bluuebunny/crossref_metadata_2025 huggingface dataset:
Cushing Syndrome in the Setting of Chronic Dilated Cardiomyopathy: Can Treatment Improve Chronic Dilated Cardiomyopathy?
Authors: Pathak Leilani , Singh Shikha , Soni Lina , Zhou Ying Yin , Skwiersky Samara
Published: May 2021

Background: Cushing syndrome (CS) is well known to be associated with metabolic syndrome, venous thromboembolism, hypertension, left ventricular hypertrophy, and rarely dilated cardiomyopathy. The pathophysiological effects of hypercortisolism on the myocardium results in cardiomyocyte hypertrophy, myofibrillolysis, myocardial fibrosis, global longitudinal and circumferential strain. Our patient presents an example of CS in the setting of chronic heart failure with reduced ejection fraction, multiple thromboembolic events, and diabetes mellitus in a young adult.

Clinical Case: A 34-year male with a past medical history of dilated cardiomyopathy with biventricular failure and left ventricle ejection fraction of 10%, pulmonary embolism, diabetes mellitus, and gout presented with shortness of breath. On physical exam he presented with symptoms of CS: moon facies, supraclavicular fat pads, dorsal fat pads, purple striae of abdominal skin, truncal obesity, ecchymosis, and skin atrophy. Labs showed elevated morning cortisol after overnight 1 mg dexamethasone suppression test (cortisol 8.6 mcg/dl, n< 5 mcg/dl), repeat morning cortisol after overnight 1 mg dexamethasone suppression test (cortisol 5.7 mcg/dl, n< 5 mcg/dl), and ACTH-concentrations <5 pg/ml. CT-scan was insignificant for adrenal hyperplasia. He was admitted and treated for acute congestive heart failure exacerbation with plans for definitive treatment of CS outpatient with further imaging studies.

Conclusion: The occurrence of CS induced heart failure results in increased mortality. There have been numerous accounts of resolution of cardiomyopathy after surgical treatment for CS secondary to adrenal adenoma. Our patient had a 10-year history of chronic dilated cardiomyopathy prior to cushingoid symptoms and confirmatory endocrinological data. The definitive treatment for CS syndrome in our patient would eventually be surgery targeting the source of hypercortisolism, however his cardiovascular risk factors would make him a poor surgical candidate. Severely reduced ejection fraction is a contraindication for generalized anesthesia needed for surgery. When surgery is contraindicated in CS medical management is recommended according to guidelines that target pituitary-directed medical treatments for Cushing’s disease and targeted therapies to treat ectopic ACTH syndrome. To our knowledge there have been few studies that demonstrate the effects of CS treatment on chronic conditions such as dilated cardiomyopathy. Studies have shown that surgical treatment for CS have reversed cardiomyopathy caused by CS but it still remains to be answered whether this same effect is achieved to some degree in chronic dilated cardiomyopathy.
Double Trouble: Co-Occurrence of Aromatase Deficiency and Non-Classic CAH in Three Siblings
Authors: Marinkovic Maja , Trujillo Marcela Vargas
Published: May 2021

