Bilateral Adrenal Enlargement Research Articles

ARMC5-associated Bilateral Macronodular Adrenocortical Hyperplasia: A Novel Germline Variant Associated with Concomitant Papillary Thyroid Carcinoma and Meningioma

Abstract Introduction/Objective Germline mutations in the tumor suppressor gene Armadillo-containing repeat protein 5 gene (ARMC5) have been very recently recognized as a cause for a familial form of bilateral macronodular adrenocortical hyperplasia (BMAH), itself a rare cause of Cushing syndrome. In patients with ARMC5 mutations, scattered case reports have also shown an association with meningiomas and cancers of the pancreas, breast, colon, and thyroid. Methods/Case Report We present the case of BMAH, arising in a 61-year-old female with a history of metastatic papillary thyroid carcinoma and meningioma. The patient presented with bilateral but asymmetric adrenal enlargement (right greater than left) and Cushing syndrome. Given history of thyroid cancer and meningioma, genetics referral was ordered. Counseling revealed a pedigree without a strongly evident familial pattern of hereditary endocrine neoplasia characteristic of any of the more common inherited dispositions to endocrine neoplasia. Additionally, a targeted capture-based NGS germline genetic sequencing study for variants in 12 genes associated with associated with hereditary thyroid cancer was performed and negative. However, based on recent scholarship regarding ARMC5, follow-up germline NGS and Sanger sequencing studies encompassing the entire coding sequences of ARMC5 were ordered. These identified a germline, heterozygous, novel (not in ClinVar) but likely pathogenic variant in (c.802C>T, p.Arg268*), providing a likely explanation for the patient’s BMAH. In attempt to control the patient’s Cushing symptoms, right-sided adrenalectomy was performed, revealing a 220g adrenal gland with marked multinodular hyperplasia with solid, nested, and tubular architecture. Results (if a Case Study enter NA) NA Conclusion While case reports exist describing an association between other ARMC5 mutations and BMAH with concomitant meningiomas and/or malignancies, greater study is needed in order to better characterize the phenotypic spectrum of this disease. Our experience with this case not only reports a novel, apparently pathogenic mutation, but it documents its association with BMAH and, additionally, papillary thyroid carcinoma and meningioma.

Diagnostic Impact of Adrenal Vein Sampling in Adrenal Cushing's Syndrome

Adrenal Cushing's syndrome is characterized by ACTH-independent hypercortisolism. Adrenal vein sampling (AVS) is not routinely employed prior to management decisions, and few studies have investigated the value of AVS in this population. We assessed whether AVS provides a diagnostic benefit for treatment planning. Six patients with imaging and biochemical evidence of adrenal Cushing's syndrome undergoing AVS at our institution from 2015 to 2020 were analyzed retrospectively, including demographic and clinical characteristics. AVS lateralization index was determined by comparing the (cortisol/ipsilateral reference hormone) ratios of both adrenal veins. lateralization index of 2 or greater was considered diagnostic of unilateral disease. Post-management clinical improvement was defined as serum cortisol normalization, symptomatic improvement, or both. Cross-sectional imaging noted bilateral adrenal enlargement or nodules in three patients, and unilateral nodules in three patients. AVS results were discordant with imaging in three patients. Treatment included medical management in two patients, percutaneous radiofrequency ablation in one patient, and laparoscopic adrenalectomy in two patients. One patient was lost to follow up. AVS results aided management planning in five patients, definitively changing treatment from surgery to medical management in one patient. All five patients demonstrated clinical improvement. AVS offered useful information for determining appropriate management of adrenal Cushing's syndrome, especially distinguishing unilateral from bilateral disease. Even in bilateral disease, AVS may show a dominant gland, potentially allowing a staged unilateral adrenalectomy, before assessing the need for completion adrenalectomy or medical management. Larger studies are needed to better establish whether AVS offers significant benefit for this population.

A Pedigree and Clinical Analysis of 11β-Hydroxylase Deficiency with Homozygous Mutation of CYP11B1 Gene

Abstract Background To analyze the clinical features and the mutation of CYP11B1 gene in a family with 11β-hydroxylase deficiency. Methods The clinical and laboratory tests data of the patient were collected. The complete sequences of CYP11B1 gene in the proband and potential mutations in other seven family members were analyzed by polymerase chain reaction and direct sequencing technique. Results A 25-year female patient showed complicated clinical symptoms, comprising hypertension, heart failure, renal failure, and pulmonary infections. Laboratory results showed higher levels of 17α-hydoxy progesterone, dehydroepiandrosterone (DHS) and adrenocorticotropic hormone (ACTH), and lower levels of cortisol and potassium in serum. Additionally, a positive reaction in mid-dose dexamethasone suppression test and a significant enlargement of bilateral adrenal glands from computed tomography scan were exhibited in this patient. Furthermore, a homozygous c.1157C>T (p.Ala386Val) in exon 7 of the CYP11B1 gene was identified in this patient. Four family members (father, mother, maternal grandmother, and aunt of proband) were heterozygous of the same mutation. Conclusion 11β-hydroxylase deficiency in this patient is caused by homozygous c.1157C>T (p.Ala386Val) in the CYP11B1 gene.

