bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-154 Clinical Presentations and Outcomes of Adrenal Metastases Vary Based on Etiology
Authors: Mao Jimmy , Bancos Irina
Published: May 2020

Background: Adrenal metastases occur in 1–8% of patients with an adrenal mass. Recognizing patterns in the presentation of adrenal metastases is critical in dictating management.

Objective: To describe the presentation of patients with adrenal metastases and identify baseline characteristics predicting the etiology.

Methods: A retrospective analysis of adult patients diagnosed with adrenal metastases between 2000–2019 at a single institution tertiary center was performed. Partial cohort analysis is presented.

Results: In 327 patients (127 (39%) women, median age at diagnosis of 67 years (range 25–92)), median tumor size was 2.7 cm (range 0.5–15), and 99 (30%) had bilateral tumors. While most patients (188, 57%) were found to have an adrenal mass during cancer staging, 117 (36%) were found incidentally and 22 (7%) based on symptoms. Adrenal metastases originated from the lung (118, 36%), genitourinary (GU) (100, 31%), gastrointestinal (GI) (47, 14%), and other (43, 13%) organ systems. Unknown primary malignancies were diagnosed in 19 (5.8%) patients.

Male predominance was observed in GU (72%) and lung (62%) metastases, but equal gender distributions were noted for all other metastases, p=0.01. Patients with GI and lung metastases were diagnosed with smaller tumors (median 2.1 and 2.6 cm, respectively) compared to those with GU (median 3.5 cm) and other (median 4 cm) metastases, p=0.0008. Bilateral metastases were more frequently found in patients with lung (37%) and other (38%) metastases compared to those with GI (17%) and GU (24%) metastases, p=0.01. Of 99 (30%) patients with bilateral metastases, 23% developed primary adrenal insufficiency (PAI), most commonly in those with lung (36%) and GU (30%) malignancies.

Only 123 (38%) patients were evaluated by an endocrinologist. Pheochromocytoma work-up was more often pursued if seen by an endocrinologist (71% vs. 15%, p<0.0001) in 118 (36%) patients. Adrenalectomy was performed in 94 (29%) patients, most frequently in those with GU metastases (57%), compared to only 10% of those with lung metastases.

Patients were followed for a median time of 14 months (range 0.1–181), and 222 (68%) died. GU metastases carried the best prognosis with a mortality rate (MR) of 43%, as opposed to a MR of >70% in all other metastases, with lung metastases carrying the worst prognosis (MR of 85%). Multivariate analysis revealed that mortality was associated with increasing age (OR 1.3 (95% CI 1.04–1.6) for each decade) and metastasis subgroup (lung vs. GU: OR 7.2 (95% CI 3.7–14)).

Conclusion: Adrenal metastases most commonly originated from lung, GU and GI malignancies, with a third of patients discovered incidentally. Bilateral metastases occurred in 30% of patients, where 1 in 4 developed PAI. Only a minority were evaluated by an endocrinologist or had work up for pheochromocytoma. Mortality was highest in those with adrenal metastases originating from the lung.
SAT-416 Novel Autoantibodies for Thyroid-Specific Transcriptional Factors in Patients with Immune-Related Adverse Events Involving the Thyroid Gland
Authors: Yamauchi Ichiro , Yasoda Akihiro , Yamashita Takafumi , Ueda Yohei , Fujii Toshihito , Taura Daisuke , Sone Masakatsu , Inagaki Nobuya
Published: May 2020

Background: Immune-related adverse events by immune checkpoint inhibitors often involve several endocrine-related organs. PD-1 pathway blockade therapy by anti-PD-1 antibodies including nivolumab frequently causes thyroid dysfunction (thyroid irAE). Thyroid irAE seems to be distinctive compared to conventional painless thyroiditis in terms of a clinical course: transient thyrotoxicosis and subsequent persistent hypothyroidism [1]. Our retrospective cohort study regarding nivolumab provided several suggestions [2]. The thyroid irAE (+) group had a longer median overall survival than the thyroid irAE (−) group in patients with lung cancer, but this observation was not seen in patients with malignant melanoma: In addition, 5 of 17 patients tested at the point of thyroid dysfunction development were double negative for TPOAbs and TgAbs, known thyroid autoantibodies. From these findings, we set a hypothesis that antibodies for unknown antigens mediate prognostic effects of thyroid irAEs if tumor tissues express the same antigens. Methods: We performed co-immunoprecipitation using Protein G beads, sera of three patients with thyroid irAEs, and lysates of HEK293T cells overexpressing candidate proteins tagged with FLAG and HiBit (NKX2-1, PAX8, FOXE1, and HHEX). The pellets were analyzed by western blot. Results: FOXE1 bands were augmented in patient 1 with lung cancer, a PAX8 band in patient 2 with malignant melanoma, and bands of FOXE1, PAX8, and HHEX in patient 3 with renal cell carcinoma, compared to a control sample of a normal subject. We performed subcutaneous injections of purified IgG fraction from the serum of patient 3 to C57BL/6 mice every 2 weeks. The mice were sacrificed after 4 weeks, but no significant changes were observed in their thyroid glands and thyroid function. Conclusions: We identified novel autoantibodies for FOXE1, PAX8, and HHEX, thyroid-specific transcriptional factors. In our experiments, the pathogenicity of antibodies were not suggested. Considering our previous observation that the thyroid gland expresses both PD-L1 and PD-L2, ligands of PD-1 receptor [1], PD-1 pathway blockade may particularly disrupt immune tolerance of the thyroid gland, resulting in autoantibody production. Because thyroid irAEs have been revealed to be a prognostic factor, these novel autoantibodies are candidate biomarkers for PD-1 pathway blockade therapy. References: 1. Yamauchi et al. Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. Thyroid. 2017; 27(7): 894–901. 2. Yamauchi et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS One. 2019; 14(5): e0216954.
MON-525 ATA and ACR TIRADS Classification Systems as Additional Predictors of Malignancy in Afirma GSC Suspicious Thyroid Nodules
Authors: Azaryan Irina , Endo Mayumi
Published: May 2020

Objective: Evaluation and management of thyroid nodules with cytologically indeterminate results remain challenging in clinical practice. Despite the implementation of molecular testing in an attempt to avoid surgical intervention, diagnostic thyroidectomy still occurs due to the relatively low positive predictive value of these molecular testing. We conducted a study to analyze whether combining US characteristics and results of molecular testing would better elucidate predicting true positive results.

