bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pheochromocytoma Masquerading as Weight Loss - a Diagnostic and Management Challenge
Authors: Palani Gurunanthan , Drake Tyler C , Sibley Shalamar Dionne 
Published: May 2021

Abstract
Introduction:
Classic pheochromocytoma symptoms include headache, diaphoresis, palpitations and symptomatic pheochromocytomas are on average around 5cm. They respond to preoperative alpha blockade followed by surgery. We present a case of a giant 15.9cm pheochromocytoma with delayed presentation and diagnosis complicated by atypical symptoms of nausea, weight loss; preoperative preparation included a modified preparation of high-dose phenoxybenzamine but she underwent successful surgery.
Case Description:
A 62-year-old female with a history of hypertension and diabetes presented with nausea and 80 lbs weight loss over 18 months. CT scan revealed large centrally necrotic mass overlying the left kidney, measuring 15.9 x 12.7 x 14.7cm. Abdominal MRI showed claw sign; she was admitted to the urology service for tube feeding prior to resection of suspected renal cell carcinoma. Given the location of the mass and history of hypertension, plasma metanephrines, included in preoperative workup, were notable for: total metanephrines &gt;40000 pg/ml (reference range &lt;=205), normetanephrines &gt;20000 pg/ml (reference range &lt;=148), metanephrines 57 pg/ml (reference range &lt;=57). Endocrine was consulted and she was started on phenoxybenzamine; she underwent volume replacement with fluids and salt tablets. Due to nausea and vomiting she was unable to reliably tolerate oral medication; BP management was challenging. Oral pill dosing was minimized. Metoprolol was converted to metoprolol SA and a phenoxybenzamine suspension that could be delivered through the feeding tube with good absorption was made. On the day prior to surgery, BP was 117/76 mmHg, supine HR 92 bpm, on a total daily dose of phenoxybenzamine 240mg, metoprolol SA 200mg and amlodipine 10mg. She underwent a radical left nephrectomy and adrenalectomy. Plasma metanephrines six weeks later were normal: total metanephrines 84 pg/ml, normetanephrines 84 pg/ml, metanephrines &lt;25 pg/ml. Pathology showed benign pheochromocytoma.
Conclusion:
Giant pheochromocytomas present significant challenges for clinicians who must be aware of the potential for nonspecific symptoms which can delay diagnosis. Paroxysmal hypertension happens in only about 50% of pheochromocytoma patients; primary hypertension is often diagnosed, as had been the case with our patient. Additionally, initial imaging related to atypical presenting symptoms may not lead to the specific diagnosis, as in our patient; metanephrine screening revealed the correct diagnosis. Regarding management, preoperative alpha blockade dosage and delivery should be tailored to individual patient needs, with adjustment as needed and alternative preparations considered to optimally control BP and reduce risk of death and other perioperative complications. Our case highlights the diagnostic and management challenge of patients presenting with giant pheochromocytomas.
Pheochromocytoma Presenting With Cardiomyopathy in an Otherwise Healthy Young Patient: A Rare Case Report
Authors: Thibodeaux Rachel , Piziak Veronica 
Published: May 2021

Abstract
Background: Pheochromocytomas are rare neuroendocrine tumors. The classic triad of symptoms includes diaphoresis, episodic headache, and tachycardia. Rarely, patients may develop cardiomyopathy associated with pheochromocytoma. It is uncommon for cardiomyopathy to be the initial presenting symptom of pheochromocytoma and can lead to a delayed diagnosis.
Clinical Case: The patient is a 30-year old female with no significant medical history who presented with complaints of dyspnea, fever and malaise. The patient had no known prior history of hypertension and did not report complaints of headache, diaphoresis or palpitations. Patient was hypertensive and tachycardic on admission. Upon treatment with intravenous fluids, the patient acutely decompensated and developed respiratory failure requiring emergent intubation. CT of the chest, abdomen and pelvis was performed which showed diffuse bilateral pulmonary edema as well as a circumscribed, heterogeneously enhancing 4.4 cm mass involving the right adrenal gland. An echocardiogram was performed which showed significant left ventricular dysfunction with ejection fraction of 5%. Patient had wide fluctuations in her blood pressure during admission ranging from hypotension to extreme hypertension. She did require the use of epinephrine and milrinone when hypotensive. Due to the use of vasopressors, plasma fractionated metanephrines and 24-hour urine fractionated metanephrines and catecholamines were not recommended to be obtained as these medications may contribute to false positive testing. A dedicated CT of the abdomen with and without contrast was performed to further assess the patient’s right adrenal mass; this revealed a 3.9 x 2.4 x 4.9 cm right adrenal mass with 33% absolute washout and 17% relative washout concerning for pheochromocytoma. The patient underwent an open right adrenalectomy during admission. Surgical pathology results were consistent with a pheochromocytoma measuring 5.2 cm at greatest dimension; the tumor was confined to the adrenal gland and completely excised. Following her surgery, the patient’s clinical status improved significantly over the next several days. She was discharged home in stable condition on hospital day #18. An echocardiogram was repeated 2 months after her hospitalization with ejection fraction improved to 58%.
