bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-716 A Novel Human Heterozygous STAT5B Variant Leads to Impaired Growth and Developmental Defects in Zebrafish Embryos
Authors: Landi Estefania , Karabatas Liliana , Ramirez Laura , Gutierrez Mariana , Scaglia Paula Alejandra , Keselman Ana Claudia , Braslavsky Debora , Sanguineti Nora , Bergada Ignacio , Jasper Hector Guillermo , Domene Horacio M , Plazas Paola , Domene Sabina
Published: May 2020

Signal transducer and activator of transcription 5b (STAT5b) has been identified as a key downstream mediator of GH signaling in somatic growth. Autosomic recessive human mutations in STAT5B lead to severe growth retardation associated to immune dysregulation. On the other hand, some heterozygous STAT5B mutations have been associated to a milder form of the disease. We have identified a heterozygous novel STAT5B mutation by Whole Exome Sequencing (WES) in a 2.2-year-old boy who presented proportionate short stature (height -2.77 SDS) with mild immune dysregulation. He also had normal GH response to provocative tests, low IGF-I levels, and a limited response to IGF generation test. This variant is located within the highly conserved SH2 domain responsible for recognizing and interacting with tyrosine-phosphorylated target peptides. The aim of our study was to evaluate the functional consequences of this novel heterozygous human STAT5B variant (K632N), using the zebrafish as a biosensor system, to determine its pathogenicity. To do this, we performed overexpression experiments microinjecting construct-derived mRNA for the wildtype (WT) and mutant variant into zebrafish embryos at the 1-cell stage and assessed the consequences at 72 hours post fertilization (hpf). The missense variant was introduced into the full length STAT5B cDNA clone (Origene) by site-directed mutagenesis. To generate mRNA, WT and mutant forms of STAT5B cDNAs were linearized by digestion with XhoI, purified and subsequently transcribed with Mmessage Mmachine T7 Transcription Kit. Zebrafish embryos microinjected with 100 and 200 pg of mutant mRNA show a dose dependent significant reduction of body length at 72 hpf compared to those microinjected with the same dose of WT mRNA (p<0.001). Body length reduction with 100 pg of mutant mRNA was 4%, while with 200 pg was 12.7% (p<0.001). In addition, a significant number of embryos injected with mutant mRNA show developmental defects including pericardial edema, bent spine, and cyclopia compared to those injected with WT mRNA (p<0.001). In the case of pericardial edema, the number of affected embryos increased significantly with the mutant mRNA dose (p<0.005). In conclusion, our study was able to evidence the pathogenic nature of the STAT5B K632N variant since it leads to growth and developmental defects in zebrafish embryos. The zebrafish, and its conserved GH-IGF-I axis, constitutes an ideal in vivo model for characterizing the functional effect of genetic variants in ortholog human genes.
SAT-605 Characterization of Dual Projection Patterns of Refeeding-Activated Neurons in the Parasubthalamic Nucleus
Authors: Wittmann Gabor , Cosentino Nicholas , Lechan Ronald M
Published: May 2020