Methods: We retrospectively reviewed thyroid ultrasound images of 172 nodules in 162 patients (mean age, 55 years +/- 14) with indeterminate cytology results (Bethesda III and IV) that underwent Afirma Gene Sequencing Classifier (GSC) testing at a single academic medical center between 2017–2019. All nodules were classified according to 2015 American Thyroid Association (ATA) and 2017 American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS).

Results: A total of 172 with subsequent Afirma GSC molecular testing were included in the study. There were 127 nodules with Bethesda III (AUS/FLUS) (73.8%), and 45 nodules with Bethesda IV (SFN/HCN) (26.2%) results. The mean nodule volume was 5.4 +/- 10 cm3. Afirma GSC identified 129 nodules (75%) as benign and 43 nodules (25%) as suspicious. Per ATA classification, 10.4% (18) of nodules were classified as very low risk, 40.7% (70) as low risk, 36.5% (62) as intermediate and 12.8% (22) as high risk for malignancy. There was a significant association between ATA classification and Afirma benign nodules (P=0.002). All nodules were also classified per TIRADS system with the following distribution: 5 (1.16%) TIRADS 1, 7 (4%) TIRADS 2, 54 (31%) TIRADS 3, 90 (52%) TIRADS 4, and 16 (9.3%) TIRADS 5. We did not observe the similar association between TIRADS system and benign nodules as we did with ATA classification (P=0.4).

35 patients (79.5%) with Afirma suspicious results underwent surgery, of which 18 (51.4%) surgical pathology were malignant. 8 patients with Afirma suspicious results decided to proceed with ultrasound surveillance. The malignancy rates of nodules with low, intermediate and high suspicion for malignancy classified by the ATA guidelines were 44% (9 of 18), 33% (56 of 18) and 22% (4 of 18). The malignancy rates of TIRADS category 3, 4 and 5 nodules were 44% (8 of 18 nodules), 44% (8 of 18 nodules) and 11% (2 of 18 nodules). Subset analysis of surgical pathology benign and cancerous nodules did not show significant association between ATA (P=0.5) or TIRADS (P=0.4) classification systems.

Conclusion: Our study showed that Afirma benign nodules were associated with a lower risk of malignancy per ATA classification but not with TIRADS system. We did not find a significant association between pathology proven cancer cases and high-risk ATA or TIRADS ultrasound classification systems.
OR06-01 The Role of Germline Defects in Cushing’s Disease
Authors: Hernández-Ramírez Laura C , Pankratz Nathan , Lane John , Faucz Fabio R , Chittiboina Prashant , Denise Kay M , Mills James L , Stratakis Constantine A
Published: May 2020

J.L.M. and C.A.S. contributed equally. Introduction: Cushing’s Disease (CD) has been described as a component of a number of familial genetic syndromes. Yet, such cases may go largely unrecognized due to phenotypic variability, incomplete penetrance, and the rarity of the disease. We determined the frequency and type of germline genetic causes of CD and characterized their clinical phenotype in a large cohort of CD patients. Methods: We studied 245 unrelated CD patients (139 females, 60.4%), referred to our Center between 1997–2018, including 230 pediatric (≤18 years at disease onset, 93.9%) and 15 adult patients (6.1%). Germline genetic causes were identified by whole exome sequencing in 184 patients and by Sanger sequencing of specific genes in 39 patients; 22 patients did not undergo genetic testing, due to low quality or insufficient DNA. When available (n=66), corticotropinoma DNA was screened for USP8 hotspot variants using Sanger sequencing. Results: Eighteen patients (7.3%) had positive family history: nine presented as FIPA with unknown genetic cause, eight presented as MEN1 (seven had confirmed MEN1 variants), and one had a family history of pheochromocytoma/paraganglioma and pituitary adenoma with unknown genetic cause. Among the 227 sporadic patients (92.7%), 13 (5.7%) simplex cases had putative pathogenic variants in the following genes: CDKN1B (n=5), CABLES1 (n=3), AIP (n=1), PRKAR1A (n=1),TP53 (n=1),TSC2 (n=1), and USP8 (n=1). Altogether, cases with potentially inheritable genetic causes(familial and simplex) accounted for 12.7% (31/245) of all patients. There were no statistically significant differences in age at disease onset, age at diagnosis or tumor diameter between patients with potentially inheritable genetic defects and the rest of the cohort. In the pediatric subset, however, there was a non-significant higher frequency of macroadenomas among familial and simplex patients (21.4%), compared with sporadic patients (12.4%, P=0.19). Somatic USP8 hotspot mutations were found in 33.3% (12/36) of sporadic patients, but only in 3.3% (1/30) of familial and simplex (e.g. patients with a disease-associated germline defect, but no affected relatives) cases (P=0.0038). The global frequency of USP8 defects was 19.7% (13/66). Conclusions: Potentially inheritable cases of CD accounted for one-eighth of the patients in our cohort: 64.5% (20/31) of them are associated with defects in genes with a known involvement in CD. Patients with germline genetic causes of CD might present as apparently sporadic cases, due variability in disease penetrance. Unlike sporadic cases, somatic USP8 hotspot mutations are rare in those with inheritable causes of CD, suggesting different drivers for tumorigenesis in each group. Identifying the genetic causes of CD should lead to a more precise genetic testing and counselling and might aid in developing targeted therapeutic strategies.
SAT-673 Acute Onset Type 1 Diabetes Mellitus Caused by the Checkpoint Inhibitor Nivolumab
Authors: Ansari Mohammad Jamal Uddin , Ahmed Mahreen , Parveen Sanober , Mariam Murtaza Ali , Jabri Hadoun , Rehman Anis , Jakoby Michael G
Published: May 2020