Introduction: Aromatase deficiency (AD), an exceedingly rare autosomal recessive condition, causes virilization in females and tall stature with metabolic derangements in males. Clinical manifestations result from decreased estrogen production and androgen excess, but presentation varies based on residual aromatase activity. Non-classic CAH (NCCAH) is a relatively common disorder. Males are often asymptomatic or present with premature adrenarche (PA). Females are typically diagnosed during childhood/adolescence with PA, acne, hirsutism, or menstrual irregularities. We present three siblings with both conditions and describe their long-term follow-up. Cases: Identical twin sisters presented at birth with virilized genitalia. Evaluation revealed 46XX karyotype, transiently elevated testosterone (unchanged with hCG stimulation), normal 17OHP and normal ovarian tissue on gonadal biopsy. Due to sporadic follow-up, their diagnosis and care were delayed until age 15y when AD was confirmed with genetic testing (compound heterozygous: whole gene deletion on one allele and c.242A>G (p.tyr81cys) mutation on the other). Both girls had acne, hirsutism and clitoromegaly, but reached spontaneous menarche at 11y and height within mid-parental height (MPH). Given the genetic nature of AD, younger brother was assessed and diagnosed with AD with the same mutation in CYP19A1. He had normal height-corrected BMD, lipids and glucose. His testosterone level was high-normal with undetectable estradiol. He had height below MPH with slow growth velocity, low IGF-1 and bone age (BA) within 2SD for age (BA 14y at CA 15y). GH stimulation test with estrogen priming revealed GH peak of 4.1 ng/ml, consistent with GH deficiency. All three siblings had high baseline and stimulated 17OHP which prompted genetic testing for CAH and confirmed NCCAH due to homozygous pVal282Leu substitution in CYP21A2. Treatment for both AD and NCCAH in females is combined estrogen+progesterone (usually given as an oral contraceptive pill), to replace estrogen and suppress androgen overproduction. The twin sisters elected clitoral reduction at age 19y with a satisfactory outcome. Their brother is not on any treatment at this time. At age 18y, his BA is still 14y-14.5y, as expected in AD, but atypical for NCCAH. Conclusion: Virilized genitalia in the newborn period prompted extensive evaluation of twin sisters that led to diagnosis of AD but also prompted assessment and diagnosis of their asymptomatic brother. Elevation of 17OHP, previously not described in AD patients, prompted testing for CAH and confirmed the unique finding of both AD and NCCAH in these three siblings. We postulate that the combined AD/NCCAH caused exacerbation of androgen excess in all three siblings. The short stature in our male patient is presumably due to GH deficiency.
Dual Adenomas: Detection of Cushing’s Syndrome of Adrenal Origin During Evaluation of Pituitary Macroadenoma
Authors: Fasen Madeline , Wehmeier Kent R , Kapadia Poonam Kalidas
Published: May 2021

Cushing’s syndrome is a rare and often severe disease associated with increased mortality and major metabolic complications with cardiovascular disease as the main cause of death. Adrenal masses are most often found by radiographic studies or autopsy as incidentalomas. The prognosis of Cushing’s syndrome is mainly affected by the difficulties in timely diagnosis and treatment of the disease, which remain a challenge due to its nonspecific presentation and multitude of etiologies. Herein, we present an atypical case of adrenal Cushing’s syndrome unveiled by the workup of a nonfunctioning pituitary macroadenoma. A 62 year-old woman presented with new intermittent headaches and worsening vision changes for the past year. She was found to have a large sellar mass measuring 2.7 x 2.4 x 3.0 cm invading the right cavernous sinus with displacement of the optic chiasm on brain magnetic resonance imaging (MRI). In the interim to neurosurgical evaluation, lab work performed to assess pituitary function showed an elevated late night salivary cortisol at 0.200 UG/DL (0.010–0.090 UG/DL range). Low early morning ACTH and elevated late night salivary cortisol, dexamethasone suppression test and 24 hour urine cortisol were observed and confirmed with repeat studies. These findings warranted a computed tomography (CT) adrenal mass protocol which revealed a left adrenal lesion consistent with a lipid rich adenoma measuring 4.9 x 3.5 x 4.1 cm in size. Subsequent urine catecholamines and metanephrines were within normal limits. The patient was admitted for transphenoidal pituitary resection with perioperative stress dose corticosteroids, but was only able to achieve partial resection due to large tumor size. Post-operatively the patient did well on a quick corticosteroid taper down to hydrocortisone 15 mg in AM and 5 in afternoon with hope to wean in the near future. Post-operative workup showed ACTH 4.6 pg/mL (7.2 – 63.3 pg/mL) and 8 am cortisol 24.7 MCG/DL (6.2–19.4 MCG/DL) which suggests autonomous adrenal secretion of cortisol. Once the patient has recovered from her partial pituitary resection she will be referred to general surgery for adrenalectomy. This case provided a review of a classic pituitary macroadenoma workup with an interesting twist to Cushing’s etiology as the cause was not from the pituitary as originally thought.
Ectopic Cushing’s Syndrome and Severe Hypocalcemia Due to Medullary Thyroid Cancer Responsive to Selpercatinib
Authors: Turin Christie Gloria , Brose Marcia S , White Caitlin A
Published: May 2021