Resistant Hypertension Due to Familial Hyperaldosteronism Type III: First Report From Indian Sub-Continent

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.

Clinical, biochemical and imaging characteristics of adrenal histoplasmosis in immunocompetent patients in a non-endemic area: A case series

Objective: To document the clinical, biochemical and imaging phenotypes of immunocompetent patients with adrenal histoplasmosis. Methods: The clinical, biochemical and radiologic data of 18 immunocompetent patients [age: 45.00 (39.25, 56.25) years, median (IQR), m/f (16/2)] with adrenal histoplasmosis presenting in the Department of Endocrinology, BSMMU between 2014 and 2020 were retrospectively analyzed. Results: All patients were seronegative for HIV infection, and 27.8% (5/18) had well controlled diabetes mellitus. The median duration of the symptoms was 6.00 (IQR: 4.00, 11.25) months. All had significant weight loss, anorexia and weakness. Fever was present in 61.1% (11/18) patients and night sweat was present in 27.8% (5/18) cases. Hypotension and hyperpigmentation were present in 55.6% (10/18) and 66.7% (12/18) cases, respectively. Three of 18 patients presented with adrenal crisis. Hyponatremia occurred in 55.6% (10/18) cases, but none had hyperkalemia. Thirteen of 18 patients had adrenal insufficiency whereas 83.3% (15/18) had high adrenocorticotropic hormone. CT scan revealed bilateral adrenal enlargement in all cases with oval shape and regular margin. All were hypodense having radiodensity 21-90 hounsfield unit, and 11.1% (2/18) were heterogeneous in contrast enhancement. None had noticeable calcification whereas 1.1% (2/18) cases had central necrosis with peripheral rim enhancement. Hepatomegaly was present in 6 cases, splenomegaly in 3 cases and 5 patients had abdominal lymphadenopathy. Histoplasmosis were confirmed by positive fine needle aspiration cytology of adrenal tissue. Conclusions: Adrenal histoplasmosis should be considered in the list of differentials of bilateral adrenomegaly in immunocompetent individuals even living in non-endemic areas.

METASTATIC SMALL CELL NEUROENDOCRINE CARCINOMA MANIFESTING AS SPONTANEOUS TUMOR LYSIS SYNDROME

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Tumor lysis syndrome is termed oncologic emergency that results from massive cell lysis. It can happen even before initiation of chemotherapy and can be an initial manifestation of malignancy itself which is termed as spontaneous tumor lysis syndrome (STLS). It is rare and is commonly associated with hematological malignancy where the proliferation and tumor burden are high. Solid tumors manifesting as STLS is extremely rare[1] CASE PRESENTATION: 62-year-old male presented after a fall to emergency department with facial and scalp laceration. Focused assessment with sonography for trauma showed multiple hypoechoic lesions of the liver. Labs showed severe metabolic acidosis with labs showing uric acid 9.9, potassium 5.7, bicarbonate 8, phosphate 8.4, creatine of 1.4, with base line creatine of 0.8, corrected calcium 8.4, Aspartate transaminase 664, Alanine transaminase 213, total bilirubin 10.1, direct bilirubin 5.3, Lactate dehydrogenase 12,677, INR 1.7, lactic acid 17. CT chest abdomen pelvis with intravenous contrast revealed small metastatic nodules in lung less than 5 mm, multiple masses in liver suggestive of metastasis, bilateral adrenal enlargement, irregularity in prostate and seminal vesicles, osteoblastic lesions in L4 lumbar vertebra. He was oliguric with no improvement with intravenous fluids requiring dialysis. A dose of rasburicase given for STLS which improved uric acid levels. He was admitted 2 weeks before fall for urinary retention requiring foley for 5 days. Prostate specific antigen (PSA) levels during present admission slightly elevated at 9. Liver biopsy showed small cell neuroendocrine carcinoma and immunohistochemical stain is negative for PSA. He developed multiorgan failure and family decided not proceed with any further interventions given poor prognosis. Primary location presumed to be prostate based on clinical findings and imaging. DISCUSSION: STLS in solid tumors is not common[2]. Close monitoring of electrolytes and kidney function is needed in patients with suspected extensive metastasis even before pathological diagnosis[2]. Although labelled as an oncologic emergency every physician need to be aware of STLS as this is true fatal emergency and can improve outcomes with timely initiation of treatment with IV fluids, rasburicase and dialysis if necessary PSA will not be significantly elevated in neuroendocrine differentiation and tumor stains will negative for PSA due to differentiation of prostate epithelium to neuroendocrine cells. CONCLUSIONS: High index of suspicion is necessary in diagnosis of STLS. Timely initiation of treatment improves patient outcome. STLS in solid tumors have poor prognosis Reference #1: 1. Serling-Boyd N, Quandt Z, Allaudeen N. Spontaneous tumor lysis syndrome in a patient with metastatic prostate cancer. Molecular and clinical oncology. 2017;6(4):589-592. doi:10.3892/mco.2017.1186 Reference #2: 2. Sommerhalder D, Takalkar AM, Shackelford R, Peddi P. Spontaneous tumor lysis syndrome in colon cancer: a case report and literature review. Clinical case reports. 2017;5(12):2121-2126. doi:10.1002/ccr3.1269 DISCLOSURES: No relevant relationships by Chandrakala Dadeboyina, source=Web Response No relevant relationships by Pushpa Khanal, source=Web Response No relevant relationships by JOYSON POULOSE, source=Web Response No relevant relationships by Harshil Shah, source=Web Response No relevant relationships by LITTY THOMAS, source=Web Response