Background. Checkpoint inhibitors are monoclonal antibodies that augment immune system antitumor activity. Nivolumab is a checkpoint inhibitor that targets the programmed cell death receptor 1 (PD-1). Approximately 15% of patients treated with checkpoint inhibitors experience endocrine immune-related adverse events (irAEs), with autoimmune thyroid disorders and hypophysitis the most common endocrine irAEs. We present a case of acute onset type 1 diabetes mellitus (T1D) complicating treatment with nivolumab.

Case. An 84 year old female received nivolumab (Opdivo) for metastatic small cell lung cancer. She tolerated twelve cycles of treatment well, but after the thirteenth cycle, she developed polydipsia and polyuria that prompted her to seek medical attention. Laboratories in the emergency department were notable for plasma glucose 998 mg/dL, bicarbonate 13 mM, anion gap 24, and strongly positive serum and urine ketones. An insulin infusion and parenteral fluids promptly resolved diabetic ketoacidosis (DKA), and the patient was then managed with subcutaneous basal/bolus insulin. Antibody markers (e.g. anti-GAD65) for T1D were undetectable, and evaluation for other endocrine irAEs was unremarkable. Given the rapid onset of DKA and the patient’s advanced age, she was diagnosed with nivolumab-induced T1D and discharged home on exogenous insulin.

Conclusions. In a recent meta-analysis of 38 immune checkpoint inhibitor trials and over 7,500 patients, T1D was the least common endocrine irAE. The incidence of T1D was 0.2% compared to 6.6% for hypothyroidism, 2.9% for hyperthyroidism, 1.3% for hypophysitis, and 0.7% for primary adrenal insufficiency. All but one case (12/13) of T1D occurred in patients treated with a PD-1 inhibitor. Markers of both cellular and humoral diabetes-associated autoimmunity have been demonstrated in patients with T1D during treatment with nivolumab, and autoimmune destruction of beta-cells is the presumed etiology of diabetes. However, diabetes autoantibodies are detected in only about 50% of cases, and the absence of humoral markers does not exclude the diagnosis of nivolumab-induced T1D. There is a slight male predominance among published cases of nivolumab-induced T1D, and though median onset of T1D1 is after 11 weeks of treatment, there is a wide range of recorded times to T1D onset. Approximately 70% of patients present in DKA, and the significant majority of patients have undetectable or low C-peptide levels. Unfortunately, loss of beta-cell function persists after stopping nivolumab, and lifelong exogenous insulin is required for diabetes management. Though nivolumab-induced T1D is rare, the high risk of DKA as in this patient’s case illustrates the importance of recognizing nivolumab as a potential cause of autoimmune diabetes in older patients receiving anti-PD-1 immunotherapy.
SAT-335 New Onset Adult Idiopathic Primary Hypoparathyroidism Concomitant with Severe Aplastic Anemia
Authors: Galustian Sophia , Galappaththy Suguni Loku , Jadhav Kavita , Cabandugama Peminda K
Published: May 2020

Introduction: Primary hypoparathyroidism is a relatively rare cause of hypocalcemia with cases of primary hypoparathyroidism in the US estimated at 24–37 per 100,000 with 75% being due to neck surgery and 25% due to non-surgical causes. The clinical presentation depends on the acuity of development of hypocalcemia and the absolute level of serum calcium. Here is a case of severe hypocalcemia secondary to hypoparathyroidism of unknown etiology followed by the development of severe aplastic anemia.Case report: A 60-year-old Caucasian male presented to our ED with fatigue, tingling, numbness in extremities and was found to have severe hypocalcemia at 6.8 mg/dl and decreased PTH at 11 pg/mL. Calcium levels 8 months prior to presentation were normal. No history of neck surgery, radiation exposure or family history of autoimmune disorders. Initial workup included creatinine, magnesium and TSH were normal. Autoimmune panel (including PTH Abs and CaSR Abs), HIV test, hepatitis panel, serum protein electrophoresis were also negative. Infiltrative causes of hypoparathyroidism including hemochromatosis, malignancy and granulomatous diseases like sarcoidosis were ruled out with tissue sampling and lab workup. Sestamibi scan obtained showed no parathyroid activity in all four glands. Patient was initially treated with IV calcium to improve serum calcium to more than 7.5mg/L and then switched to oral calcium carbonate 500mg TID and calcitriol 0.5mcg BID until the calcium level was brought up to the lower limit of normal. Patient was seen in follow up and was doing well without any adverse effects. Consequently, the patient developed severe aplastic anemia which was treated with steroids and interestingly, has caused a gradual but consistent increase in PTH levels.Discussion: Idiopathic hypoparathyroidism (IHP) is a rare condition with an incidence of 0.02%. IHP can occur sporadically or as part of a familial condition with autosomal dominant, recessive and X-linked recessive patterns. Certain autosomal forms of hypoparathyroidism have mutations in the PTH gene and Calcium-Sensing Receptor (CaSR) gene. The challenging nature of this case is due to the subacute nature of the patient’s presentation along with the lack of a definitive etiology. The patient’s negative family history and older age makes genetic causes less likely, and Abs against PTH and CaSr were also negative. The patient’s diagnosis of severe aplastic anemia has made the case more fascinating, especially since its management with steroids has causes an improvement in the patient’s PTH status. Regardless of etiology, primary hypoparathyroidism is treated with lifelong supplementation of calcium and calcitriol to a goal serum calcium level at the lower limit of normal. Reference: Abate EG,Clarke BL. Review of Hypoparathyroidism. Front Endocrinol (Lausanne). 2017; 7:172. Published 2017 Jan 16
SUN-474 An Unusual Case of Poorly Differentiated Thyroid Carcinoma with an Excellent Prognosis
Authors: Pulipati Vishnu Priya , Amblee Ambika Pinakini
Published: May 2020