Introduction: Cushing’s syndrome (CS) due to ectopic ACTH production from medullary thyroid carcinoma (MTC) is characterized by rapid progression of disease, leading to hyperglycemia and hypokalemia. However, hypercortisolemia leading to hypocalcemia is rarely seen. Initiation of selpercatinib greatly improved hypocalcemia and ectopic CS in this case. Clinical Case: A 41-year-old man with a history of MTC (variant RET p.M918T) post thyroidectomy in 2018 developed progressive weight gain, lower extremity edema, weakness, new onset diabetes, severe refractory hypocalcemia and hypokalemia requiring multiple hospitalizations. On initial presentation to our institution, he was lethargic, had multiple ecchymoses, peripheral edema and proximal myopathy. Laboratory evaluation revealed Ca 5.4 mg/dL (NR 8.9 - 10.3), albumin 3 g/dL (NR 3.5 - 5.1), iPTH 1.4 pmol/L (NR 1.6 - 6.9), 25-OH vitamin D 23 pg/mL (NR 25–80) while taking elemental calcium 1500 mg every 6h, calcitriol 0.25 mcg/d and vitamin D3 1000 IU/d. Serum cortisol measured at 9:30 pm was 136 ug/dL (NR 2.5–11.9), ACTH 1,145 pg/mL (NR 7.2–63.3) and 24-h UFC 27,629 ug/d consistent with CS due to ectopic ACTH production. Calcitonin and CEA were 18,687 pg/mL (NR 0–7.5) and 3,766 ng/mL (NR 0–4.7). CT abdomen revealed numerous bilateral liver lesions and bilateral adrenal hyperplasia. In addition to high doses of oral calcium and calcitriol, he required calcium drip up to 1.5mg/kg/hr for about 1 week. He simultaneously began cabozantinib, ketoconazole and metyrapone. Hospital course was complicated by infections and recurrent scrotal bleeding, so he was switched to selpercatinib. Two days after starting selpercatinib, ketoconazole was discontinued, and metyrapone has been gradually reduced. Most recent calcitonin was 149 pg/mL, CEA 97.8 ng/mL and 24-h UFC 10 ug/d on metyrapone 250 mg twice daily. Similarly, refractory hypocalcemia greatly improved, last serum Ca was 8.3 mg/dL on elemental calcium 480 mg/d. He has made significant clinical gains and has returned home from rehab. Clinical Lesson: Hypocalcemia is rarely described as a complication in patients with CS. Our patient had underlying hypoparathyroidism and vitamin D deficiency; however, hypocalcemia was initially refractory to high doses of calcium and calcitriol and only improved with treatment of CS. We suspect hypercortisolemia impaired 25 to 1,25 D activation, thereby reducing calcium absorption, and likely inducing hypercalciuria. These deleterious effects of severe hypercortisolemia combined with underlying hypoparathyroidism led to severe and refractory hypocalcemia requiring repeated admissions, and only improved once his ectopic CS due to MTC was recognized and controlled. The RET kinase inhibitor, selpercatinib, induced a rapid decline in calcitonin, CEA and ACTH levels, and with metyrapone, enabled control of hypercortisolemia and its complications.
Glucocorticoids and Pheochromocytoma- a Recipe for Disaster?
Authors: Chandrashekar Nikhitha , Asp Arnold Allan
Published: May 2021