Primary adrenal insufficiency secondary to bilateral adrenal lymphoma

Involvement of adrenal glands in lymphoma is rare; the patient may have variable presentations. We report a case of a 62-year-old Saudi female who presented to our center with a few-week history of fatigue, weight loss, subjective fever, and a recent change in skin color. On examination, she looked dehydrated and had a drop in blood pressure with postural change and hyperpigmentation of the skin of the face and hands. Morning cortisol levels were low, and adrenocorticotropic hormone levels were high, which indicated primary adrenal insufficiency (PAI). An adrenal computed tomography (CT) scan revealed bilateral adrenal enlargement. After excluding pheochromocytoma, a CT scan-guided trucut biopsy of the adrenals confirmed non-Hodgkin lymphoma. The patient was started on steroid replacement therapy, and after stabilization, a plan was made to initiate chemotherapy for the treatment of lymphoma; unfortunately, the patient died shortly after diagnosis because of rapid progression of the disease. Adrenal lymphoma can present with PAI and should be considered in the presence of bilateral adrenal enlargement; it is an aggressive tumor and carries poor prognosis if the treatment is delayed.

MON-209 Identification of a New Heterozygous Germline ARMC5 Deletion in a Familial Case of Primary Bilateral Macronodular Adrenal Hyperplasia Co-Secreting Cortisol and Aldosterone

Context. Approximately 50% of familial cases of primary bilateral macronodular adrenal hyperplasia (PBMAH) are caused by mutations in the ARMC5 gene. Case report. We report the case of a 37 year-old patient of Haitian origin, who presented with resistant hypertension. His workup showed high aldosterone (410 pmol/L) with suppressed renin levels (0.2 ng/mL/h) with an aldosterone to renin ratio (ARR) of 2050. Patient also had suppressed ACTH levels (<0.5 pmol/L (N: 2-12)) and high UFC (1103 nmol/d (N: <330)). He had an aberrant cortisol and aldosterone response to catecholamines and vasopressin (V1R). An abdominal CT scan showed bilateral enlargement of adrenal glands and a 3.3cm dominant nodule on the right gland. Moreover, a 2.8cm mass on the pancreatic tail was present. Patient underwent left laparoscopic adrenalectomy and distal pancreatectomy; the pathology confirmed PBMAH and a pancreatic neuroendocrine tumor (NET). Following surgery, ARR and UFC remained high and patient was treated successfully with B-blockers and MR antagonists. A head MRI showed no sign of intracranial meningiomas. Genetic analyses. Following genetic counselling, MEN1 gene analysis was performed using sequencing/MLPA techniques but did not reveal a mutation. Initial genetic testing included ARMC5 gene analysis using direct Sanger sequencing which was negative. However, using Next-Generation Sequencing (NGS) and MLPA analysis, a heterozygous germline ARMC5 deletion of exons 5-8 was identified. The deletion is predicted to prematurely truncate the protein product and cause loss of function. The ARMC5 deletion segregated with the disease in his 24 yo son who had bilateral adrenal adenomas that appeared to be non-functional. The patient’s father was also known for having bilateral adrenal masses and hypertension.To our knowledge we report the second case of ARMC5 deletion in familial PBMAH. Suzuki et al. reported two patients, a mother and her son, carrying ARMC5 deletion of exons1-5 and interestingly they were also affected by PBMAH co-secreting cortisol and aldosterone (1). As in this case report, the ARMC5 deletion was missed using Sanger sequencing initially. Conclusion. These cases demonstrate that large deletions may be missed by Sanger sequencing and that the real prevalence of ARMC5 mutations may have been underestimated. The link between deletion of ARMC5 and correlation with PBMAH co-secreting aldosterone and cortisol remains to be determined but may be a step forward for genotype-phenotype correlation.1.Suzuki S, et al. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015;21 (10):1152-60.