We have observed that following a fast, animals terminate their food intake within 2h after refeeding accompanied by a pattern of neuronal activation as identified by c-fos immunostaining that involves a number of brain regions associated with the regulation of food intake including the nucleus tractus solitarius (NTS), parabrachial nucleus (PBN), central nucleus of the amygdala (CEA), hypothalamic arcuate and paraventricular nuclei, and bed nucleus of the stria terminalis. We also observed striking c-fos activation in the posterior-lateral hypothalamus called the parasubthalamic nucleus or PSTN, raising the possibility that it may also be an important anorectic center in the brain. To establish how the PSTN is integrated into the CNS, we performed dual-label retrograde tract tracing studies to characterize whether refeeding-activated PSTN neurons project to one, or more than one target area in the CNS. Adult, Sprague-Dawley rats received dual stereotaxic injections of Alexa Fluor 488- and Alexa Fluor 555-conjugated cholera toxin β subunit (CTB; 0.1%, 0.5–1 µl volume) into the 1) PBN and NTS, 2) PBN and CEA and 3) NTS and CEA. After 7–12 days, the animals were fasted for 24 h and then given free access to food for 2 h before euthanasia by transcardial perfusion with 4% paraformaldehyde. Brains with successful dual injections were further processed for c-fos immunohistochemistry. The results showed that 26.5±3.8% of PSTN neurons projecting to the PBN also project to the CEA, and 34.6±7.6% of PSTN neurons that project to the CEA also project to the PBN. In addition, 20.2±2.7% of PSTN neurons that project to the PBN also project to the NTS, and 38.1±9.7% of PSTN neurons that project to the NTS also project to the PBN. Furthermore, 35.0±12.5% of PSTN neurons that project to the CEA project to the NTS and 37.1±4.0% of PSTN neurons that project to the NTS project to the CEA. Finally, up to 15% of the neurons with dual projections to the PBN and CEA contained c-fos after refeeding; up to 18% of the neurons with dual projections to the PBN and NTS contained c-fos; and up to 30% of neurons with dual projections to the NTS and CEA contained c-fos. We conclude that a large number of PSTN neurons have more than one projection site within the brain, thus the PSTN appears to have the capability of simultaneously communicating information about appetite to several, major feeding-related sites within the brain, presumably to terminate feeding.
SAT-568 Hypertriglyceridemia-Induced Pancreatitis in a Pregnant Female Treated with Plasmapheresis
Authors: Nath Priti , Shakir Mohammed , Hoang Thanh Duc
Published: May 2020

Hypertriglyceridemia-Induced Pancreatitis in a Pregnant Female Treated with Plasmapheresis

Background: Gestational hypertriglyceridemia can lead to critical and even life-threatening consequences to both mother and fetus. A well-known consequence is hypertriglyceridemia-induced acute pancreatitis. Few case reports described the successful management of triglyceride (TG) induced pancreatitis in pregnant women using plasmapheresis.

Clinical Case:

A 28-year-old primigravida patient, in the 29th week of gestation, was admitted with acute onset of epigastric pain and nausea for 24 hours. Laboratory findings were remarkable for an elevated serum lipase of 505 U/L (ref 23–300) and an abnormal lipid profile. Her total cholesterol was 1651 mg/dl and triglycerides (TG) from an undiluted sample was 1361 mg/dl. When a 1:5 dilution was performed the result was higher at >4000 mg/dl. She was transferred to the ICU for treatment of acute pancreatitis. She has no family history of hypertriglyceridemia. No MRI was obtained. Gemfibrozil, Lovaza™ (omega-3-acid ethyl esters), and an insulin infusion were started but serum TG levels did not improve. On hospital day 2 she developed worsening tachycardia, tachypnea with laboratory findings of metabolic acidosis and hypocalcemia. As there was no reduction in triglyceride levels with medical therapy and her clinical status was deteriorating, the treating multidisciplinary team decided to initiate plasmapheresis. After one session, TG levels decreased from >4000 mg/dl to 1829 mg/dl and continued to decline to 721 mg/dl. Hospital day 6 her TG level rose to 1245 mg/dl prompting a second plasmapheresis. TG levels decreased to 770 mg/dl shortly after but rose the next day to 1365 mg/dl. She underwent a 3rd plasmapheresis after which her TG ranged from 400–700 mg/dl for the remainder of her hospitalization. On the day of discharge, her TG level was 733 mg/dl. She was advised to restrict fat intake and continue both gemfibrozil and Lovaza™ but despite this her TGs again increased to 1693 mg/dl. From that point she started weekly sessions of plasmapheresis for a total of 8 sessions prior to an uneventful vaginal delivery at 36 weeks of gestation. One month later her lipid profile dramatically improved. Total cholesterol was 233 mg/dl and triglycerides were 304 mg/dl while on lipid lowering therapy.