Conclusion: Catecholamine-induced cardiomyopathy in pheochromocytoma is rare, occurring in approximately 8–11% of patients with pheochromocytoma. Cardiomyopathy as the initial presentation of pheochromocytoma is very uncommon. It is important to accurately diagnose pheochromocytoma-related cardiomyopathy as early detection and resection can lead to marked improvement in cardiac function and prevent catastrophic consequences including death.
Polyglandular Autoimmune Syndrome Type II in a Patient Presenting With Hypotension After Acute Illness
Authors: Sokoloff Samantha , Mundada Rachana , Simon Barbara 
Published: May 2021

Abstract
Introduction: Polyglandular Autoimmune Syndrome Type II (PAS-2) is a rare disorder characterized by two or more endocrine diseases (primary adrenal insufficiency, autoimmune thyroid disease, type 1 diabetes). Of these, the most common is autoimmune thyropathy, followed by Type 1 Diabetes (1). These endocrinopathies rarely have concurrent onset. This case reports a 22-year-old male, recently recovered from severe pneumonia, who presented to the Emergency Department in acute adrenal crisis and was diagnosed with PAS-2.
Case: A 22-year-old male with past medical history of celiac disease presented with abdominal discomfort, nausea, vomiting, fatigue and dizziness for 1–2 weeks. Review of systems included a 20-pound weight loss over several months. Recent history included a hospitalization at another facility three weeks prior for pneumonia and septic shock requiring admission to the ICU and vasopressor treatment. He was not discharged on any medications. He was afebrile with heart rate of 105/min, blood pressure 78/48 mm Hg and BMI of 17.2. Physical exam revealed dry mucous membranes and mild diffuse abdominal tenderness. Skin was warm and dry without hyperpigmentation. Laboratory values included sodium 123 (135 - 146 mmol/L), potassium 6.8 (3.3 - 4.8 mmol/L), glucose 47 (70 - 100 mg/dL), TSH 37.67 (0.3 - 5.00 uIU/mL), and FT4 0.7 (0.7 - 1.7 ng/dL). He was started on fluids and intravenous hydrocortisone. Cortisol and ACTH levels drawn prior to the initiation of steroids resulted at 0.6 (6–20 mcg/dl) and 977 (9 - 46 pg/mL) respectively. Additional labs included: aldosterone &lt; 1 ng/dL, 21 hydroxylase antibody positive, TPO antibody &gt; 1000 (0 - 100 Units) and GAD-65 antibody &gt; 47 IU/mL (&lt;5 IU/mL). Levothyroxine was initiated after hydrocortisone. Blood glucose was elevated during hospitalization, peaking at 227 mg/dL. He was discharged on prednisone, fludrocortisone and levothyroxine. At 2 week follow up, he reported overall improvement in health and was pleased with a weight gain of 12 lbs. Blood glucose remained mildly elevated (123 - 143 mg/dL).
Conclusion: The patient had pneumonia and septic shock septic at an outside hospital three weeks prior to presentation. There was no record of steroid administration or suspicion of adrenal insufficiency. We postulate that his severe illness contributed to significant depletion of his adrenal reserve, and therefore he presented to our facility a short time later in overt adrenal crisis. Adrenal crisis is unusual to be the first presentation of PAS-2. It is important to have a high index of suspicion for adrenal insufficiency and PAS-2 in patients presenting with severe illness or hypotension who have known autoimmune disorders.
Reference: 1. Kahaly, G.J., Frommer, L. Polyglandular autoimmune syndromes. J Endocrinol Invest. 2018; 41: 91–98.
PTH-Independent Hypercalcemia in Undiagnosed Adrenal Insufficiency
Authors: Turner Jennifer , Haider Adnan , Barghouthi Nadia , Symczyk Oksana 
Published: May 2021

Abstract
In contrast to PTH-dependent hypercalcemia, the differential diagnosis of PTH-independent hypercalcemia is extensive. Thorough history and physical examination can help direct the clinician in the right direction and avoid extensive and unnecessary work up.