SUN-499 Extragonadal Germ Cell Tumor Induced Thyrotoxicosis

Background: Extragonadal Germ Cell Tumors (EGCTs) are extremely rare, with an incidence of around 1/1,000,000 and highly variable prognosis dependent on subclassification as seminomatous or non-seminomatous. Non-seminomatous germ cell tumors can cause significant enough elevations in hCG to induce thyrotoxicosis via structural homology allowing for cross-reactivity with the TSH-receptor. Limited cases involving EGCTs inducing thyrotoxicosis have been studied. Case: A 27-year-old male presented to the emergency department with intractable abdominal and back pain. He reported night sweats, nausea, dizziness, and a 10 lb weight loss in 1 week. He was resting comfortably and only complaining of pain. He was moderately tachycardic, tachypneic and hypertensive, with a physical exam only remarkable for tenderness to palpation of the abdomen. Abdominal CT revealed mesenteric and retroperitoneal lymphadenopathy, bilateral adrenal enlargement, a mass in the head of the pancreas, as well as gallbladder and common bile duct distention. Lymph node biopsy was conducted for a suspected lymphoma; however, pathology found a poorly differentiated carcinoma. A diagnosis of a non-seminomatous EGCT was made when ultrasound of the testes was negative for masses and labs revealed elevations in hCG (74842 mIU/ml), and LDH (1421 U/L) with normal AFP (6.98 ng/mL). Further workup showed a slightly elevated T4 Free Thyroxine (1.55 ng/dl) with normal TSH (0.555 mIU/L); thus his thyrotoxicosis was secondary to the high HCG. Treatment for thyrotoxicosis was deferred with the expectation that symptoms would resolve when the tumor burden was decreased. Our patient had numerous other complications requiring management from nephrology, GI and urology teams in addition to endocrinology and hematology-oncology. Bleomycin, Etoposide and Cisplatin (BEP) combination chemotherapy was initiated after recovery from acute complications. Further pathology evaluation suggested tumor susceptibility to the biologics nivolumab and pembrolizumab. Conclusion: Patients with thyrotoxicosis secondary to metastatic non-seminomatous germ cell tumors often present with widespread metastasis and relatively few symptoms of thyrotoxicosis that resolve as the hCG levels decrease with chemotherapy without specific antithyroid medication. This case highlights the importance of considering clinically occult thyrotoxicosis in patients who have elevated hCG secondary to germ cell tumors. Early detection of germ cell tumor and recurrence is crucial for chemotherapeutic success. Thus, patients should be closely followed for thyrotoxicosis relapse which could potentially herald a carcinoma relapse and aid in early diagnosis.

Abstract #767262: Mysterious Case of Stress Induced Severe Transient Hypercortisolism Associated with Reversible Bilateral Adrenal Enlargement and Cardiomyopathy

Abstract #767262: Mysterious Case of Stress Induced Severe Transient Hypercortisolism Associated with Reversible Bilateral Adrenal Enlargement and Cardiomyopathy

Recurrent Invasive Ductal Breast Carcinoma Presenting as Primary Adrenal Insufficiency with Adrenal Crisis

We report the first case of recurrent ductal breast carcinoma presenting as primary adrenal insufficiency. We describe a patient who developed a recurrence of invasive ductal breast carcinoma which went undetected until the patient presented with fulminant adrenal crisis. We describe here an overview of the clinical presentation, work-up, diagnosis, and treatment of adrenal crisis. Adrenal crisis due to bilateral adrenal metastases secondary to invasive ductal breast carcinoma is an exceedingly rare occurrence. To our knowledge, this is the first case of recurrent breast carcinoma in which the presenting feature is primary adrenal insufficiency. Patients with a history of breast carcinoma and bilateral adrenal enlargement should be evaluated for the presence of primary adrenal insufficiency.

