bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of Paraneoplastic Cushing’s Syndrome in Recurrent Squamous Cell Carcinoma
Authors: Goettemoeller Travis , Tsushima Yumiko , Madhun Nabil Zuhayr , Olansky Leann
Published: May 2021

Background: Ectopic production of ACTH causing Cushing’s syndrome (CS) is rare but has been well described in association with bronchial carcinoids, thymomas, pancreatic malignancies, and small cell lung carcinomas. We report a rare case of CS caused by ACTH-producing non-small cell carcinoma.

Clinical Case: A 71 year-old man with a history of squamous cell carcinoma of the lung (T2bN1M0) 10 years prior who underwent lobectomy and adjunctive chemotherapy, presented with a new cough, weight loss, and bilateral lower extremity edema. He was also noted to have significant fatigue, hypertension, symptomatic hyperglycemia, and hypokalemia. CT chest revealed a large right perihilar mass with mediastinal adenopathy and numerous hepatic lesions.

A biopsy of the liver lesions revealed a poorly differentiated carcinoma with neuroendocrine features strongly positive for AE1/3 with focal p40+, CK7, synaptophysin, chromogranin, and TTF1. It was negative for p63, CK5/6, CDX2, CK20, and GATA3. The morphology and immunohistochemical staining favored a squamous primary. Unfortunately, there was insufficient tissue sample to stain for ACTH. Biochemical evaluation revealed: post-1 mg dexamethasone serum cortisol 74.8 µg/dL (N < 1.8 µg/dL), 24 hr urine free cortisol 2987 µg/g creatinine (normal: < 32 µg/g creatinine), and ACTH 170 pg/mL (N < 47 pg/mL). Other notable findings at presentation were potassium 2.8 mmol/L (N: 3.7-5.1 mmol/L) and glucose 371 mg/dL (N: 74-99 mg/dL). MRI brain revealed focal pituitary infundibular thickening up to 6 mm in diameter and an enlargement of the pituitary gland concerning for metastasis. The patient’s clinical course was complicated by persistent hypokalemia and hyperglycemia which were treated with spironolactone 100 mg twice a day and insulin therapy, respectively. Ketoconazole 100 mg twice a day was initiated for the hypercortisolemia; etoposide, carboplatin, and atezolizumab were started for the neuroendocrine tumor. The patient expired due to sepsis one month after the diagnosis of Cushing’s syndrome. Conclusion: We report a rare case of paraneoplastic Cushing’s syndrome due to poorly differentiated neuroendocrine tumor with a squamous cell carcinoma primary. ACTH producing non-small cell carcinomas have been seldom reported in the literature. Although we were unable to provide ACTH staining on pathology, the existence of an obvious neuroendocrine tumor, marked elevation in ACTH, and an MRI which was negative for a pituitary adenoma, strongly suggests paraneoplastic Cushing’s syndrome.
Biochemical and Genomic Changes of a Devastating Metastatic Medullary Thyroid Cancer
Authors: Soe Myat Han , Liu Chienying , Neinstein Aaron Barak , Murphy Elizabeth J
Published: May 2021

Introduction: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of thyroid parafollicular C cells. About 25% of cases are hereditary, associated with MEN2 syndromes. RET M918 mutation (somatic or germline) is associated with the most aggressive form of MTC. If MTC is hereditary, further tumor genomic analysis is not routinely performed. Therefore, the somatic mutational landscape of hereditary MTCs is not frequently described in the literature. We present an unusual case of MTC with a germline M918 RET mutation, displaying an initial smoldering course followed by rapidly fatal widespread metastases. Whole exome sequencing (WES) of primary tumor and metastases revealed intertumoral heterogeneity with many somatic mutations including p53 mutation.

Clinical Case: The patient with characteristic facies of MEN 2B presented with a neck mass at age 28. She had no family history of MEN. At diagnosis, calcitonin was 11,392 pg/mL and CEA was 729.7 ug/L. Pathology showed MTCs of 5 cm (right) and 2.1 cm (left) with lymph node metastases (pT3N1bMx). Genetic testing showed RET M918 mutation. Postoperative calcitonin and CEA were 3.3 pg/ml and 1.7 ug/L respectively. Tumor markers doubling time was initially about 1 year, but progressively shortened over time. Three years after surgery, calcitonin and CEA were 101 pg/ml and 387 ug/L respectively. CT chest and abdomen identified no distant metastasis. Over the next 4 months, calcitonin and CEA increased dramatically to 1821pg/ml and 3974 ug/L. The patient was admitted for acute liver failure and passed away. Autopsy revealed widely metastatic disease to liver, lungs, spleen, pituitary, right adrenal gland, bones, and brain. WES revealed 87, 283 and 591 somatic mutations in the primary tumor, lung and liver metastases respectively. The primary tumor had chromosome 1p loss whereas liver and lung metastases had somatic mutation of TP53 and single copy loss of chromosome 17 (biallelic inactivation of p53).

