepristone, his hypertension control improved without orthostatic hypotension or nausea. His hot flashes remained and he developed breast enlargement and tenderness. A repeat testosterone was found to be low, but the rest of his evaluation for gynecomastia was negative otherwise. His pre-treatment am testosterone was 281 ng/dL (normal 250–1100 ng/dL) and post mifepristone treatment am testosterone level was &lt;7 ng/dL. He had suppressed gonadotrophins (LH &lt;0.2 mIU/mL; normal 1.4–7.77 mIU/mL, FSH &lt;0.2 mIU/mL; normal 2.5–17.1 mIU/mL), normal prolactin (PRL 11 ng/mL; normal 2.6–12 ng/mL) and a normal pituitary MRI.
Conclusion: This is the first case demonstrating severe hypogonadotropic hypogonadism in a male using low dose mifepristone treatment for mild ACTH independent Cushing’s Syndrome.
Reference: Escudero, E. and et al. Mifepristone Is an Effective Oral Alternative for the Prevention of Premature Luteinizing Hormone Surges and/or Premature Luteinization in Women Undergoing Controlled Ovarian Hyperstimulation for in Vitro Fertilization. J Clin Endocrinol Metab. 2005; 90(4):2081–2088.
Modified GRAS Score for Prognostic Classification of Adrenocortical Carcinoma: An ENSAT Multicentre Study
Authors: Elhassan Yasir , Altieri Barbara , Berhane Sarah , Cosentini Deborah , Calabrese Anna , Haissaguerre Magalie , Kastelan Darko , Fragoso Maria C , Bertherat Jerome , Baudin Eric , Haak Harm , Boudina Maria , Canu Letizia , Loli Paola , Sherlock Mark , Kimpel Otilia , Marta Laganà , Kroiss Matthias , Arlt Wiebke , Terzolo Massimo , Berruti Alfredo , Deeks Jonathan , Libe Rossella , Fassnacht Martin , Ronchi Cristina Lucia 
Published: May 2021

Abstract
Background: Adrenocortical carcinoma (ACC) has an aggressive but heterogeneous behaviour. ENSAT stage and Ki67 proliferation index are used to predict clinical outcome but are limited in distinguishing patients with different risk of disease progress. We aimed to validate the prognostic role of a previously proposed points-based score (mGRAS) in a large ACC cohort.
Methods: We included ACC patients who underwent adrenalectomy between 2010 and 2019, had complete clinical and histopathological data, and did not participate in our previous studies (Libe et al. Ann Oncol 2015; Lippert et al. JCEM 2018). The mGRAS score was calculated as follows: age (&lt;50yr=0; ≥50yr =1), symptoms (no=0; yes=1), ENSAT stage (1–2=0; 3=1; 4=2), resection status (R0=0; RX=1; R1=2; R2=3), and Ki67 (0–9%=0; 10–19%=1; ≥20%=2 points), generating scores from 0 to 9 and four mGRAS groups (scores 0–1, 2–3, 4–5, and 6–9). Progression-free survival (PFS) and disease-specific survival (DSS) were the primary and secondary endpoints, respectively. The discriminative performance of mGRAS was investigated using the Harrell’s C-index and Royston-Sauerbrei’s R2D statistic.
Results: A total of 942 ACC patients from 14 ENSAT centres were included (38% men; median age 50yrs (interquartile range 38, 61)). The four mGRAS groups showed superior prognostic discrimination compared to the individual clinical and histological parameters for both PFS and DSS (C-index 0.71, R2D=0.30 and 0.77, R2D=0.46, respectively); ENSAT staging was the second best discriminator (C-index 0.67, R2D 0.21 and 0.72, R2D=0.35, respectively). An even better prognostic discrimination was observed using the ten mGRAS scores individually (C-index 0.73, R2D=0.30, and 0.79, R2D=0.45 for PFS and DSS, respectively). The superiority of mGRAS was confirmed when separately considering patients treated or untreated with adjuvant mitotane (n=481 vs 314). In mitotane-treated patients, the four mGRAS groups showed better performance in predicting PFS than Ki67 index (C-index 0.66, R2D 0.18 vs C-index 0.62, R2D 0.12).
Conclusion: The prognostic performance of mGRAS is superior to that of ENSAT staging and Ki67. This simple score may guide personalised treatment decisions in patients with ACC, e.g. regarding the need for adjuvant therapy and frequency of monitoring.