Histoplasmosis: An Emerging or Neglected Disease in Bangladesh? A Systematic Review.

Histoplasmosis is uncommon in many parts of the world, including Bangladesh, where, in recent years, cases are increasingly reported. We sought to describe the sociodemographic characteristics, clinical presentation, investigations, treatment, and outcome of histoplasmosis in Bangladesh. We conducted a retrospective data review of published literature from 1962 to 2017, containing information on histoplasmosis in and/or from Bangladesh. Unpublished, well-documented histoplasmosis cases were also included. A total of 26 male patients aged 8–75 years, with a diagnosis of histoplasmosis were included; nine were farmers, seven had diabetes, one was a renal transplant recipient, and four had HIV/AIDS. Fever (n = 20), weight loss (n = 17), anemia (n = 15), lymphadenopathy (n = 9), and hepatosplenomegaly (n = 7) were common. Eleven patients had bilateral adrenal enlargement. Diagnosis was confirmed by histo/cytopathology from skin (n = 1), oropharyngeal ulcers (n = 8), lymph nodes (n = 3), adrenal glands (n = 11), paravertebral soft tissue (n = 2), and bone marrow (n = 4). Cultures of representative samples and antibodies were detected in three and two cases, respectively. Twenty-two patients had disseminated histoplasmosis and four patients had localized oropharyngeal disease. Nine patients were prescribed anti-tuberculosis drugs empirically before establishing the diagnosis of histoplasmosis. Treatment consisted of amphotericin B and itraconazole. Six patients died in hospital, 14 patients recovered with relapse in two cases, and the outcome of the other patients could not be ascertained. Histoplasmosis is thought to be endemic in Bangladesh, but few cases are reported to date, which may be due to many asymptomatic, undiagnosed, misdiagnosed, or under-reported cases. Histoplasmosis should be considered as a differential in appropriate clinical scenarios.

Aortic and iliac thrombosis in a dog with adrenal-dependent hypercortisolism due to bilateral adrenocortical adenoma

ABSTRACT: Hypercortisolism is a common endocrinopathy in dogs; however, in a few cases, bilateral functional adrenocortical adenomas cause spontaneous disease, and thrombotic events are considered uncommon complications. The aim of this report was to describe a case of bilateral adrenocortical adenoma in a dog with hyperadrenocorticism associated with distal aortic and iliac thrombosis, with emphasis on clinical and pathological aspects. A 15-year-old spayed female Dachshund with a previous clinical history of hyperadrenocorticism presented with acute bilateral hindlimb paraparesis. A vertebral thoracolumbar radiography was performed and did not present any evidence of intervertebral disk disease or vertebral abnormalities; however, abdominal ultrasound and vascular Doppler evaluation revealed bilateral adrenal enlargement in addition to an aortic and external iliac artery thrombus. The animal was euthanized. At necropsy, both adrenal glands were enlarged by well-demarcated neoplastic nodules in the parenchyma, and a thrombus caudal to the abdominal aorta bifurcation within the external iliac arteries that extended to the left external iliac artery was noted. Histological evaluation revealed a well-differentiated neoplastic proliferation of cortical epithelial cells, consistent with bilateral adenoma, and muscular necrosis in the pelvic limbs was also observed. Bilateral functional adrenocortical adenoma; although, very rare, should be considered as a cause of hypercortisolism, and aortic thrombosis in dogs should be considered as a possible consequence.

SUN-382 Heterogeneous Clinical Presentation In Familial Cases Of Primary Macronodular Adrenal Hyperplasia (PMAH): The Influence Of Somatic Event Of ARMC5.