Background: Pheochromocytomas are catecholamine-secreting tumors that arise from the chromaffin cells of the adrenal medulla. The catecholamine release manifests as episodic headaches, diaphoresis, and palpitations which can lead to hypertensive emergency known as a pheochromocytoma crisis(PC). This crisis can be precipitated by commonly used medications including corticosteroids, metoclopramide, and anesthetic agents like ketamine and halothane. Case report: We present a 60 year old Caucasian male with a past medical history significant for SVT on metoprolol and diltiazem and long-standing hypertension. He was admitted directly from the clinic to the ED after complaining of severe abdominal pain, multiple episodes of vomiting, and diaphoresis following prednisone intake for a presumed gout flare. He had a blood pressure of 180/100 and tachycardic to 120s on arrival. He was also found to be hypoxemic with a chest x-ray concerning for pulmonary edema along with evidence of a demand related type II NSTEMI. He underwent a CT abdomen pelvis with contrast which showed evidence of high grade distal ileum obstruction with no obstructing mass or inflammatory process. There was also 5-cm solid right adrenal mass which was initially thought to be an incidentaloma. Following stabilization, he underwent an exploratory laparotomy which did not show an obvious mechanical etiology of bowel obstruction. This raised concerns for a pheochromocytoma. Oral verapamil with doxazosin was started to provide appropriate alpha blockade. Subsequently, metoprolol was reintroduced for beta blockade. He was officially diagnosed with glucocorticoid-induced pheochromocytoma after his labs returned with elevated levels of serum metanephrines 43.7(0.00 - 0.49 nmol/L), serum normetanephrine 22.2 (0.00 - 0.89 nmol/L),), 24-hr urine epinephrine 1021 ug/g (0 - 20 ug/g), and 24-hr urine norepinephrine 838 ug/g (normal: 0 - 45 ug/g). Ultimately 3 weeks later he underwent successful R sided adrenalectomy and is doing well. Conclusion: This case demonstrates a rare but life-threatening adverse reaction associated with commonly used glucocorticoids in a patient with an undiagnosed pheochromocytoma. Pheochromocytomas are exceedingly rare and can go undiagnosed in up to 50 percent of patients (1). Failure or delays in diagnosis of PC can lead to increased morbidity and mortality. When managing a pheochromocytoma crisis, it is imperative to avoid selective beta-blockers, as it can worsen hypertension due to unopposed alpha agonism by the secreted catecholamines. This also demonstrates the importance of keeping a broad differential in order to avoid anchoring bias, particularly when there is conflicting clinical information. References: 1. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc. 1981 Jun;56(6):354–60. PMID: 6453259.
Looking Beyond Diabetes: A Case of Worsening Hyperglycemia as a Manifestation of Ectopic Cushing’s Syndrome Secondary to an Adrenocorticotropic Hormone-Producing Pheochromocytoma
Authors: Anwar Kanwal , Alpertugna Ipek , Detelich Danielle , Balonov Konstantin , Tarnoff Michael , Vercollone Jeffrey , Siegel Richard D , Tischler Arthur S , Lechan Ronald M
Published: May 2021

A 76-year-old woman presented with worsening fasting hyperglycemia on routine blood sugar measurement, previously well-controlled on Metformin, requiring initiation of insulin. Her medical history included type 2 diabetes mellitus, hypertension, and aortic stenosis. Over the next few weeks, she developed bilateral upper and lower extremity proximal muscle weakness, episodes of confusion, rapid weight loss and increasing lower extremity edema. She did not have typical Cushingoid features of moon facies, easy bruising, centripetal obesity, abdominal striae, dorsocervical fat padding, or hyperpigmentation. Laboratory data revealed severe hypokalemia, elevated cortisol of 138 (3.7–19.4 ug/dL) and ACTH of 368 (6–50 pg/mL) consistent with ACTH-dependent Cushing’s syndrome. She was hospitalized for emergent therapy with etomidate infusion, potassium supplementation, and started on spironolactone. 24-hour urinary analysis demonstrated elevated catecholamines and metanephrines: epinephrine 552 (2–16 mcg/g cr), norepinephrine 1881 (7-5 mcg/g cr), metanephrine 4095 (21–153 mcg/g cr), normetanephrine 3920 (108–524 mcg/g cr).

CT abdomen showed 3.8 cm mass in the left adrenal gland with enhancing walls and central hypoattenuation and a normal contralateral adrenal gland. MR brain showed a partial empty sella without any mass. 123I-metaiodobenzylguanidine scintigraphy showed uptake in the left adrenal mass. Once cortisol was reduced to <25 ug/dL, she was transitioned from etomidate to metyrapone; alpha-methyltyrosine and prazosin was also begun. Following left laparoscopic adrenalectomy, ACTH decreased to <5 pg/mL confirming that the pheochromocytoma was the source of ectopic Cushing’s. Gross examination of the mass was notable for a spongy, tan, roughly spherical medullary neoplasm (3 cm in diameter) with a rim of brown and focally yellow adrenal cortex up to 4 mm thick. Marked diffuse adrenal cortical hyperplasia was noted. The tumor showed varied growth patterns, including solid areas and spongy, angioma-like areas with prominent small blood vessels. Immunohistochemical staining was positive for somatostatin receptor 2A, tyrosine hydroxylase and ACTH in tumor cells and negative for T-PIT. She was discharged on replacement hydrocortisone therapy, minimal insulin for diabetes and has shown substantial clinical improvement.