Background: Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive subtype with morphological/behavioral features between differentiated thyroid carcinoma (DTC) and anaplastic thyroid carcinoma (ATC).

Clinical case: A 43-year-old female presented with 3 cm right thyroid mass noted on US neck. FNA biopsy showed undifferentiated carcinoma, large cell type. Additional immune-stains were suggestive of ATC. Pre-surgery non-stimulated thyroglobulin (NSTG) was 311 (RR 0–55 ng/dl). Pathology post-total thyroidectomy with bilateral level VI lymph node dissection showed a 3.2 x 2.5 x 2.5 cm carcinoma with vascular and capsular invasion. Most of the mass consisted of very atypical pleomorphic cells, mitosis was difficult to find. The tumor did not show the widely invasive-destructive pattern commonly seen in ATC. An adjacent differentiated component showed predominantly follicular pattern and was described as dedifferentiated follicular carcinoma. All lymph nodes were negative for metastatic disease. Post-surgery NSTG was <0.2 (RR <0.1ng/ml as athyreotic), stimulated TG was 2.22 with negative TG antibodies. Four months later, she received 193.5 mCi radioactive iodine (RAI) therapy. The post-therapy scan showed no Iodine-131 avid uptake in neck or distant metastasis. Neck imaging and TG levels done periodically showed no structural or biochemical evidence of recurrence. Currently the patient is cancer-free for 14 years since diagnosis with no need for additional therapies.

Discussion: PDTC accounts for 1–15% of all thyroid cancers. Although PDTC is rare, it is a clinically significant histological diagnosis as it represents the main cause of death from non-anaplastic follicular cell-derived thyroid carcinoma. The Turin proposal published in 2007 suggested three criteria for the diagnosis of PDTC which included the pattern of growth and high-grade features. PDTC presents more frequently with locally invasive extra-thyroidal disease, metastasis to regional lymph nodes and distant organs compared to DTC. Despite the capacity to have RAI uptake, there has been no evidence of significant improvement in survival due to tumor heterogeneity in differentiation. Recent data suggest that age more than 45 years, tumor size more than 4cm, extra-thyroidal extension, higher pathological T stage, positive margins, and distant metastasis predict worse prognosis.

Conclusion: Our patient showed an excellent response to therapy in spite of having PDTC with positive margins. We hypothesize that this could be likely due to young age at the time of diagnosis, early detection of tumor while it was localized in the thyroid without distant metastasis as well as heterogeneity in the tumor with differentiated cells that are responsive to RAI. We conclude that with early detection, timely surgery, and adjuvant therapy, excellent prognosis can be achieved in patients with PDTC.
SUN-205 Pseudo-Cushing Syndrome Secondary to Malnutrition and Gluco-Toxicity Mimicking Type 1 Diabetes Mellitus
Authors: Pulipati Vishnu Priya , Hwang Jessica
Published: May 2020

Background: Pseudo-Cushing Syndrome (PCS) is an under-recognized clinical entity that is a reversible consequence of alterations in cortisol production. We present a case of a patient with presumed type 1 Diabetes Mellitus (DM) who was found to have PCS secondary to malnutrition. Once the nutritional status normalized, the patient’s glycemic control remarkably improved and became well-controlled on metformin alone.

Clinical case: A 54-year-old female with poorly controlled insulin-dependent DM for 10 years was referred for concern for adrenal insufficiency after an ACTH came back elevated in the setting of intractable nausea, vomiting and considerable weight loss over 1 year. Prior HbA1c was 16.2% (RR 4.4–6.7). On exam her vitals were normal, body mass index (BMI) was 15 kg/m2. Workup confirmed an elevated ACTH of 100 pg/ml (RR 6–50 pg/ml), however, random PM cortisol was unexpectedly elevated at 26.58 ug/dL (RR 4.46 – 22.7). 8 AM labs for ACTH and cortisol were similarly elevated at 91 pg/ml and 28.33 ug/dl, respectively. She had no evidence of classic Cushingoid features. Subsequent low dose dexamethasone suppression test and 24-hour urine free cortisol were negative. Over 18 months, with optimization of her insulin therapy, BMI improved to 19 kg/m2, ACTH and cortisol started to downtrend spontaneously. After 30 months, her BMI improved to 20 kg/m2. Repeat blood work showed A1C 6.5%, ACTH and cortisol completely normalized to 42 pg/dl and 8 ug/dL, respectively. After being adherent to insulin for a few years, her gluco-toxicity state resolved. A month prior to following up, she self-discontinued insulin due to hypoglycemia but continued on metformin. Currently she continues to remain off insulin.

Discussion: PCS is a challenging diagnosis to recognize and differentiate from Cushing Disease (CD) especially due to overlap in biochemical profile. It is important to be aware of this clinical condition to avoid misdiagnosis, delay in treatment or over-treatment. Common etiologies causing PCS include depression, chronic alcoholism, obesity, physical stress, malnutrition, eating disorders, uncontrolled DM, obstructive sleep apnea. PCS occurs due to chronic activation of the hypothalamic-pituitary-adrenal axis, it is usually mild and resolves with treatment of underlying etiology. In our case, first-line screening tests could differentiate between PCS and CD hence she did not require late-night salivary cortisol testing or corticotropic-releasing hormone testing.