Conclusion: This case illustrates intertumoral spatial and temporal genetic heterogeneity. Mutations detected by WES may or may not be cancer-related and their clinical relevance is often uncelar. We hypothesize TP53 biallelic loss might have contributed to the aggressive phenotype of this tumor. Also of note, even before the appearance of metastases, CEA was disproportionately higher than calcitonin, reflecting tumor dedifferentiation. Further studies are needed to address CEA threshold for additional imaging and imaging modality for early detection of metastases.
Glucagonoma: “A Diagnostic Challenge”
Authors: Shah Aashka M , Thumma Soumya , Stout Jessica , Thandassery Ragesh , Williams-Wuch Kerry , Burdine Lyle , Jackman Kimberly , Ambrogini Elena
Published: May 2021

Introduction: Glucagonoma is a rare pancreatic α-islet cell tumor accounting for nearly 1% of all the neuroendocrine tumors (NET), with an incidence of 1 in 20 million people. We present here a patient with glucagonoma with uncontrolled diabetes mellitus (DM) for over ten years and necrolytic migratory erythema (NME) for two years. Clinical Case: A 50-year-old Caucasian male was referred to the endocrinology team for uncontrolled DM type 2. The DM was diagnosed over 10 years prior with initial HbA1c of 10.2% and remained uncontrolled with HbA1c >9%, despite compliance with lifestyle modifications and treatment with multiple agents including metformin, glipizide, empagliflozin, and pioglitazone. Given poor glycemic control, the treatment was escalated to glargine and lixisenatide. Over the years, the patient presented with unintentional weight loss of 105 pounds, fatigue, normocytic normochromic anemia, and diffuse erythematous rash with plaques and scaling on the trunk, flexor surfaces of lower and upper extremities, soles of hands and feet. Punch biopsy of the lesions revealed neutrophilic infiltration. He denied diarrhea, deep venous thrombosis, pulmonary embolism, psychiatric symptoms, or family history of neuroendocrine tumor (NET) or MEN 1 syndrome. A CT chest abdomen and pelvis revealed a 5 cm mass on the pancreatic tail along with liver metastasis. The biopsy confirmed a well-differentiated NET. Serum glucagon and chromogranin-A levels were elevated at 2967 pg/mL (N: 50-150 pg/mL) and 263.8 ng/mL (N: 0-101.8 ng/mL) respectively, consistent with pancreatic glucagonoma. Octreoscan revealed diffuse uptake in the liver, omentum, and spleen. He was started on Octreotide injections monthly, followed by distal pancreatectomy, splenectomy, hepatic wedge resection, and excision of the omental implant with the plan to treat the residual liver metastasis with radioembolization. Pathology analysis showed local invasion and metastasis to local lymph nodes with immunostaining positive for AE1/3, synaptophysin, chromogranin, and Ki67 index <2% consistent with Grade I well-differentiated NET. Post-surgery, serum glucagon and chromogranin-A levels dropped to 400 pg/mL and 68.8 ng/mL respectively. Insulin requirements markedly dropped with an improvement in glycemic control and resolution of the rash. Conclusions: Glucagonoma is an uncommon, slow-growing pancreatic neoplasm resulting in excessive glucagon secretion and it is characterized by diabetes mellitus, NME, chronic diarrhea, and deep vein thrombosis. Nearly 50% of glucagonomas are metastatic at the time of diagnosis. Patients without metastasis have a 10-year survival rate of almost 100%, compared with 51.6% of patients with metastasis, emphasizing the importance of early diagnosis and multidisciplinary treatment approach to achieve a better therapeutic outcome.
Laparoscopic Bilateral Adrenalectomy Should Be an Early Consideration in Ectopic Adrenocorticopic Hormone Secretion
Authors: Francis-Emmanuel Patrice M , Siddique Rana M , Soong Elaine , Tauni Rahat A , Wijenaike Nishan A
Published: May 2021

Introduction: Ectopic ACTH secretion (EAS) causes myriad metabolic derangements which may be effectively managed with laparoscopic bilateral adrenalectomy (LBA) in fit-for-surgery candidates. Clinical Case: A 67-year old woman with a remote 12-pack year smoking history presented with unintentional weight loss, cough, fever and chest pain. Imaging revealed a right-sided lung mass with liver lesions. Liver biopsy confirmed a well-differentiated neuroendocrine tumour (NET). Attempt at palliative lung resection was aborted due to disease extent. She was treated with multiple courses of chemotherapy but her disease progressed. Two years later, she presented with hypokalemia of 2.8 mmol/L (3.5 - 5.0 mmol/L) and uncontrolled hypertension. She was treated with spironolactone and oral potassium. She was notably hyperglycaemic with clinical features of cortisol excess. A random cortisol of 2742 nmol/L (<500 nmol/L), corresponding ACTH of 201 ng/L (5 - 50 ng/L) and lack of diurnal variation in cortisol day curve were in keeping with EAS. Metyrapone and spironolactone normalised blood pressure and biochemical derangement. With her initially high cortisol levels and its associated immunocompromised state, she developed pneumocystis jirovecii pneumonia (PCP), and was briefly admitted to the intensive care unit. In hospital, monitoring her response to EAS management necessitated multiple blood investigations, which proved burdensome for the patient. To effect definitive management of EAS and reduce invasive monitoring, she wished to have LBA and underwent an uneventful procedure. She was discharged on fludrocortisone and hydrocortisone along with lanreotide for primary disease management. Metyrapone and spironolactone were stopped. At initial outpatient follow up, she had normal blood pressure and electrolytes. By her report, her quality of life had improved tremendously, given the reduced need for multiple clinic visits and blood investigations. Unfortunately, her primary disease progressed with gradual deterioration of physical function. She died six months after LBA but, as per her desire, spent her final months with loved ones. Clinical Lesson: In patients with EAS who have unresectable primary disease but otherwise good performance status, LBA is a viable alternative to medical management and should be discussed with patients early after diagnosis. References1. Alberda et al., Endoscopic bilateral adrenalectomy in patients with ectopic Cushing’s syndrome. Surgical Endoscopy 2012; 26:1140-1145

2. Reincke et al., A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur Journal of Endocrinology 2015, 173M23-M32
The Story of a Radiologically Undetectable, Testosterone Producing Leydig Cell Tumor
Authors: Kappus Natalie , Karadsheh Oday , Jayathilaka Dhammi K K , Dandona Paresh
Published: May 2021

Introduction: Leydig stromal cell tumors are uncommon ovarian tumors that produce testosterone leading to hyperandrogenism. We present a case of a 63 year old lady with significantly elevated testosterone levels that did not have clear ovaries visualized on imaging, but was subsequently found to have a Leydig cell tumor on pathology after ovarian resection.