A 27-year-old-female with a medical history significant only for untreated subclinical hypothyroidism was admitted to the hospital for hypercalcemia and acute kidney injury after presenting with dizziness, nausea, vomiting, dyspnea, and multiple syncopal episodes prior to admission. Serum calcium on presentation was elevated to 15.9 (8.5–10.2 mg/dL) with an intact parathyroid hormone level of 3.6 (8.5–75 pg/mL). On initial presentation, she was hypotensive, tachycardic, and was noted to be underweight with a body mass index of 17 kg/m2. The patient’s skin was diffusely hyperpigmented, with increased pigmentation in the creases of her hands and on the sides of her fingers. Further lab evaluation was remarkable for hyponatremia and hyperkalemia as well as an undetectable 8 AM cortisol of &lt;1.0 (7–25 µg/dL), adrenocorticotropic hormone (ACTH) level significantly elevated to &gt;1,250 (6–58 pg/mL), aldosterone &lt;4 (&lt;21 ng/dL), and plasma renin activity elevated to 18 (&lt;0.6–3 ng/mL/h). Antibodies to 21-alpha hydroxylase were positive, confirming a diagnosis of Addison’s disease. Prior to the workup confirming an elevated ACTH and low cortisol levels, the patient was treated with aggressive intravenous fluid repletion and calcitonin with overnight improvement in calcium to 11.4 mg/dL. After the diagnosis of primary adrenal insufficiency was confirmed, she was treated with stress doses of intravenous hydrocortisone then gradually tapered to physiologic doses of oral hydrocortisone and fludrocortisone with resolution of her hypercalcemia by the fourth day of hospitalization.
Adrenal insufficiency is a known but uncommon cause of PTH-independent hypercalcemia, but the exact mechanism is unknown. Hypercalcemia is thought to result from a combination of a hypovolemic state seen in adrenal insufficiency which leads to decreased urinary calcium excretion as well as increased bone resorption, which may result from increased serum sclerostin concentrations.
Adrenal insufficiency should be considered in the differential of PTH-independent hypercalcemia. This case highlights the improvement in hypercalcemia that is seen with correction of glucocorticoid deficiency, and supports delaying additional work up for other PTH-independent causes until appropriate treatment has been given.
Severe Virilization in a Girl With the Homozygous G200SNicotinamide Nucleotide Transhydrogenase Mutation Is Surprisingly Caused by Rare Bilateral Para-Overian Adrenal Rest Tumors
Authors: Cahn Ranit , Mendelson Espen Eliyahu , Lavi Eran , Sharaf Muna , Florsheim Natan , Atlan Karine Anabel , Bauman Dvora , Zangen David 
Published: May 2021

Abstract
Background: Patients with NNT (Nicotinamide Nucleotide Transhydrogenase) gene mutations, a rare cause of glucocorticoid and mineralocorticoid deficiency require hormone replacement therapy. Adrenal Rest Tumor (ART) in females is very rare (&lt;20 cases world-wide) and was reported only in noncompliant patients with congenital adrenal hyperplasia having extremely elevated ACTH levels. This study characterizes the clinical characteristics, the pathophysiology and the molecular ontogeny of a unique ART in a female with adrenal failure due to the G200S mutation in NNT.
Clinical presentation and Method: A 15-year-old girl, with homozygous G200S NNT-mutation that caused adrenal insufficiency reappeared to follow-up after several years with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (&gt; 1500 pmol/l) levels. Pelvic MRI and Ultrasound demonstrated one sided para-ovarian round tumor with pathological vascularization. Laparoscopic exploration revealed bilateral para-ovarian mesosalpinx masses involving the serosa of the Fallopian tube (3 and 1 cm in diameter); the testosterone level normalized within one day after removal of those masses (0.2 nmol/l).
Results: Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1, inhibin and the pituitary corticotroph marker-ACTH. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the presence of CYP17A1, CYP21A2 and MC2R (ACTH receptor) cDNA confirming typical adrenocortical transcriptional pattern in the tissue. cDNA of POMC was not detected suggesting that in spite of dense ACTH staining the tissue is not classically originated from pituitary corticotrophs. Methylome studies to further characterise the tissue are underway.
Conclusion: This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue that was caused by incompliance to treatment in a patient with NNT gene mutation. Given the ubiquitous expression of NNT and its reported pathophysiology as free radicals scavenger in all adrenocortical layers, it is surprising to have high ACTH induced severe virilization in spite of severe NNT dysfunction and adrenal insufficiency. This study may indicate timely testosterone screening in females with NNT mutation and when increased they should probably be laparoscopically surveyed for ART even when not detected by imaging. How NNT mutation damages mineralo and glucocorticoid secreting cells while androgen secreting cells are rescued is a theme for further studies.