Cushing’s syndrome due to ectopic ACTH-producing pheochromocytoma is rare. Worsening hyperglycemia in the presence of hypertension, even without typical clinical findings of Cushing’s, should prompt further hormonal work up. The absence of the transcription factor TPIT, which is a lineage determinant for pituitary corticotrophs, suggests that novel pathways are involved in differentiation of cells that produce ectopic ACTH.
Malignant Testicular Paraganglioma: The Importance of Adequate Clinical Follow-Up
Authors: Alves Pantaleão Priscilla Maris Pereira , Leal Angela Cristina Cristina
Published: May 2021

Background: Paragangliomas (PGL) are rare neuroendocrine tumors derived from neural crest cells. The presence of metastases is the only absolute criterion of malignancy. Clinical Case: A 59 y.o. male patient reports the appearance of a tumor in the right inguinal region operated in 2014 with tumor removal and right orchiectomy, with anatomopathological (AP) outcome spermatic cord adenomathoid tumor and immunohistochemistry (IHC) compatible with PGL: Ki-67 1% (S 100 diffusely positive protein), diffusely positive chromogranin A, weak positive CD99. However, no new tests were performed in the follow-up. After 5 years, the patient started to present sporadic episodes of sweating, palpitations and increased tension levels after doxazosin suspension. Investigation for reoccurrence with Urinary Catecholamines: Noradrenaline (VR< 97 mcg/24h) 112/179, Adrenaline (VR< 27 mcg/24h) 4/4, Dopamine (< 500 mcg/24h) 184/ 342, Plasma Metanephrines: Normetanephrines (VR< 196 pg/ml) 880.7/ 2402 Metanephrines (VR< 65 pg/ml) 44.6/ 53.1. Tests was performed: chest CT Multiple bilateral non-calcified pulmonary nodules with contrast enhancement, measuring 1.2 cm. Abdominal CT: Two retroperitoneal solid lesions located anteriorly to the inferior vena cava and aorta, in a discretely paramedian position on the right, intense arterial enhancement, with a hypoattenuating center. The largest lesion is located just below the emergence of the renal arteries and after the head of the pancreas and third portion of the duodenal. It measures 4.4 x 3.2 x 4.4 cm (LL x AP x CC). The smallest lesion is immediately inferior to the largest and measures 3.1 x 2.6 x 3.6 cm (LL x AP x CC). The lesions have contact with retroperitoneal vascular structures, notably with the inferior vena cava and with the vascular pedicle of the right kidney. Scintigraphy with MIBG: Radiopharmaceutical hyperconcentration in focal areas in the projections of lung fields, in greater number on the left, with intensity of uptake varying from mild to moderate; two contiguous focal areas in the median projection of mesogastrics, in moderate/acentuated degree. Patient was reoperated and removed abdominal lesions with new conclusive AP for PGL whit PASS 3, currently performing therapeutic MIBG for thoracic injury control. Clinical Lesson: Patients with lesions suggestive of PGL but without confirmatory AP should request IHC and clinical follow-up will be according to the findings in it.
Nephrotic Syndrome Following Resection of an Adrenal Incidentaloma:A Case Report
Authors: Batool Maria , Leen Eamon , Glavey Siobhan , Sreenan Seamus K , McDermott John
Published: May 2021