Clinical Case: A 63 year old female with a past medical history of COPD, hypothyroidism, hyperlipidemia, hypertension and uterine fibroids status post hysterectomy and left oophorectomy in 1995 was referred to endocrinology for hirsutism. The patient reported first noticing abnormal hair growth approximately one year prior to presentation having developed increasingly coarse and thick facial hair, abdominal wall hair, and chest hair. On physical examination, she was noted to have coarse hair across her upper lip and chin continuous along the jawline along with fine, dark hair diffusely across her anterior abdomen. Initial laboratory cell evaluation revealed total testosterone 378 ng/dL, free testosterone 53ng/dL, DHEAS 64 ug/dL. Repeat labs drawn three months later confirmed the markedly elevated total testosterone of 362 ng/dL and free testosterone 44.2 ng/dL, concentrations normally seen in males. A CT scan of the abdomen and pelvis was done and did not reveal any masses. In addition, no ovaries were appreciated on imaging. A transvaginal ultrasound also did not reveal any clear ovaries. The patient ended up undergoing a right oophorectomy. Histological examination was consistent with a Leydig cell tumor. Following oophorectomy, her testosterone concentrations normalized (5ng/dL) and hirsutism began to regress.

Clinical Lesson: Hyperandrogenism in women is typically classified into non-tumorous and tumorous. The differential for non-tumorous hyperandrogenism includes PCOS, congenital adrenal hyperplasia (CAH), and ovarian hyperthecosis. Tumorous causes include ovarian tumors such as Sertoli-Leydig cell tumors, hilus cell tumors, and theca cell tumors. Adrenal tumors secreting testosterone are extremely rare. Often with these tumors, there is significantly increased testosterone levels (> 140ng/dL) and rapid progression of symptoms. Sex cord stromal tumors account for only 5-8% of all ovarian tumors with Leydig stromal tumors a rare group that accounts for less than 0.1% of all ovarian tumors. The tumors are functional producing testosterone leading to marked hyperandrogenism and virilization. They are also usually benign and unilateral. This patient had hyperandrogenism manifested by hirsutism with markedly elevated testosterone concentrations. In addition, this case is unique in that a CT scan and transvaginal ultrasound did not clearly demonstrate her right ovary. Despite having a normal appearing right ovary during surgery, patient was found to have Leydig cell tumor following histological examination.
Acute Adrenal Infarct in a Pregnant Female With Severe Abdominal Pain
Authors: Warda Firas , Gandhi Gunjan Yogendra
Published: May 2021

Background: The differential diagnosis for pregnant patient presenting with abdominal pain is broad. Adrenal infarction is a rare cause of such presentation. Clinical Case: A 24-year-old woman, 30 weeks pregnant, presented to the emergency room with severe, sharp, left upper quadrant abdominal pain that radiated to the back and was associated with nausea and vomiting. Abdominal exam showed tenderness to light palpation in the left upper area with voluntary guarding. Genitourinary exam revealed a closed cervical os. Abdominal MRI noted a T2 hypointense left adrenal gland with loss of normal diffusion restriction. Edematous changes were identified within the left perinephric and anterior pararenal spaces. Left adrenal gland non-hemorrhagic infarction with necrosis was diagnosed, and patient was started on enoxaparin. Patient was admitted for hydration and pain control. A morning serum cortisol was equivocal at 10.3 µg/dL with a mid-normal ACTH of 38.9 pg/mL. ACTH stimulation noted a suboptimal cortisol response with a serum cortisol at baseline of 9.1 µg/dL, at 30 minutes 10.7 µg/dL, and at 60 minutes 11.0 µg/dL. Patient was started on stress dose intravenous hydrocortisone. Evaluation for thrombophilia was undertaken and patient initiated on therapeutic weight-based enoxaparin. Investigations for etiology included normal factor V leiden, proteins C and S activity, antithrombin III antigen, antiphospholipid screening, C3 and C4 complement, anti-double stranded DNA antibody, anti-neutrophil cytoplasmic antibody, cryoglobulin, homocysteine, and factor II mutation. Factor VIII activity was increased >200%, which is within expected range during pregnancy. Patient was heterozygous for MTHFR C677T and A1298C mutations. Hydrocortisone was tapered and patient discharged on a physiologic dose, in addition to enoxaparin. Conclusion: Unilateral adrenal infarction is an uncommon entity in general, and even more uncommon during pregnancy (1). Thrombophilia evaluation is warranted as antiphospholipid syndrome and MTHFR gene mutations have been associated with this condition. Given the rarity of this disease, it may not be included in the differential diagnosis of pregnant patients who present with acute abdominal pain. MRI is superior to other imaging modalities due to its sensitivity in detecting adrenal infarct and even hemorrhage, if present. Unfortunately, there are no guideline on managing such patients, but the focus is usually placed on anticoagulation to prevent the infarction of the contralateral adrenal gland, with cautious monitoring as hemorrhagic conversion is possible. Screening patient for adrenal insufficiency for prompt supplementation of corticosteroids if needed is necessary, while attempting to find the underlying cause. Reference: (1) Green P., et al. Unilateral adrenal infarction in pregnancy. BMJ Case reports. 2013; bcr2013009997
Bilateral Adrenal Adenomas Attributed to Extrapulmonary Mycobacterium Tuberculosis
Authors: Elmaaz Ahmed , Akel Alberto Antonio Franco , Belokovskaya Regina
Published: May 2021