Conclusion: In our patient, PCS occurred secondary to malnutrition and severe gluco-toxicity which mimicked insulin-dependent type 1 DM. Interestingly, once her nutritional status and insulin compliance improved, cortisol levels normalized, gluco-toxicity state resolved and she no longer required exogenous insulin therapy.
SAT-368 CYP24A1 Mutation Masking Malignancy Mediated Hypercalcemia
Authors: Cheng Cheng , Liu Chienying , Bikle Daniel D , Shoback Dolores M
Published: May 2020

Background: Mutations in CYP24A1, resulting in reduced conversion of 1,25(OH)2D to its inactive metabolite 24,25-(OH)2D3,are rare causes of parathyroid hormone (PTH)-independent hypercalcemia. While manifestations may range from the severe idiopathic infantile hypercalcemia due to biallelic mutations, heterozygous loss-of-function mutations causing milder phenotypes are increasingly reported in adults. Elevated 1,25(OH)2D and hypercalciuria often accompanied by a history of nephrolithiasis are characteristic. Worsening hypercalcemia, under conditions such as pregnancy or sunlight exposure that enhance 1,25(OH)2D and 25(OH)D production, respectively, has been described in CYP24A1 mutations. We describe a patient with hypercalcemia and a history of lymphoma who was found to have elevated 25-OH-D3 and low 24,25-(OH)2D3 levels, suggesting a mutation in CYP24A1. Clinical Case: An 80 year-old Caucasian male with history of indolent non-Hodgkin lymphoma diagnosed in 2016,well controlled after several courses of chemotherapy,was referred for recurrent hypercalcemia. Laboratory studies showed levels of 1,25(OH)2D of 78 (18–72 pg/mL) and PTH 22 (10–65 pg/mL) with calcium ranging from 10.3 to 12.6 (8.5–10.1mg/dL), an undetectable PTHrP, 25(OH)D level of 32.9 (30–100 ng/mL), and 24-hour urinary calcium of 378mg. He was treated with high dose prednisone for presumed 1,25(OH)2D-mediated hypercalcemia. Despite initial good response, hypercalcemia became progressively difficult to control requiring escalating doses of steroids. Repeat 1,25(OH)2D levels improved to 30–40 pg/mL, but subsequently rebounded to >150. Oncologic re-evaluation found low-grade follicular lymphoma in inguinal lymph nodes,which were thought to be the source of 1,25(OH)2D overproduction. Detailed history and records review, however, revealed that onset of hypercalcemia dated back to 2006, concurrent with the development of several episodes obstructive uropathy due to stones. These events preceded the diagnosis of lymphoma by a decade, and resulted in CKD stage 4. Family history is notable for nephrolithiasis in his fatherand son. We suspected CYP 24A1 mutation. Vitamin D metabolite analysis demonstrated a 25-OH-D3 of 27 (20-50ng/mL) and 24,25-(OH)2D3 of 0.56 ng/mL with a ratio elevated to 48.21 (<25), indicative of a defect in vitamin D degradation that potentially exacerbates oversupply of 1,25(OH)2D, mediated via its reduced metabolism. Genetic evaluation is in progress. After initiation of treatment with Rituximab, his serum calcium levels declined along with regression of his lymphoma. Conclusion: Although mutations in CYP24A1 are an uncommon cause of hypercalcemia, they should be considered in the differential diagnosis of elevated 1,25(OH)2D levels without a clear source, as confirming this diagnosis strongly impacts treatment decisions and clinical outcome.
MON-466 Dual Ectopic Thyroid with Normally Located Thyroid Gland in a Patient Presenting with Subclinical Hypothyroidism: A Case Report
Authors: Rueda Stephen M , Joven Mark H , See Nixon , Gharib Hossein
Published: May 2020

Background: Ectopic thyroid involves the presence of thyroid tissue in sites other than its normal anatomic location. Dual ectopic thyroid with normally located thyroid gland is extremely rare with only a few cases reported in the literature.

Clinical Case: A 24-year-old female presented to the clinic with subclinical hypothyroidism (TSH of 10.54 uIU/ml [ref, 0.27–4.2] and free T4 of 12.96 pmol/L [ref, 12–22]). She noted a gradually enlarging submental mass during the preceding year, which had been present since her adolescent years.

Examination was notable for a 2-cm firm, non-tender mass at the submental region that slightly moved with deglutition. The thyroid was not palpable in its normal location. The relaxation phase of the deep tendon reflex was prolonged. Repeat laboratory testing showed persistently elevated TSH of 13.3 uIU/ml and normal free T4 of 13.39 pmol/L. TPO antibody was normal. Thyroid ultrasonography showed a hypoplastic thyroid measuring 2.7 x 0.7 x 0.4 cm on the right and 3.0 x 0.7 x 0.4 cm on the left. A well-circumscribed complex nodule measuring 2.7 x 3.2 x 2.1 cm was noted on the submental region corresponding to the patient’s submental mass. Computed tomography of the neck with contrast showed two hyperdense foci - measuring 3.0 x 2.4 cm at the submental region and 1.4 x 1.2 cm at the base of the tongue. No enhancing thyroid tissue was seen anterior to the thyroid cartilage. 99mTechnetium-pertechnetate scan showed absent focal tracer uptake in the anterior neck and thorax. There were foci of increased tracer activity in the submental and lingual regions. Ultrasound-guided biopsy of the submental area showed cytomorphologic features of a colloid nodule with cystic degeneration (Bethesda Category II). The patient was started on levothyroxine and remained biochemically euthyroid afterwards. The submental neck mass reduced in size.