Conclusion: Pancreatitis during pregnancy is associated with a high maternal and fetal death rate. Early treatment is important for the survival of the mother and fetus. Plasmapheresis is an alternative and safe treatment for cases that are not responsive to medical therapy. It can be administered safely to reduce triglyceride levels and diminish the systemic inflammatory response leading to a shortened hospital stay and better outcomes.
SAT-579 Experiences with Hypertriglyceridemic Pancreatitis: A Mini Case Series
Authors: Majety Priyanka , Siegel Richard D
Published: May 2020

Background: Hypertriglyceridemia (HTG) is a well-established cause of acute pancreatitis (AP) in up to 14% of all cases & up to 56% cases during pregnancy. The triad of HTG, Diabetic ketoacidosis (DKA) and AP is rarely seen posing diagnostic challenges. Early recognition of HTG-induced pancreatitis (HTGP) is important to provide appropriate therapy & prevent recurrence. In this case series, we discuss the diagnostic challenges and clinical features of HTGP. Clinical cases: Our first patient was a 65-year-old male with a history of hypertension who presented to the ER with abdominal pain and new-onset pruritic skin rash after a heavy meal. His exam and labs were notable for a diffuse papular rash on his back, triglycerides (TG) of 7073mg/dL (normal: <150mg/dL). The rash improved with the resolution of HTG. Our second patient was a 29-year-old male with a history of alcohol dependence who was found to have AP complicated by ARDS requiring intubation. Further testing revealed that his TG was 12,862mg/dL & his sodium (Na) was 102mEq/L. Although HTG was known to cause pseudohyponatremia, it was a diagnostic challenge to estimate the true Na level. In a third scenario, a 28-year-old female with a history of T2DM on Insulin presented with nausea & abdominal pain. Labs were suggestive of DKA and lipase was normal. CT abdomen showed changes consistent with AP. The TG level that was later added on was elevated to 4413mg/dL. She was treated with insulin that improved her TG level. Discussion: We present three cases of hypertriglyceridemic pancreatitis. While the presentation can be similar to other causes of acute pancreatitis (AP), there are factors in the diagnosis and management of HTGP that are important to understand. Occasionally, physical exam findings can be suggestive of underlying HTG. In the first scenario, our patient presented with eruptive xanthomas - a sudden eruption of crops of papules that can be pruritic. They are highly suggestive of HTG, often associated with serum TG levels > 1500mg/dL. Our second patient presented with pseudohyponatremia. HTG falsely lowers Na level, by affecting the percentage of water in plasma. Identifying this condition is important to prevent possible complications from aggressive treatment. This can be corrected either by using direct ion-specific electrodes or with the formula: Na change = TG * 0.002. DKA is associated with mild-moderate HTG in 30–50% cases. This is due to insulin deficiency causing activation of lipolysis in adipocytes & decreased activity of lipoprotein lipase (LPL). However, severe HTG is a rare complication of DKA, increasing the risk of AP. Diagnosis of AP in DKA poses many challenges: the common presenting complaint of abdominal pain, non-specific hyperlipasemia in DKA. AP with DKA has also been associated with normal lipase levels. A high clinical index of suspicion is required to diagnose HTGP in patients with DKA.
MON-593 Single-Dose Effects of Anti-Obesity Drugs on Human Basal Metabolic Rate
Authors: Israni Nikita Sanjay , Cassimatis Thomas , Fletcher Laura A , Leitner Brooks P , Duckworth Courtney J , Hattenbach Jacob D , Bell Sarah L , McGehee Suzanne , Brychta Robert J , Courville Amber B , Bernstein Shanna B , Muniyappa Ranganath , Reitman Marc L , Cypess Aaron M , Chen Kong Y
Published: May 2020

Design and rationale: Obesity results from energy intake exceeding energy expenditure (EE) over a prolonged period. Many anti-obesity drugs are designed to decrease energy intake. However, their potential impact on EE is not well documented. We designed a placebo-controlled, double-blind, randomized cross-over study to determine the acute effects of several FDA-approved anti-obesity drugs on basal metabolic rate (BMR) under well-controlled conditions.