Introduction: Adrenal infections are rare, with the Mycobacterium tuberculosis (MTB) being the most common causative agent in the developing world. MTB usually spreads to the adrenal glands hematogenously where it may be clinically manifested years after systemic infection. Here, we present a case of bilateral adrenal MTB infection associated with MTB peritonitis. Case Presentation: A 46-year-old male, from Ecuador, without significant medical history and no medical follow-up presented to the emergency room with a two-week history of abdominal pain, nausea, diarrhea, and significant weight loss. He denied fever, cough, or night sweats. No smoking, alcohol, or illicit drug use. He works as a construction worker without a history of sick contacts. Vital signs were stable, with abdominal distension and fluid shifting dullness on exam. Blood work revealed leucocyte count of 5.58K (4-11K), INR 1.2 (0.9–1.1), Sodium 132 mEq/L (136–145 mEq/L) with albumin 3.3 mg/dL (3.5–5.2 mg/dL), total bilirubin level, 1.3 mg/dL (0–1.2 mg/dL), and AST and alkaline phosphatase levels, 73 U/L (0–40 U/L) and 186 U/L (40–129 U/L) respectively. Computerized tomography (CT) of the abdomen showed large ascites, omental nodularity, calcified gall bladder, bilateral adrenal nodules, and multiple abdominal lymphadenopathies. Chest CT revealed right apical reticulonodular densities. A diagnostic paracentesis revealed an exudative effusion with serum ascites albumin gradient of 0.7, and negative acid fast bacilli (AFB) and adenosine deaminase enzyme. Ascitic cellular analysis was negative for malignant cells. AFB blood and sputum cultures were negative, though Quantiferon gold test was positive and a skin tuberculin test was 13x13mm. Tumor markers CA19-9, CEA, and alpha-fetoprotein came back negative. Additionally, serum aldosterone, plasma metanephrines, DHEA-S, AM Testosterone, ACTH, and morning cortisol levels were normal. The patient had a negative 1-mg dexamethasone suppression test. Positron emission tomography (PET) scan showed a hypermetabolic left adrenal mass (4.9x3.2 cm) and nodular peritoneum with no fluorodeoxyglucose (FDG) uptake in the enlarged abdominal lymph nodes. Peritoneal biopsy analysis revealed non-caseating granuloma positive for MTB. The adrenal biopsy was not performed given the extensive intra-abdominal disease. The patient was started on anti-MTB treatment (Isoniazid, rifampicin, pyrazinamide, and ethambutol) with significant clinical improvement and a slight decrease in the adrenal masses following abdominal imaging. Conclusion: Extrapulmonary MTB should be part of a differential diagnosis for bilateral adrenal masses. Adrenal glands could be infected by a variety of pathogenic microorganisms either by direct contact or hematogenous dissemination. A high index of suspicion is required for the diagnosis of MTB in patients with atypical presentation.
Bypassing the Adrenals: A Rare Case of Adrenal Insufficiency Following Bariatric Surgery
Authors: Raco Joseph , Shamloul Norhan , Jain Rohit
Published: May 2021

Background: Adrenal insufficiency (AI) is a life-threatening disorder that is generally caused by primary adrenal failure or by hypothalamic-pituitary impairment of the corticotropic axis. Patients often present with fatigue, hypotension, anorexia, and weight loss. There are few reported cases of AI following bariatric surgery; a type of procedure designed to cause weight loss and anorexia - two of the cardinal symptoms of AI. Establishing a diagnosis of AI in patients who have undergone bariatric surgery can be challenging due to symptom overlap, but it is of critical importance given that an acute stressor has the potential to precipitate adrenal crisis with risk of death. Clinical Case: A 42-year-old woman presented 15-months after sleeve gastrectomy with biliopancreatic diversion and duodenal switch with nausea, vomiting, decreased oral intake, weight loss, weakness and fatigue. Her symptoms were severe, requiring admission to the hospital and were initially thought to be a result of her bariatric surgery. Initial intake exam and labs were notable for mild hypotension, persistent hypoglycemia with hemoglobin A1c <3.4%. Further evaluation revealed a low AM cortisol (5.5 μg/dL) and diagnosis of AI was confirmed by a failed cosyntropin stimulation test with cortisol levels of 7.0 μg/dL and 10.6 μg/dL 30- and 60-minutes after cosyntropin administration, respectively. Her diagnosis remained confounded by the presence of concomitant micronutrient deficiencies including copper, zinc, vitamin D and vitamin B6. Furthermore, she was found to have low insulin and c-peptide levels of 1 μU/mL and 0.4 ng/ml, respectively, despite persistent hypoglycemia. The patient was treated with enteral nutrition via nasojejunal feeds and glucocorticoid replacement therapy with daily oral hydrocortisone and fludrocortisone. Each of her symptoms improved after initiation of steroid replacement therapy and she was discharged home. Conclusion: Clinicians should keep a high degree of suspicion for adrenal insufficiency in patients who have undergone bariatric surgery due to the degree of symptom overlap in this population.
Cardiac Arrest in a Child with Non-classic Lipoid Congenital Adrenal Hyperplasia Associated with a New STAR Gene Mutation
Authors: Yan Yun , Thiffault Isabelle , Tsai Sarah , He Luke , De Luca Francesco
Published: May 2021