Conclusion: Dual ectopic thyroid with normally located (eutopic) thyroid gland could present with subclinical hypothyroidism. There is no single diagnostic modality that would best identify dual ectopic thyroid; thus, thyroid scan, ultrasonography, CT scan and biopsy are recommended to be used complementarily. For patients with dual ectopic thyroid and hypothyroidism, levothyroxine replacement is recommended to reduce the size of ectopic thyroid and render the patient euthyroid.
MON-725 Transcriptome Profiling in Postnatal Pituitary Gland Identifies Cell Type-Driven Sex-Specific Changes
Authors: Hou Huayun , Chan Cadia , Uusküla-Reimand Liis , Yuki Kyoko E , Sokolowski Dustin , Roy Anna R , Zhang Zhaolei , Wilson Michael D , Palmert Mark
Published: May 2020

The pituitary gland is integral to the regulation of growth, metabolism, puberty, reproduction, and stress responses. Previously, we found that many genes associated with age-at-menarche in genome-wide association studies (GWAS) displayed increasingly sex-biased expression across the pubertal transition in the mouse pituitary. However, whether this trend exists beyond puberty-related genes was not known. In addition, the regulatory mechanisms underlying these gene expression changes remained to be explored. To answer these questions, we profiled the transcriptome, including microRNAs, of mouse pituitary in both sexes across pubertal transition in an unbiased manner and leveraged a recently published pituitary single cell transcriptome to explore cellular composition changes. We found that the most dynamic temporal changes in both mRNA and miRNA expression occur prior to puberty, underscoring a role for regulation of early pituitary postnatal development. We also observed ~900 genes displaying sex-biased expression patterns, arising during early development and becoming increasingly biased across puberty, including known sex-biased genes such as Fshb and Lhb. However, sex differences in miRNA expression are less pronounced, only 13 miRNAs were found to be sex-biased, suggesting lesser contribution of miRNAs to sex-biased gene expression relative to other forms of regulation. To assess whether pituitary cellular composition could underlie changes in gene expression across pubertal transition, we performed single cell deconvolution of our bulk pituitary gland gene expression. Interestingly, we found that sex differences in cell proportions were estimated to emerge across puberty: a greater proportion of lactotropes was found among females, and greater proportions of gonadotropes and somatotropes were found among males. We observed sex-biased expression patterns of marker genes for these cell types, including Prl, Fshb, and Gh. This finding suggests that cell proportion differences between sexes likely contribute to whole pituitary transcriptome changes we observed, however, to what extent remains to be studied. Together our study indicates that miRNAs play a substantial role in regulation of pituitary postnatal development but that differences in cellular composition may contribute more robustly to sex-biased gene expression.
MON-183 Adrenal Androgen Control and Steroidal Side Effects in Adolescents and Adults with Congenital Adrenal Hyperplasia Treated with Glucocorticoids
Authors: Falhammar Henrik , Farber Robert , Chan Jean L , Farrar Mallory , Yonan Chuck , Kuranz Seth , Auchus Richard J
Published: May 2020

Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive disorder that results in little or no cortisol biosynthesis, increased production of precursor steroids, and excess production of adrenal androgens. Glucocorticoid (GC) treatment, the current standard of care for CAH, is used to correct cortisol deficiency and reduce excessive androgens. Elevated 17-hydroxyprogesterone (17OHP) is used for diagnosis and management. GC titration to achieve 17OHP <1000 ng/dL may be targeted for adrenal androgen control; however, patients with 17OHP <1000 ng/dL might be at risk for complications of long-term GC excess. This real-world study evaluated adrenal androgen levels and potential GC complications in adolescents and adults with CAH.

Methods: TriNetX, a research network that includes electronic medical records from >37 million U.S. patients, was searched on 30Aug2019 for patients who met the following criteria: diagnosis code of E25.0 (ICD-10) or 255.2 (ICD-9); history of GC use; available 17OHP laboratory result; and ≥15 years of age (“grown”) at the most recent 17OHP assessment. Patients were categorized as “adequately controlled” (17OHP <1000 ng/dL) or “poorly controlled” (17OHP ≥1000 ng/dL). Assessments included: demographics; laboratory results for 17OHP, adrenocorticotropic hormone (ACTH), and androstenedione (A4); and low-density lipoprotein (LDL). Adequately vs. poorly controlled groups were compared using Chi-square tests and t-tests.

Results: Of 511 grown CAH patients, 352 were adequately controlled and 159 were poorly controlled. Mean concentrations for 17OHP were 244 and 5939 ng/dL in the adequately and poorly controlled cohorts, respectively (p<0.01). Adequately controlled patients also had lower ACTH and A4 than poorly controlled patients: ACTH (72 vs 389 pg/mL, p<0.01); A4 (82 vs 256 ng/dL, p<0.01). Compared to poorly controlled patients, adequately controlled patients were more likely to be female (81% vs 57%, p<0.01) and older (mean birth year: 1981 vs 1986, p<0.01). Adequately controlled patients also had evidence of more metabolic and infection complications, including higher mean LDL (105 vs 94.3 mg/dL, p=0.02), more type 2 diabetes mellitus (9% vs 4%, p=0.08), and more respiratory tract infections (21% vs 11%, p=0.01).

Conclusions: In this retrospective analysis, patients with adequately controlled CAH (17OHP <1000 ng/dL) had better adrenal androgen control (lower A4) but also higher rates of complications potentially related to excessive GC exposure. These findings highlight the current challenges of managing CAH with GC regimens alone.
SUN-203 Hyponatremia and Hyperkalemia in a Child with Chylothorax: Is This Adrenal Insufficiency?
Authors: Ovando Dennerd , Iregui Adriana Carrillo , Christin Nicole M
Published: May 2020

Hyponatremia and Hyperkalemia in a child with chylothorax: Is this adrenal insufficiency?