Synchronous Malignant Pheochromocytoma With Renal Cell Carcinoma: A Case Report
Authors: Ma Charles , Bloomgarden Noah , Stefan Simona 
Published: May 2021

Abstract
Introduction: In the US, Pheochromocytoma/paraganglioma incidence is estimated to be 2–8 per 1 million people each year with around 100–200 of these cases being malignant. Malignant pheochromocytoma is defined by documented presence of metastases or evidence of extensive local invasion. There are certain genetic syndromes which are also associated with renal cell carcinoma, including SDHB mutations type 4, VHL disease and familial pheochromocytoma. These syndromes are important to recognize as they may signify a worse prognosis. Here, we describe a case of co-occurrence of malignant PC with renal cell carcinoma.
Case Report: A 53-year-old Hispanic male with history of HTN and recently diagnosed metastatic pheochromocytoma was admitted for surgical debulking of the left retroperitoneal/adrenal and renal masses. Symptoms began five months prior after he presented with an ischemic stroke in the setting of labile hypertension. He was diagnosed with a 6.3 x 4.6 x 6.8 cm incidental left retroperitoneal mass and suspicious left renal mass on CT imaging but also noted several lytic bony lesions concerning for bone metastasis. A spinal biopsy was obtained which was consistent with a well-differentiated metastatic neuroendocrine tumor. Laboratory evaluation was notable for Chromogranin A level of 6959ng/mL (25–140). He was started on Lanreotide. Given persistently difficult to control HTN he underwent work up for secondary hypertension. Hormonal evaluation was notable for plasma free metanephrine of 534pg/mL (&lt;57pg/mL), normetanephrine 6155pg/mL(&lt;148pg/mL), and total metanephrine of 6689pg/mL (205pg/mL) consistent with metastatic Pheochromocytoma. After appropriate alpha blockade he underwent left adrenalectomy, nephrectomy and liver tumor microwave ablation. Pathology was consistent with an 8.7cm pheochromocytoma with extensive retroperitoneal soft tissue invasion and PASS score of 9 as well as a 3.6 cm renal cell (clear cell-papillary type) carcinoma. On follow up, Plasma metanephrine decreased significantly postoperatively to a free metanephrine of 28pg/ml, normetanephrine 1153pg/ml, and total metanephrine of 1181pg/mL. He was referred for genetic testing but unfortunately, he was readmitted one month later with cerebral hemorrhage and expired.
Conclusion: Advancements in genetics have led to improved understanding of the molecular etiologies of pheochromocytomas. A number of genetic defects are associated with PC and RCC, including SDHB mutations type 4, VHL and familial pheochromocytoma. Our case underscores the high morbidity and mortality in patients with metastatic PC with RCC and perhaps the catastrophic outcomes in such patients. Assessing patient’s genetics in these cases is now the standard of care, however further research studies are warranted to better understand the significance of tumor genetics on prognosis and management.
Taking it with a Grain of Salt: A Woman with ‘PCOS’ and Infertility Diagnosed with Nonclassic Congenital Adrenal Hyperplasia and a Large Renal Mass
Authors: Villarreal Marcos D , Desai Viraj , Kumar Pratima V 
Published: May 2021

Abstract
Background: Clinical manifestations of Nonclassic CAH (NCCAH) in women may range from asymptomatic to hirsutism, oligo-menorrhea, or infertility. Testicular adrenal rest tumors are common in men with classic CAH though uncommon in NCCAH. In women with classic CAH, ovarian adrenal rest tumors are even rarer. 11–58% of patients with classic CAH will have at least one adrenal nodule but the prevalence is unknown in NCCAH (1).
Clinical Case: A 34-year-old Hispanic woman was seen by reproductive endocrinology for evaluation of infertility. She had been unable to conceive for the past 7 years. She was diagnosed with PCOS by her PCP. She was referred to our clinic for further workup. The patient denied galactorrhea. Laboratory evaluation revealed prolactin 49.3 (&lt; 20.0 ng/ml), TSH 2.290 (0.5–5.0 μU/mL), fT4 1.14 (0.9–2.3 ng/dL), total testosterone 92 (15 -70 ng/dL for women), DHEAS 361 (45 -270 µg/dL), 8 AM cortisol 20.0 (5–23 μg/dL), ACTH 59.0 (6–76 pg/ml), 17-hydroxyprogesterone (17OHP) &gt;2000 ng/dL, and A1c 5%. 24-hour urinary free cortisol was 26.4 (3.5–45 mcg/day). MRI of the pituitary did not show any adenoma. Pelvic ultrasound did not reveal any ovarian cysts.