Introduction: Steroidogenic acute regulatory (STAR) protein regulates steroid hormone synthesis by transporting cholesterol into mitochondria. STAR gene mutations lead to lipoid congenital adrenal hyperplasia (LCAH), the rare but most severe form of congenital adrenal hyperplasia in children. We present an unusual case with an episode of cardiac arrest in a young girl during an acute febrile illness and later she was diagnosed with adrenal insufficiency secondary to a non-classic LCAH. Case: 2-year 11-month-old previously healthy white female was brought to an urgent care clinic due to severe lethargy and a seizure-like activity during a fever illness. She was found to have an undetectable blood glucose level and went into cardiac arrest shortly after arrival. CPR was performed for approximately 11 minutes. She then developed sever respiratory distress and was intubated. She was transferred to the PICU with IV sodium bicarbonate given en route. On admission, her body weight was 13.26 kg (36.80th percentile), height 90 cm (17.56th percentile), and BMI 16.17 (62.88th percentile). Her physical exam revealed normal external female genitalia and normal skin pigmentation. Lab evaluation revealed normal sodium and potassium but elevated anion gap, hyperuricemia, elevated creatinine kinase, abnormal liver function tests and abnormal coagulation profile. Brain MRI revealed findings consistent with hypoxic-ischemic encephalopathy. Renal function improved within 24 hours and hepatic function returned to normal after 20 days. Due to her severe hypoglycemic event, a high-dose ACTH stimulation test was performed. The results were consistent with adrenal insufficiency: baseline cortisol level, 7.3 μg/dL; 30 minutes cortisol, 7.8 μg/dL; 60 minutes cortisol, 9 μg/dL (normal response, ≥18 mcg/mL at 30 or 60 minutes). The baseline ACTH level was significantly elevated, 1688 pg/mL (0–46) as well as the renin activity, 24.3 ng/hour (1.7–11.2). Genetic testing revealed a 46 XX karyotype. STAR gene analysis identified compound heterozygosity; a novel deletion (c.811delC, p.Leu271Cysfs*50) and a previously reported missense mutation (c.661G>A, p.Gly221Ser). The girl is now 11 years old and exhibits normal growth, normal cognitive development, and she has developed early signs of puberty (Tanner stage 2 for breast). She takes daily hydrocortisone, fludrocortisone and stress dose hydrocortisone as needed. Conclusion: In non-classic LACH, the onset is generally late or not acute. Initial clinical features are variable and nonspecific. For this reason, non-classic LCAH may be overlooked. Adrenal crisis is a life-threatening complication, and it is important that clinicians are aware of

the clinical features of non-classic LCAH and consider it in the differential diagnoses. Genetic testing for STAR should be considered in individuals with non-autoimmune primary adrenocortical insufficiency.
Concurrent Pseudohyperaldosteronism and Primary Glucocorticoid Deficiency From Posaconazole
Authors: Chang Julia J , Villar-Prados Alejandro , Stevens David A , Wang Xiao-Yan , Chen Julie
Published: May 2021

Background: Posaconazole can cause pseudohyperaldosteronism via inhibition of 11-beta hydroxylase and 11-beta-hydroxysteroid dehydrogenase type 2 (1). The accumulation of 11-deoxycorticosterone and increased cortisol-to-cortisone ratio in the kidney causes apparent mineralocorticoid excess. The effect of posaconazole on the glucocorticoid axis is less established.

Clinical Case: A 56-year-old Hispanic man with a history of chronic septic arthritis of the left ankle from Coccidioides presented with 3 months of malaise, nausea, weight loss of 30 pounds, and recurrent hypokalemia. He was recently switched from long-term fluconazole therapy to posaconazole around the time his symptoms began. His initial labs at our hospital were notable for low potassium (2.9 mmol/L, nl 3.5–5.5 mmol/L) and a random cortisol of 5.8 mcg/dL (nl ≥2.0 mcg/dL). A Cosyntropin stimulation test revealed elevated ACTH (168 pg/mL, nl 7.2–63.3 pg/mL) with minimal rise of cortisol from 4.6 to 7.2 mcg/dL at 1 hour after Cosyntropin administration (nl ≥18 mcg/dL at 1-hour post-Cosyntropin). His plasma renin activity was below detection (<0.6 ng/ml/h, nl 0.6–3.0 ng/mL/h), consistent with renin suppression from apparent mineralocorticoid excess. Hydrocortisone for glucocorticoid deficiency was started. A posaconazole determination indicated elevation (5240 ng/mL, usual therapeutic range ≥1000 ng/mL). His posaconazole was stopped, and he was switched back to fluconazole. Three months later, his symptoms were improved with regain of lost weight. Repeat Cosyntropin stimulation test showed ongoing primary glucocorticoid deficiency (ACTH 123 pg/mL, cortisol 4.1 mcg/dL at 1-hour post-Cosyntropin) but normal levels of plasma renin activity (1.2 ng/mL/h), aldosterone (8.6 ng/dL, nl ≤21 ng/dL), and potassium. Quantiferon TB and 21-hydroxylase antibody tests were negative. Hydrocortisone has been continued with plans to repeat Cosyntropin testing in 3 months to reassess.

Conclusion: Pseudohyperaldosteronism with glucocorticoid deficiency requiring hydrocortisone treatment has thus far not been reported with posaconazole. Our case shows that posaconazole may lead to true primary glucocorticoid deficiency that can persist after discontinuation of posaconazole and reversal of pseudohyperaldosteronism.