Context: Chylothoraces are relatively rare within the pediatric population. Drainage of a chylothorax can lead to potentially serious complications including electrolyte imbalances and protein loss. The literature on hyponatremia and hyperkalemia developing after a chylothorax drainage is sparse. We report a case of electrolyte derangements after a chylothorax drainage in a pediatric patient. Repeated drainage of a large-volume chylothorax without adequate fluid replacement may lead to electrolyte imbalances that in our case mimicked adrenal insufficiency. Early identification and correct fluid replacement can avoid unnecessary complications of a chylothorax.

Case Description: A 2-year-old female with history of congenital left pulmonary lymphangectasia and subsequent pleural effusion was admitted to a pediatric hospital for persistent tachycardia after an outpatient elective chest MRI. A chest tube was placed to drain the effusion with large volume output was noted over the first day (1200 cc/24 hours). Further chemical analysis determined the effusion to be consistent with a chylothorax. Blood work done after chest tube placement demonstrated severe hyponatremia and hyperkalemia. Additionally, the patient was noted to be irritable. Both lab and clinical findings raised concern for possible underlying adrenal insufficiency, and further work-up (i.e. cortisol level, ACTH level) was sent. The patient was started on stress-dose steroids. ACTH and cortisol levels resulted normal. Steroids were subsequently discontinued. The patient’s chest tube output was slowly replaced with normal saline with noted improvement in both lab and clinical findings.

Conclusion: Although not well documented in pediatric literature, hyponatremia and hyperkalemia are complications of large-volume drainage of chylothoraces without proper fluid replacement. The subsequent lab findings could be consistent with adrenal insufficiency, however a full clinical picture along with a cortisol and an ACTH level can help differentiate etiologies.
SAT-236 Unusual Presentation of a Stable Pituitary Macroadenoma with Pituitary Apoplexy Causing SIADH and Pan-hypopituitarism
Authors: El-Zein Louna S , Abushanab Dania , Chaker Bayan
Published: May 2020

We are reporting a case of SIADH hyponatremia and pan-hypopituitarism in an otherwise stable appearing non-functional pituitary macroadenoma on MRI that suddenly developed apoplexy.

Patient is a 52-year-old hispanic male with a history of a pituitary adenoma diagnosed initially on 06/2017 during MRI head for chronic headaches. MRI Pituitary on 07/2018 showed “well-circumscribed lesion” measuring approximately 12.7 x 14.8 x 13.4 mm in AP. Hormonal work up was normal in 06/2017, 01/2018, and 07/2018. In 07/2018 labs showed: IGF-1 247 ng/mL (65–222), ACTH 28 pg/mL (7–69), random cortisol 8.58 microg/dL (3.09–22.4), TSH 2.3 mIU/mL (0.4–5.5), fT4 1.06 ng/dL (0.8–1.8), LH 4.6 mIU/mL (0.98–79.7), FSH 6.2 MIU/mL (1–18), prolactin 2.92 ng/mL (2.1–24), and testosterone 310 ng/dL (87–814). Oral glucose tolerance test was done and showed: GH was 0.34 ng/mL at baseline and 1.01 ng/mL after 75 g oral glucose (equivocal result). Repeat IgF1 was normal after that.

Subsequently, patient was admitted on 09/24/2018 with severe headaches, nausea, vomiting, polyuria, and polydipsia. He was hypotensive and tachycardic and was found to be hyponatremic with a Na of 124, lowest at 119 where hypertonic saline was given at that point. Urine output was 1.5 L in 24 hours while he was on an 0.8 L fluid restriction, and then 6 L the following day while he was on 1.5 L fluid restriction, serum osmolality was 251, urine osmolality was 1003, urine specific gravity was >1.030. Nephrology agreed to the diagnosis of SIADH.

Blood work on 09/24 showed: random cortisol 0.67 microg/dL, TSH 0.19 mIU/mL, free T4: 0.63 ng/dL, ACTH 11 pg/mL, LH 2.4 mIU/mL, FSH 4.7 MIU/mL, testosterone 13 ng/dl. Patient was started on Levothyroxine 125 mcg and hydrocortisone stress dose. MRI brain was done and showed a pituitary macro-adenoma, measuring approximately 14 x 11 x 11 mm with no significant change in size since 6/30/2017, without optic nerve compression, no hemorrhage was mentioned. Work up for other causes of panhypopituitarism, i.e. hemochromatosis was done and was negative: Ferritin: 258 ng/mL (22–322). CT abdomen and pelvis was also done and showed normal adrenal glands. We thought about granulomatous infiltrative diseases like sarcoidosis since 1–25 (OH) vitamin D was high at 120 pg/mL (19.9–79.3). CT neck and chest was done but was negative for sarcoidosis or lymphadenopathy. Patient was seen outpatient by neurosurgery in 1/2019 and a repeat MRI was done which reported resolution of cystic and blood material from a pituitary adenoma, and per neurosurgery there is resolution of a pituitary cystic adenoma with apoplexy that now looks like a partial empty sella. Patient currently continues to be pan-hypopituitary requiring hydrocortisone, levothyroxine and testosterone replacement. SIADH has resolved.

An otherwise non-functioning stable pituitary macroadenoma on MRI, can suddenly present as symptomatic apoplexy with SIADH and pan-hypopituitarism.
SUN-504 A Case of T3 Thyrotoxicosis
Authors: Peloquin Isabelle Daneault , St-Jean Matthieu
Published: May 2020

Clinical vignette ENDOCRINE SOCIETY 2020

Title: A case of T3 thyrotoxicosis induced by a dietary supplement.