Background: PMAH is a cause of adrenal hypercortisolism and it is a genetic disease linked to ARMC5 gene in most cases. Heterogenous phenotypes due to cortisol secretion and also due to different germline mutations in the ARMC5 have been described in around the world. The diversity of the molecular second hits in adrenal nodules may be able to justify different clinical outcome in the same family. We report two sisters with the same germline mutation and different clinical outcome. Case: A 45-year-old female patient presented with clinical evidence of hypercortisolism. Metabolic syndrome has been evidenced since the age of 35. Hormonal data confirmed an autonomous cortisol secretion. Abdominal CT revealed a bilateral enlargement of adrenal glands with multiples nodules (up to 2 cm, with 10 Housfield Units). 18F-FDG-PET/CT identified a slight SUV (left SUV 3.4 and right SUV 2.7). A heterozygous germline pathogenic variant of ARMC5 was identified at exon 1: c.165_166insG, p.Ile58Asnfs*45 at BTB (POZ) domain associated with a somatic LOH of the germline mutation. In 2013, the patient underwent Adrenal Sparing Surgery (ASS). She presented an excellent control of metabolic syndrome associated with adrenal insufficiency (AI) for 12 months. After 2 years a clinical recurrence of hypercortisolism was observed and confirmed by laboratory data. A new abdominal 18F-FDG-PET/CT and CT showed an increase of SUV and enlargement of the right residual adrenal gland (SUV - 3.4). The patient was submitted to a partial right adrenalectomy. Interesting, she did not present total or partial AI after the second surgical procedure. Inversely, her sister (46 years of age), with classical Cushing´s syndrome and carrier of same germline mutation (with similar hormonal data and SUV of 18F-FDG-PET/CT), presented a long-term remission of hypercortisolism after ASS. The analysis of somatic mutation of ARMC5 revealed a new event c.2082_2088delCCCGCTC, p.Pro695Serfs*20 in heterozygous status at exon 6. Analysis of PMAH sections HE stained showed a different pattern in the proportion and distribution of clusters of compact cells (60%) relative to clear spongiocytic cells. Her sister presented 13% of compact cells, similar to the PMAH pattern. Discussion: The macronodules of PMAH are composed of clear spongiocytic cells which preferentially express 3βHSD steroidogenic enzyme, and small or compact cells, which differentially express CYP17A1 steroidogenic enzyme and are located in dispersed clusters among the clear cells. CYP17A1 has both 17α-hydroxylase activity and 17,20-lyase activity. Conclusion: The somatic events of ARMC5 should be considered and could be involved in heterogeneous cortisol secretion and clinical presentation in familial cases with different outcome. Further familial cohorts and functional studies should increase our understanding of this challenged adrenal disorder.

MON-350 Disseminated Histoplasmosis Manifesting as Adrenal Insufficiency: A Rare Presentation of a Common Infection

Background: Histoplasmosis is a common fungal infection in endemic areas, however it can rarely cause symptomatic disease requiring medical care in some patients. 1 We describe the case of a patient with untreated human immunodeficiency viral (HIV) infection who developed adrenal insufficiency (AI) from disseminated histoplasmosis (DH). Clinical Case: A 56-year-old male with untreated HIV infection and hypertension was evaluated for left upper jaw swelling and pain of 3 months duration. Exam was remarkable for palpable cervical lymph nodes, oral thrush, mass in the posterior maxillary region near the left molars and generalized rash on the upper chest and back. CT chest showed bilateral adrenal gland enlargement measuring 4.1 x 3.6 cm on the left and 2.7 x 2.3 cm on the right with ground glass opacity on the right lower lobe of the lung and hilar lymphadenopathy. MRI brain showed a 3.9 x 5.8 x 4.3 cm soft tissue mass in the posterior aspect of the left maxilla with erosion into maxillary sinus. Biopsy from maxillary mass was positive for histoplasmosis. Laboratory testing showed significant hyponatremia and hyperkalemia. A 250 mcg cosyntropin test was obtained and was consistent with primary AI with an elevated ACTH level of 86 pg/ml (7-69 pg/ml). He was treated with amphotericin for histoplasmosis with good clinical response. He was also started on mineralocorticoid and glucocorticoid replacement for adrenal insufficiency and eventually weaned off mineralocorticoids. Repeat adrenal CT scan 3 years after treatment showed reduction in the size of the adrenal gland however patient continues to be on glucocorticoid replacement for AI. Conclusion: Adrenal involvement is not commonly seen in DH. Even in patients with adrenal involvement, development of adrenal insufficiency in DH is rare.2 Addison’s disease was reported in 14.3% of patients with adrenal histoplasmosis in one case series 3. Kauffman et al reported only 12 out of 58 elderly patients with histoplasmosis had adrenal involvement and none of them had adrenal insufficiency. Adrenal histoplasmosis though rare, should be considered as a differential in patients presenting with unilateral or bilateral adrenal masses and adrenal insufficiency, especially in endemic areas. Our case demonstrates the importance of being vigilant about this association, since delay in treatment could result in life threatening consequences.