Reference: (1) Sanchez-Niño MD, Ortiz A. Unravelling drug-induced hypertension: Molecular mechanisms of aldosterone-independent mineralocorticoid receptor activation by posaconazole. Clin Kidney J 2018;11(5):688–90.
Differentiating Between CAH and PCOS Using Hormone Levels and LC-MS/MS
Authors: Hauck Zane Z , Kimball David W , Zava David T
Published: May 2021

Introduction: PCOS is one of the most common endocrine issues affecting women today, with almost 10% of women suffering from this condition. CAH is a rarer disease that affects both men and women at a rate of around 1:1000 people. The problem with these two disorders arises in the fact that variants of these conditions may have very similar clinical presentations. This makes a proper diagnosis and treatment protocol difficult. Both PCOS and CAH present with high androgens but differ in that the former usually presents with high cortisol/insulin resistance, and the latter with low cortisol and aldosterone. Another difficulty in diagnosis is due to CAH presenting itself in 4 variants; 21-hydroxylase deficiency, the most common with over 95% prevalence, 11-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase type 2 deficiency, and 17α-hydroxylase deficiency. We have developed and validated an LC-MS/MS assay using a first morning saliva that measures a full panel of steroids necessary to clearly differentiate PCOS from all 4 variants of CAH. This full spectrum of steroids includes precursors of the active steroids (pregnenolone sulfate, DHEA, androstenedione) as well as parent steroids (progesterone, testosterone, estradiol, cortisol, aldosterone) and their precursors (17-OH progesterone) and downstream metabolites (11-hydroxycortisol, corticosterone) that differentiate PCOS from CAH and define the 4 variants of CAH. Clinical Case: We will present several example case reports showing that PCOS presents with high androgens and normal to high cortisol and aldosterone, and in sharp contrast, classic CAH presents with high androgens and 17-hydroxy progesterone, but very low steroids distal to 21-hydroxylase deficiency (i.e low 11-deoxycortisol, cortisol, cortisone, corticosterone, and aldosterone). In contrast the more rare variant of 11-hydroxylase deficiency shows a typical pattern of low cortisol and cortisone and elevated 11-deoxycortisol. 3β-hydroxysteroid dehydrogenase type 2 deficiency is extremely rare to see in an adult as most babies born with this condition do not survive. 17α-hydroxylase deficiency is also very rare but shows elevated progesterone, 11-deoxycorticosterone, corticosterone, and aldosterone. For all these cases aldosterone can be tricky to interpret as there are multiple mechanisms at which aldosterone is produced and thus should not be used as a definitive marker for CAH.
Epinephrine to the Rescue: Identifying the Offending Side in Bilateral (B/L) Macronodular Adrenal Hyperplasia (BMAH) With Cushing Syndrome (CS) and Hyperaldosteronism
Authors: Vedere Tarunya , Madhavan Parvathy , Malchoff Carl D
Published: May 2021

Management of ACTH-independent CS in the setting of B/L adrenal masses can be challenging. We present a patient with concomitant cortisol and aldosterone hypersecretion and B/L adrenal masses who was treated with unilateral adrenalectomy (UA) based on simultaneous B/L adrenal vein sampling (AVS) results normalized to plasma epinephrine levels, to correct for flow and dilution. A 60-year-old lady presented for evaluation of incidentally discovered B/L adrenal masses. CT abdomen with contrast revealed B/L lobulated adrenal glands measuring 3.4 x 5.5 x 4.1 cm on the right and 3.8 x 4.2 x 2 cm on the left (pre contrast density of 37 and 44 Hounsfield Units respectively). She had a recent diagnosis of HTN and prediabetes. She reported fatigue, easy bruising, and muscle weakness. Family history was notable for a sister with CS and B/L adrenal masses who was successfully treated with UA. On physical examination her BP was 160/94 mm Hg and she did not have an obvious cushingoid appearance. Laboratory testing included an elevated AM serum cortisol level of 16.6 mcg/dL following 1 mg of dexamethasone given at 11 pm the previous night. ACTH was <1.0 pg/mL consistent with ACTH-independent CS. She had a serum aldosterone level of 26.6 ng/dL(4.0 - 31.0 ng/dL),simultaneous plasma renin activity of 0.5 ng/ml/hr (0.5–4 ng/ml/hr) and serum potassium level of 4.4 mmol/l. She underwent B/L simultaneous AVS. Given concomitant hyperaldosteronism, plasma epinephrine levels were measured to determine successful catheter placement and to correct for flow and dilution between the adrenal veins. Right adrenal vein to peripheral vein cortisol ratio was 9.27 (> 6.5) consistent with cortisol hypersecretion. The right to left cortisol ratio was 2.3 (>/= 2.3), consistent with right sided predominance. Right to left ratio of the epinephrine corrected cortisol level was 2.7. She underwent right adrenalectomy, and pathology showed macronodular adrenal hyperplasia. Postoperatively, she had resolution of HTN and normalization of 24 hour urine free cortisol. UA is increasingly becoming recognized as a successful treatment for BMAH due to lower risk of adrenal crisis when compared to B/L adrenalectomy. In a recent publication, remission from CS was seen in 94.4 % of patients with BMAH following UA, with recurrence in 19% of patients. The mean time to recurrence was 5 years. We utilized cutoff values that were previously reported for cortisol lateralization in interpreting AVS. Our patient attained remission of CS 9 months post UA. Epinephrine levels were not significantly different between the adrenal veins, possibly due to simultaneous AVS, so we were also able to calculate epinephrine corrected cortisol ratios. Simultaneous B/L AVS with epinephrine to localize autonomous hypercortisolism in the setting of concomitant hyperaldosteronism can be beneficial in guiding surgical management of patients.
Levetiracetam Treatment Causing False Negative Screening Test in a Woman With Aldosterone Producing Adenoma
Authors: Sawah Ahmed , Mallisho Abdullah , Abd Ulmalik Alshareef Muneera , Alzahrani Amirah Husseian
Published: May 2021

Background: Endocrine hypertension accounts for 5–10% of hypertensive population, with primary hyperaldosteronism being the most frequently encountered diagnosis. Biochemical tests are subject to interference with many drugs that may lead to false positive or negative results.

We present a case of aldosterone producing adenoma associated with false negative screening test due to Levetiracetam use.