Cosyntropin stimulation test showed baseline 17OHP 1076 ng/dL, 30 minutes 8812 ng/dL, and 60 minutes 9452 ng/dL. She was begun on hydrocortisone and cabergoline. CT of the abdomen did not reveal any adrenal masses but showed mildly thickened adrenal limbs suggesting adrenal hyperplasia. A 4.5 cm exophytic enhancing mass on the left kidney was noted representing an adrenal rest tumor versus angiomyolipoma.
Given the exophytic nature of the mass and increased risk of hemorrhage with angiomyolipomas greater than 4 cm, the patient was referred to urology and interventional radiology for radioembolization and possible biopsy of the mass. We are unsure if this renal mass is an angiomyolipoma or an adrenal rest tumor, which are uncommon in the kidneys. The patient was also referred for genetic counseling. Patients with CAH typically have CYP21A2 gene mutations, and the chance that a patient with NCCAH will have a child with classic CAH is reported to be 1 to 2% in two large cohort studies (2).
Conclusion: This case is a reminder that evaluation of infertility/subfertility includes less common diagnoses, such as NCCAH. This genetic disorder is seen more frequently in certain ethnic groups, including Hispanics; and after diagnosis, patients should be referred to a genetic specialist. Additional abdominopelvic imaging should be considered in both men and women with a new diagnosis of NCCAH to evaluate for rare but clinically significant tumors.
Reference: 1. Nordenström, A., Falhammar H. Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency Eur J Endocrinol. 2019 Mar;180(3):R127-R145.2. Merke, D, Auchus, R Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. NEJM 2020;383:1248–61.
Insights From Targeted Genetic Analysis of 364 Adrenocortical Carcinomas
Authors: Pozdeyev Nikita , Fishbein Lauren Michelle , Gay Laurie M , Sokol Ethan S , Hartmaier Ryan , Ross Jeffrey S , Darabi Sourat , Demeure Michael J , Kar Adwitiya , Foust Lindsey J , Koc Katrina , Bowles Daniel W , Leong Stephen , Wierman Margaret E , Kiseljak-Vassiliades Katja 
Published: May 2021

Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy affecting individuals across a broad age spectrum. Disease rarity, scarcity of pre-clinical models, lack of effective targeted therapy and limited clinical trials have contributed to poor prognosis for patients with ACC. Identifying targetable genetic drivers and pathways to guide precision medicine approaches is therefore critical to improve outcomes. The purpose of this study was to analyze the genomic profile of a large cohort of ACC to identify potential therapeutic targets. FoundationOne (Foundation Medicine Inc.; FMI, Cambridge, MA) is a next-generation sequencing-based platform for somatic genetic testing in solid tumors. The FoundationOne genomic data and limited demographic data through 2018 for 364 unique ACC specimens were analyzed. The cohort of 364 tumors were from 222 females and 141 males (1 gender unknown). The mean age (SD) was 48.6 (13.6) for females and 50.6 (12.20) for males with overall median age of 52 years. A total of 3117 genomic alterations were identified impacting 457 genes. The median number of genomic alterations per tumor was 7 (range 1–56), with single nucleotide variants and indels being the most common alterations (median=4), followed by copy number alterations (median=1) and rearrangements (median=0). The most frequently altered genes were TP53 (38%), CTNNB1 (28%), ZNRF3 (17%), CDKN2A (13%), ATRX (11%), TERT promoter (10%). Several novel recurrent alterations were identified including IL7R (6%), LRP1B (8%), FRS2 (4%), PTCH1 (4%) and KRAS (3%). Pathway enrichment analysis confirmed that tumor suppressor genes (51%) and Wnt signaling pathways (51%) are the most commonly dysregulated in ACC tumors. Epigenetic alterations, including histone modification (38%), SWI/SNF (21%) and DNA methylation (8%), affected upwards of one third of ACC tumors. Mutation signature analysis identified tumors with signatures 6, 15 and 26 associated with defective DNA mismatch repair (MMR), which was not reported previously. In addition, fifty ACCs (13.7%) exhibited 60 genomic alterations in MMR genes, MLH1, MSH2, MSH6 and PMS2, which included 49 SNVs/indels, 10 CNAs and one truncating rearrangement. In addition to MMR gene alterations, potentially actionable (www.oncokb.org) genomic alterations were found in 46 genes in 213 (58.5%) ACCs. In summary, this study represents the largest to date genomic analysis of ACC that showed that over 50% of ACC tumors had potentially actionable genomic alterations. Approximately 13% of tumors had an alteration in MMR pathway, suggesting that immunotherapy is a relevant therapeutic modality in a significant subset of patients with ACC.