MON-362 Undiagnosed Non-classic Congenital Adrenal Hyperplasia as a Driving Force for Persistent Hyperandrogenemia in Prostate Cancer

Background Non-classic congenital adrenal hyperplasia (CAH) is a common condition and can lead to adrenal hyperandrogenemia. Clinical case We present a case of an 82-year-old man with prostate adenocarcinoma (Gleason 4+3=7) diagnosed 5 years prior to presentation. During surveillance, he was found to have lymphadenopathy, extra-capsular extension, and rising prostate specific antigen (PSA) (from 4.5 to 14.2 ng/ml, n< 4). Stereotactic radiation therapy and androgen deprivation therapy (ADT) with Gonadotropin-releasing hormone (GnRH) analog leuprolide (22.5 mg every 3 months) were initiated. Post-treatment labs showed inadequate testosterone suppression (total testosterone [TT], 87 ng/dl; target,<5.0). Therefore, bicalutamide (50 mg daily), an androgen receptor inhibitor, was added. Subsequently, PSA declined to 0.29 ng/ml and TT remained at 88.4 ng/dl. Prostate cancer remained stable and Leuprolide was discontinued. Three months prior to presentation, F18-Fluciclovine PET/CT revealed skeletal metastases and incidental bilateral adrenal enlargement. PSA increased to 10.86 ng/dl and TT to 218 ng/dl. ADT was resumed with the GnRH analog degarelix (240 mg monthly). Subsequently, PSA remained elevated (10.6 ng/dl) with TT only partly suppressed (90 ng/dl). Further work-up revealed 17-hydroxyprogesterone 4910 ng/dl (n<220), DHEAS 312 mcg/dl (n<166), corticotropic hormone 39 pg/mL (n,7.2-63), cortisol 5.6 mcg/dl (n,5-23), plasma normetanephrine 1.1 nmol/l (n<0.9), plasma metanephrine 0.39 nmol/l (n<0.5), aldosterone 4.0 ng/dl (n<21), and TT 119 ng/dl. An adrenal CT showed diffuse bilateral adrenal hyperplasia, with a 5.6-cm right adrenal gland and 6.7-cm left adrenal gland. The patient shared that he underwent precocious puberty, was shorter than predicted based on the sex adjusted mid-parental height, and never fathered children. In light of his history, he was diagnosed with non-classic CAH due to partial 21-hydroxylase deficiency (21-OHD), causing inadequate testosterone suppression and progression of prostate cancer despite ADT and androgen receptor blocker. Following the diagnosis, the patient was treated with abiraterone (1000 mg daily), a CYP17A1 inhibitor, and prednisone (2.5 mg twice daily), to suppress adrenal androgen production. TT became undetectable (< 5 ng/dl) and PSA declined from 12.93 to 1.27 ng/ml. Conclusion: Non-classic CAH is a common autosomal recessive disorder and presents in late childhood as premature pubarche and accelerated bone age. The prevalence of non-classic CAH is 0.1%-1% among Caucasians and even higher among Ashkenazi Jews and Hispanics. Treatment in men is generally not required unless there is oligospermia in those desiring fertility. Adrenal hyperandrogenemia can be treated with systemic steroids. Non-classic 21-OHD CAH should be considered in men with prostate cancer with inadequate testosterone suppression after ADT.

MON-351 Bilateral Adrenal Haemorrhage Secondary to Intra-Abdominal Sepsis: A Case Report

Introduction Adrenal failure secondary to bilateral haemorrhage is a rare presentation with a significantly high mortality rate. Sepsis, caused by a deregulated inflammatory response to infection, can result in bilateral adrenal haemorrhage particularly with predisposing factors such as major surgery and anticoagulation. Clinical Case A 58-year-old white man presented to the emergency department with a two-week history of diarrhoea and vomiting. On examination, the abdomen was tender over the right lower quadrant with guarding. An abdominal CT confirmed diverticulitis with small bowel perforation. Patient deteriorated with conservative management, and a repeat abdominal CT showed worsening colonic inflammation with new pelvic collection suggesting of intra-abdominal sepsis. The patient underwent urgent laparotomy for Hartman’s procedure. However, he did not improve post-operatively, remaining hypotensive and febrile with elevated inflammatory markers despite continuous IV antibiotics. The working diagnosis remained as intra-abdominal sepsis. He had a series of abdominal CT scans at different intervals, and on the 4th scan, a new bilateral adrenal enlargement consistent with haemorrhage/infarction was identified. However, an unreported early haemorrhagic transformation is visible on the previous scan from ten days earlier. A random Cortisol was 157nmol/L (200-650nmol/L-morning peak) which appeared low for critical illness. Serum Aldosterone was 206pml/L (61-980pmol/L) and Aldosterone/Renin ratio was 12.6 (<70). The patient was treated with intravenous hydrocortisone with excellent response and later discharged on oral hydrocortisone. He remains well with stable blood pressure. A repeat adrenal CT, five months post discharge show normal adrenal glands. He is due for an ATCH stimulation test prior to weaning of oral steroids. Conclusion This case describes a potentially life-threatening complication of bilateral adrenal haemorrhage following intra-abdominal sepsis and surgery. It highlights the importance of screening for adrenal insufficiency with close attention to adrenal anatomy on imaging, for patients who remain in shock despite treatment for sepsis.