A 69 year old man had a 5 cm right adrenal lesion discovered incidentally while being investigated for a deterioration in previously well-controlled hypertension. Routine investigations including serum albumin were normal. Further investigation confirmed a non-functioning adrenal lesion. MRI revealed a ‘non-fat-containing T1 hyperintense indeterminate adrenal lesion with speckling of T2 hyperintensity, not typical for adenoma, hyperplasia, myelolipoma, haemangioma or pheochromocytoma’. An uncomplicated laparoscopic adrenalectomy was performed. Histology revealed a 118 g adrenal neoplasm, modified Weiss score 0, with abundant hyaline deposits.3 months later the patient complained of peripheral oedema. Investigations revealed a serum albumin of 24 g/L and 14 g of proteinuria in 24 hours. Serum protein electrophoresis revealed a monoclonal IgA type lambda band. Renal biopsy revealed amorphous material displaying apple green birefringence on staining with Congo Red, which stained with antibodies to lambda light chains, confirming AL amyloid. Therefore the patient’s resected adrenal specimen was retrieved and stained with Congo Red, revealing apple green birefringence in the walls of the blood vessels, confirming the presence of amyloidosis. Although adrenal gland involvement in secondary amyloidosis is common, adrenal involvement in primary amyloidosis is less well described. This case illustrates the indolent nature of primary amyloidosis, prior to the development of often catastrophic symptoms. Consideration should be given to Congo Red staining of resected pathologic specimens containing hyaline deposition, to potentially allow for earlier recognition of this devastating disease. A pathophysiologic link between the patient’s incidentaloma, adrenalectomy, and onset of nephrotic syndrome remains a matter for conjecture.
Pheochromocytoma Masquerading as Weight Loss - a Diagnostic and Management Challenge
Authors: Palani Gurunanthan , Drake Tyler C , Sibley Shalamar Dionne
Published: May 2021

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 >40000 pg/ml (reference range <=205), normetanephrines >20000 pg/ml (reference range <=148), metanephrines 57 pg/ml (reference range <=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 <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

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

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 < 1 ng/dL, 21 hydroxylase antibody positive, TPO antibody > 1000 (0 - 100 Units) and GAD-65 antibody > 47 IU/mL (<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

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 <1.0 (7–25 µg/dL), adrenocorticotropic hormone (ACTH) level significantly elevated to >1,250 (6–58 pg/mL), aldosterone <4 (<21 ng/dL), and plasma renin activity elevated to 18 (<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

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 (<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 (> 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

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 (<57pg/mL), normetanephrine 6155pg/mL(<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

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 (< 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) >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

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.
Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
Authors: Vanova Katerina Hadrava , Pang Ying , Krobova Linda , Kraus Michal , Nahacka Zuzana , Boukalova Stepana , Pack Svetlana , Zobalova Renata , Zhu Jun , Huynh Thanh , Jochmanova Ivana , Uher Ondrej , Hubackova Sona , Dvorakova Sarka , Garrett Timothy , Ghayee Hans , Schuster Bjoern , Knapp Philip , Frysak Zdenek , Hartmann Igor , Nilubol Naris , Cerny Jiri , Taieb David , Rohlena Jakub , Neuzil Jiri , Yang Chun Zhang , Pacak Karel
Published: May 2021

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells that are frequently linked to mutations including those in Krebs cycle enzymes, particularly succinate dehydrogenase (SDH). Succinyl-CoA ligase (SUCL) catalyzes reversible conversion of succinyl-CoA to succinate providing the substrate for SDH. While mitochondrial diseases were documented for the mutations in SUCL subunits G1 and A2, the association of GDP/GTP-specific subunit SUCLG2 mutations with specific pathologies including cancer have not been reported. In our study, 352 patients with apparently sporadic PPGLs underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health. Additionally, human pheochromocytoma (hPheo1) cells were used for gene manipulation to produce SUCLG2 knock-out (KO). Tumor tissues and hPheo1 SUCLG2 KO cells were used for further analysis focusing on mechanism of germline variants effect on mitochondrial functions. We detected eight germline SUCLG2 mutations in 15 patients which represents 4.3% of the cohort. Germline variants together with LOH led to decreased levels of SDH subunit B resulting in aberrant respiration and accumulation of succinate, well recognized oncometabolite. Manipulation of SUCLG2 in hPheo1 cells confirmed decrease in SDHB leading to faulty assembly of mitochondrial complex II and alteration of its respiration and activity. In summary, our study identified an association between SUCLG2 and PPGL. Larger scale sequencing and uncovering additional cases bearing SUCLG2 variants will further clarify the relationship between SUCLG2 and SDHx, particularly SDHB, as well as their role in disease etiology.