Clinical Case: A 30 year-old Middle Eastern woman was referred to endocrinology clinic for evaluation of secondary hypertension and persistent hypokalemia. Six years ago, she presented to emergency room during the 3rd trimester of her second pregnancy with severe preeclampsia and seizure. Postpartum, she was discharged on Levetiracetam (Keppra) 500 mg orally BID. Upon follow up visits, she continued to have persistent elevation of blood pressure readings with spontaneous hypokalemia ranging 2.5–3.2 mEq/L. She was started on Perindopril 10 mg daily and potassium supplement. Amlodipine 5 mg daily was added shortly later on. Clinically, she had regular menstrual cycle. She did not have plethora, central obesity, easy bruising, or proximal muscle weakness. Her review of systems including thyroid-related symptoms were normal. There was no family history of hypertension or adrenal tumors. On examination, BP 180/110, pulse rate 78, weight 58 kg and BMI 25. Her physical examination was otherwise unremarkable. After holding Perindopril for 4 weeks, biochemical tests showed creatinine 0.52 mg/dL (0.49–1.1), urea 16.8 mg/dL, potassium 2.9 mEq/L (3.5–5.2), direct renin concentration (DRC) 100.6 pg/mL, aldosterone 54.25 ng/dL. Plasma fractionated metanephrines were normal and morning cortisol level after 1 mg overnight dexamethasone suppression test was 0.72 mcg/dL. Renal arterial doppler showed normal renal blood flow without any significant stenosis. Despite increasing potassium supplement she continued to have hypokalemia. As levetiracetam was reported by literature review to cause severe hypokalemia, it was stopped after discussion with neurology. Four weeks later, repeated DRC was suppressed 4.0 pg/mL with elevated aldosterone 62.73 ng/dL. Furthermore, primary hyperaldosternism was confirmed after normal saline suppression test revealed unsuppressed aldosterone 15 ng/dL. An Adrenal CT scan showed a small hypodense right adrenal lesion measuring 11x9 mm with a pre-contrast density of 7 HU and post contrast absolute washout more than 60%. Patient elected to undergo right adrenalectomy. 24 hours post surgery, aldosterone level dropped to 4.0 ng/dL and potassium increased to 5 mEq/L. Fortunately, hypertension and hypokalemia have both resolved after surgery. Conclusion: We are first to report that Levetiracetam can cause unsuppressed direct plasma rennin concentration (DRC) and potentially could result in a false negative screening test for primary hyperaldosteronism.
Presentation of ACTH Independent Cushing’s as Severe Insulin Resistance During Pregnancy
Authors: Faisal Sobia , Kaur Manmeet , Samat Ashish
Published: May 2021

Introduction: Cushing’s syndrome is very rare in pregnancy with around 200 cases reported in literature. It remains a diagnostic dilemma as pregnancy itself is a hypercortisolemic state. Several clinical characteristics of Cushing’s syndrome such as insulin resistance and hirsutism may overlap with normal variants of pregnancy and therefore leading to a missed diagnosis. We hereby present a case of a young pregnant woman with severe insulin resistance, with workup consistent with Cushing’s syndrome.

Clinical Case: This was a 27-year-old pregnant woman with DM type 2 diagnosed about 7 years ago. During her pregnancy she was started on insulin and was later admitted to the hospital at 32 weeks for inpatient management of pre-eclampsia and uncontrolled hyperglycemia. Endocrine was consulted for severe insulin resistance and persistent hyperglycemia. On exam patient was noted to be obese with facial plethora, frontal balding and significant facial hirsutism. During the pregnancy she had noted significant weight gain with substantial worsening of frontal balding and hirsutism. Her current pregnancy was spontaneous but was after many years of trying to conceive. Prior pregnancy 8 years ago was uncomplicated with no history for GDM at that time. Review of recent pre-pregnancy imaging revealed left adrenal mass measuring 3.5 cm with 40 HU which measured around 2 cm 8 years ago. Biochemical work up revealed elevated 8 am cortisol at 35.4 ug/dL (ref range 6.2 - 19.4) with suppressed ACTH <5 pg/mL (6 – 50). Testosterone was high at 299 ng/dL (8 – 48) and DHEAS was low normal at 37 mcg/dL (18 – 391). Plasma and 24 hour urine metanephrine collection results were normal. 24-hour urine free cortisol was measured and was elevated at 628.5 mcg/24(4.0–50.0). Midnight salivary cortisol was 0.87 mcg/dL (<OR=0.09). Patient was managed conservatively with plan for surgical intervention post-delivery. Pregnancy was complicated by PPROM at 35 weeks with subsequent cesarean section. Baby was of average weight but developed mild hyperbilirubinemia which required short NICU stay. On reevaluation at 4-week postpartum period, repeat biochemical workup revealed elevated cortisol of 22.5 mcg/dL, ACTH <5 pg/ml, elevated 24-hour urine cortisol 163.9 mcg/24h with appropriate urinary creatinine. Testosterone level was improved postpartum to 9 ng/dL. DHEAS was 39 mcg/dL. Repeat imaging with CT with adrenal protocol revealed left adrenal mass measuring 2.3 cm with 20 HU with absolute washout of 79%. She was started on ketoconazole is now awaiting surgical intervention.