SUN-381 Somatic PRKACA Mutations In Patients With Transition From Pituitary-dependent To Adrenal-dependent Cushing’S Syndrome

Background. Transition from ACTH-dependent to ACTH-independent hypercortisolism has been described in patients with long-standing Cushing´s disease (CD). The underlying molecular mechanisms are unknown. Clinical case.Case 1. A 41-years old woman was referred for Cushing’s syndrome (cortisol after 1-mg dexamethasone suppression test (DST) 410 nmol/L, urinary free cortisol (UFC) 2xULN, midnight cortisol 440 nmol/L). High-dose DST: no suppression. CRH test: no ACTH/cortisol increase. Basal ACTH: 18 pmol/L. Pituitary MRI showed a 7-mm adenoma. The inferior petrosal sinus sampling showed central source of ACTH. She was treated by trans-sphenoidal surgery (pituitary adenoma confirmed histologically) followed by clinical remission. Cushing’s syndrome recurred 1 year after. ACTH was undetectable and pituitary MRI normal. Abdominal CT-scan showed a left adrenal macronodule. Left adrenalectomy was performed, followed by glucocorticoid replacement therapy (1 year) and clinical/biochemical remission at last follow-up (15 years). Histopathology showed a 35-mm adrenal nodule and micronodular hyperplasia. We found a p.L206R missense mutation of PRKACA in the adrenal nodule. The functional implication of the mutation has been described (1). Case 2. A 31-years old woman was referred for Cushing´s syndrome (cortisol after 1-mg DST 579 nmol/L, UFC 4xULN, midnight cortisol 773 nmol/L). Basal ACTH: 18 pmol/L. CRH and desmopressin tests: indicative of CD. High-dose DST: no suppression. A pituitary MRI revealed a microadenoma, treated by trans-sphenoidal surgery (confirmed by histology). She had persistence of Cushing’s syndrome, undetectable basal ACTH and negative pituitary MRI. An abdominal CT-scan showed bilateral adrenal enlargement with a left nodule, treated by bilateral adrenalectomy. Histology showed a macronodule in micronodular hyperplasia. We found a p.S213R somatic missense mutation of PRKACA in the adrenal macronodule. Functional analyses showed that mutant cells had higher cAMP-independent PKA activity than wild-type, and similar to the L206R mutation. Conclusion. This is the first evidence showing that PRKACA somatic mutations can be found in adrenal nodules of patients with CD, possibly explaining the mechanism underlying transition from ACTH-dependent to ACTH-independent hypercortisolism. References. 1. Calebiro D et al. PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit. Nat Commun. 2014;5:5680.

Lymphoma as a cause of bilateral adrenal gland enlargement and Adrenal insufficiency

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Clinical outcomes and cortical reserve in adrenal histoplasmosis-A retrospective follow-up study of 40 patients.

Detailed studies of Addison's disease resulting from disseminated adrenal histoplasmosis (AH) are not available. We describe the presentation and prognosis of AH and cortisol status before and after antifungal therapy. Single-centre retrospective hospital-based study of 40 consecutive adults with AH [39 males; age (mean±SD) 53±11years] was conducted between 2006 and 2018. The median duration of follow-up was 2.5years (range 0.2-12years). AH was diagnosed by bilateral adrenal enlargement on CT scan and presence of Histoplasma by histology and/or culture of biopsied adrenal tissue. All patients received oral itraconazole and, if required, amphotericin B as per guidelines. ACTH-stimulated serum cortisol (normal>500nmol/L) was measured in 38 patients at diagnosis and re-tested after one year of antifungal therapy in 21 patients. Seventy-three per cent of patients had primary adrenal insufficiency (PAI) and one-third had an adrenal crisis at presentation. HIV antibody was negative in all patients. Of the 29 patients who completed antifungal therapy, 25 (86%) were in remission at last follow-up. Overall, 8 (20%) patients died: three had a sudden death, four had severe histoplasmosis and one died due to adrenal crisis. No patient with PAI became eucortisolemic on re-testing after one year of antifungal therapy. Of the eight patients with normal cortisol at diagnosis, two developed adrenal insufficiency on follow-up. All patients with AH tested negative for HIV antibody. While patients achieved a high rate of clinical remission after antifungal therapy, overall mortality was significant. Cortisol insufficiency did not normalize despite treatment.