A 24 yo man consulted for a 2 weeks history of diaphoresis, fatigue, insomnia, palpitations and headache associated with a 20 pounds lost. The patient didn’t have a goiter or any signs of orbitopathy.

The results revealed a free T3 level of 45.8 pmol/L upon arrival (normal (N) 3.4- 6.8 pmol/L), free T4 level of 6.4 pmol/L (N 11.0–22.0 pmol/L) and TSH level less than 0.005 mUI/L (N: 0.35 to 3.50 mUI/L). Facing those results, a complete review of the patient medication and natural product consumption was done. The patient revealed that he was using, since a month, a vegetable extracts nutritional supplement that didn’t included iodine. He was asked to stop the nutritional supplement and propranolol 10 mg twice daily was prescribed. Thyroid function tests were done 3 days after. The results demonstrate a fT3 level of 4.6 pmol/L, a fT4 level of 5.6 pmol/L and a TSH that still suppressed. A thyroid scintigraphy was performed 7 days later and showed a homogeneous uptake of 18.5% (N 7.0% – 35.0%). We saw the patient 2 weeks later and we ordered another thyroid function test with TSH receptor antibodies, TPO antibodies and thyroglobulin. The results were the following: fT3 of 5.1 pmol/L, fT4 of 12.1 pmol/L, TSH of 2.31 mUI/L, thyroglobulin of 19.8 ug/L (N: 1.4 – 78) and normal levels of antibodies against TPO and TSH receptors. To confirm the contamination of the nutritional supplement by fT3 we used a plasma pool of normal patients in which we measured thyroid function tests at baseline and after we have added the nutritional supplement powder to reflect the dose suggested by the manufacturer. The results showed that fT3 level increased by 36.5%, fT4 by 11.2% and TSH didn’t changed. The powder was then analyzed by an external laboratory that wasn’t able to demonstrate the presence of fT3 nor fT4. The two diagnostic possibility facing those results were that the powder induced an interference with immunoassay used to measure fT3 and fT4 but not TSH or thyrotoxicosis induced by the nutritional supplement with limitation in the technique that tried to identify fT3 in the powder. Given the presentation of the patient, we are convinced that this case represents a thyrotoxicosis induced by a nutritional supplement.

In conclusion, Graves’ disease is responsible for 60–80% of the cases of hyperthyroidism. However, there are few cases reports of thyrotoxicosis induced by nutritional supplement1,2, but some studies demonstrate the presence of thyroid hormone in significant amounts in some commercially available health supplements3. This case highlights the importance of verifying exposition to medications and natural products when confronted to cases of thyrotoxicosis.

1.Regina A et al. MMWR Morb Mortal Wkly Rep. 2016

2. Panikkath R et al. Am J Ther. 2014

3. Kang GY et al. Thyroid. 2013
SAT-283 Generation of a Long-Acting Human Growth Hormone Receptor Antagonist by Site-Specific Pegylation
Authors: Wang Yue , Langley Ries J , Tamshen Kyle , Maynard Heather D , Jamieson Stephen M F , Perry Jo K
Published: May 2020

Growth hormone (GH) is a peptide hormone that mediates actions through binding to a cell surface GH receptor (GHR), activating key signalling pathways including the JAK/STAT pathway. Excess GH secretion leads to acromegaly and tumoral expression has been implicated in cancer progression, suggesting that GH is also a potential target for anticancer therapy. Pegvisomant is the only GHR antagonist approved for clinical use. This antagonist is a PEGylated form of a mutated GH (B2036) that binds and blocks the receptor. Conjugation to polyethylene glycol (PEG) at multiple amine residues reduces in vitro bioactivity but extends the serum half-life resulting in improved in vivo bioactivity. We investigated whether we could generate a long-acting PEGylated GHR antagonist through site-specific conjugation of PEG. A codon optimised GHR antagonist, with an introduced free cysteine residue at amino acid site 144 (S144C), was generated by gene synthesis and recombinantly engineered by gene fusion with thioredoxin. Recombinant protein was expressed in E. coli and purified using a series of chromatographic methods. Antagonists were PEGylated using cysteine-specific conjugation chemistry. In vitro activity was determined using a Ba/F3-GHR viability assay, and in vivo pharmacokinetic and bioactivity was determined in mice. Fusion to thioredoxin was found to improve soluble protein expression at 30℃, resulting in dramatically increased yield. After a series of purification steps, including Ni-NTA, 3C protease cleavage and ion-exchange chromatography, a single band with a molecular mass of 22 kDa was observed by SDS-PAGE analysis. The recombinant antagonist was conjugated to 20 kDa or 30 kDa-PEG at amino acid site S144C. After purification, a single band with an effective molecular size of approximately 60 kDa (PEG-20kDa conjugate) or 70 kDa (PEG-30kDa conjugate) was observed by SDS-PAGE analysis. The unconjugated antagonist inhibited the proliferation of Ba/F3-GHR cells in a dose-dependent manner with a half maximal inhibitory concentration (IC50) of 10.1 ± 2.5 nM. Following PEGylation and purification, the PEG-20kDa and PEG-30kDa conjugates retained high in vitro bioactivity with an IC50 of 66.2 ± 3.8 nM and 106.1 ± 7.1 nM, respectively. Pharmacokinetic analysis demonstrated that PEGylation increased the serum half-life to approximately 15 hours in mice. Subcutaneous administration of the PEG-30kDa conjugate (10 mg/kg/day) reduced serum IGF-I levels in mice. In conclusion, we have generated a novel long-acting human GHR antagonist conjugate by introducing a free cysteine at a non-essential site of the antagonist and targeted attachment of PEG.