Conclusion: We suspect that this patient may have had pregestational subclinical Cushing’s syndrome which eventually progressed to Cushing’s syndrome during pregnancy. Although this is a rare finding during pregnancy, workup for Cushing’s should be considered in pregnant women with severe insulin resistance, hirsutism, hypertension and pre-eclampsia.
Primary Aldosteronism as the Initial Presentation of Adrenocortical Multiple Hormone Producing Tumor
Authors: Uehara Erika , Nagata Tomohiro , Ota Tomoko , Ogawa Tomoe , Minegishi Rieko , Yoshii Keisuke , Naiki Yasuhiro , Horikawa Reiko
Published: May 2021

Introduction: Primary aldosteronism (PA) accounts for ∼10% of cases of hypertension in adults, however it’s a rare disease in children. We present a rare pediatric case with PA as the initial presentation of adrenocortical multiple hormone producing tumor. Case: A 7-year-old Japanese girl, who had right-sided hypoplastic leg and foot syndactyly, presented to our hospital due to abnormal ECG of ST depression at V6 on school health check-up. She showed normal growth, no signs of virilization nor Cushingoid appearance. She had elevated blood pressure (164/98 mmHg), low potassium (2.6–3.0 mEq/L) and low cardiac ejection fraction (30–40%). Her plasma aldosterone concentration (PAC) was 441 pg/mL and aldosterone/renin ratio (ARR) was 1470. Contrast-enhanced CT and MRI showed a right adrenal mass (34×22×30 mm) with high lipid content, which led to the diagnosis of primary aldosteronism by the right adrenal adenoma. Adrenal venous sampling failed to identify localization of aldosterone production. Since the possibility of bilateral production of aldosterone remained, the girl was treated with multiple anti-hypertensive medicine including spironolactone and potassium supplementation. Although the serum potassium levels were maintained within normal range, exercise-induced PVCs occurred 6 months after first visit. Abdominal US showed no changes in size of the tumor. Ten months later, she showed gradual weight gain without growth deceleration. Twelve months later, abdominal US revealed apparent enlargement of the right adrenal mass, and MRI scan showed a 156% increase in size of the right adrenal mass (32×50×53 mm). She showed further weight gain with moon face, hirsutism and acne. Hormonal analysis revealed elevated serum and urine cortisol levels (30–40μg/dL and 269–337 μg/m2/day, respectively), and suppressed ACTH levels with no diurnal variation. Serum testosterone levels elevated to 1.00 ng/mL and serum DHEA-S to 273 μg/dL. Retrospective analysis of serum testosterone at the first visit was already mildly elevated to 0.47 ng/mL. Although no distant metastases were detected before surgery, direct liver invasion was found at right adrenal tumor rejection. Clinical Lessons: Primary aldosterone producing adenoma is extremely rare in childhood. In our case, initially the adrenal tumor produced aldosterone predominantly, and it revealed to produce glucocorticoid and androgen later on. Androgen producing adrenal tumor in children tends to have malignant nature. Although initial presentation was compatible with the primary aldosteronism, intense follow-up with detailed monitoring of various hormone levels and images, and early surgical intervention should be considered.
Resistant Hypertension Due to Familial Hyperaldosteronism Type III: First Report From Indian Sub-Continent
Authors: Alam Sarah , Goyal Alpesh , Kandasamy Devasenathipathy , Bansal Virinder Kumar , Asuri Krishna , Agarwal Shipra , Khadgawat Rajesh
Published: May 2021

Background: Familial hyperaldosteronism type III (FH-III) is caused by germline mutations in KCNJ5 gene. FH-III presents with phenotypic variability from spironolactone-responsive hypertension to massive adrenal hyperplasia requiring bilateral adrenalectomy. Till date, seven different pathogenic mutations in KCNJ5 gene have been identified. Here we describe a sporadic FH-III case, due to a Gly151Arg mutation, first from Indian subcontinent, presenting with extremely high plasma aldosterone concentration (PAC) values, further expanding our knowledge of this rare condition. Clinical Case: A 24-year-old female, symptomatic since age of 5 years with periodic limb weakness and gradual increase in frequency of episodes over the years. Her blood pressure (BP) was recorded for first time at 9 years of age, and it was 170/110 mm Hg. On evaluation at this time, PAC was highly elevated at 1007 ng/dL and plasma renin activity (PRA) was suppressed at 0.04 ng/ml/h with aldosterone renin ratio (ARR) of 25,175 ng/dL per ng/mL/h (>20 suggestive of primary aldosteronism). CT scan demonstrated mild enlargement of bilateral adrenal glands. A presumptive diagnosis of Glucocorticoid-remediable aldosteronism was made. She was started on dexamethasone, spironolactone and nifedipine but was not improved. Dexamethasone was stopped after 1 year of initiation. Before presenting to our referral center in 2018, she was having uncontrolled hypertension with recurrent episodes of hypokalemic paralysis. She was on maximal doses on four antihypertensive agents, further increased to six agents (including spironolactone 100 mg BD), and potassium chloride supplementation (120 mEq/day). Despite this, she had a serum potassium of 2.6 mEq/L. Her biochemical investigations demonstrated that PAC was 2070 ng/dL, direct renin concentration (DRC) was 2.35 µIU/mL (PRA 0.2 ng/ml/h) and ARR was 880.9 ng/dL per µIU/mL. CT scan revealed massive bilateral adrenal hyperplasia. Genetic analysis by whole exome sequencing detected KCNJ5 (p.Gly151Arg) mutation, confirming the diagnosis of FH-III. She was subjected to bilateral adrenalectomy and she became normokalemic. Dramatic reduction in antihypertensives with BP control achieved only on amlodipine post-operatively. Genetic testing of family members was not done but they were normotensive and normokalemic. Histopathological examination revealed bilateral adrenal hyperplasia. PAC levels up to 297 ng/dL have been described previously in FH-III but our patient had exceedingly high-level of 2070 ng/dL. Conclusion: This case demonstrates florid clinical and biochemical manifestations of FH-III and gradual worsening of symptoms, consistent with progression of disease with age. It illustrates that proper investigations and treatment can lead to remission of symptoms. Further studies are warranted to elucidate the full clinical and biochemical spectrum of FH-III.