Protocol and inclusion criteria: This ongoing study is limited to healthy males of all ethnicities aged 18–35 years with a BMI of 18.5 to 25.0 kg/m2. Following an overnight stay in the Metabolic Clinical Research Unit, fasting subjects were measured from 8:00am to 12:00pm in a whole-room indirect calorimeter, which was maintained at a thermoneutral temperature (26.7±0.9°C) to prevent non-shivering thermogenesis. The six treatments include placebo, caffeine as the positive control (300 mg), phentermine (37.5 mg), topiramate (200 mg), Qsymia (phentermine 15 mg / topiramate 92 mg), and naltrexone (100 mg), with a 1-week outpatient washout period after each treatment. Drug-naïve subjects received a single dose of each drug to minimize potential metabolic adaptations that may occur with weight-loss or chronic use. The prespecified primary outcome was a ≥5% increase in BMR vs. placebo for each drug. This difference can be detected for 16 subjects with 0.83 power at α=0.05 allowing for ≤25% dropout. Secondary outcomes include respiratory quotient (RQ), heart rate (HR), mean arterial pressure (MAP), and self-reported hunger.

Preliminary data: To date, 7 subjects were recruited and 6 have completed the study (26.1±4.3 years, BMI 23.1±1.4 kg/m2, body fat percentage 18.4±4.1%). Interim analysis using paired t-tests shows, compared to placebo, caffeine trended towards increasing EE (1.17±0.07 vs. 1.27±0.12 kcal/min; p=0.07) and increased MAP by 5.5±4.2% (88±2 vs. 93±4; p<0.05), but did not change heart rate (59±10 vs. 61±13 bpm). Naltrexone increased EE by 5.9±4.3% (p<0.05). No treatments altered resting RQ compared to placebo (0.83±0.05). Phentermine increased resting HR, both alone (15.7±7.9%, p<0.01) and in Qsymia (9.2±3.6%, p<0.05), compared to placebo. Of the five drug-treatments, only Qsymia reduced self-reported hunger scores compared to placebo.

Summary and future directions: Anti-obesity drugs may increase energy expenditure by upregulating sympathetic nervous system activity. Combined with appetite suppression, the impact on energy balance can lead to weight loss. We aim to complete our study to determine whether these drugs can acutely increase EE with minimal cardiovascular side-effects and compare our findings with long-term interventions.
SUN-561 Genetic Variants Related to Familial Hypercholesterolemia in Clusters from Minas Gerais - a Southeast State of Brazil
Authors: de Paiva Silvino Júnea Paolucci , Jannes Cinthia Elim , Tada Maurício Teruo , Lima Isabella Ramos , Silva Iêda Fátima Oliveira , Gomes Karina Braga , Pereira Alexandre Costa
Published: May 2020

Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disease, characterized by high levels of the cholesterol fraction present in low density lipoprotein (LDLc). FH is associated to early atherosclerotic coronary disease, which can result in acute myocardial infarction and angina pectoris. Clinical diagnosis of FH in adults is based on elevated LDLc levels ≥ 4,9 mmol/L and total cholesterol (TC) ≥ 7,5 mmol/L; in untreated children and adolescents LDLc ≥ 4,0 mmol/L and TC ≥ 6,7 mmol/L, associated or not with physical signs (xanthomas, corneal arch). In Brazil, it is estimated that there are from 402,000 to 607,000 cases of FH. This study aimed to evaluate the genetic variants related to FH in a small region from Minas Gerais, a southeast state in Brazil. Fifteen index cases (IC) were selected in two cities (Bom Despacho and Moema), that comprise 1.416 km2 in that region. Family members (n=69) were also selected, when possible, for genetic analysis, which was carried out by the NGS (Next Generation Sequencing) method, using Illumina® technology. Six different genetic variants were identified: 1) Pathogenic variants in LDLR gene - Asp224Asn in 74 individuals (10 IC); Cys34Arg in 1 individual (1 IC); Asp601His in 2 individuals (1 IC); and Ser854Gly in 2 individuals (1 IC); 2) Variant of uncertain significance (VUS) in APOB gene - Met499Val in 1 individual (1 IC); and 3) VUS in PCSK9 gene - Arg237TRP in 4 individuals (1 IC). All variants were identified in heterozygosis. The data suggest that the high prevalence of FH in that small region in Brazil is related to inbreeding observed in the families investigated. In addition, a founder effect could also contribute to the elevated frequency of LDLR gene variants, mainly Asp224Asn. The data show the importance of molecular investigation on clinical conduct in FH Brazilian patients and their family members.
SUN-508 Dissociation of Clinical Course of Coexisting Autoimmune Hepatitis and Graves Disease
Authors: Patel Aesha , Stanback Camille , Vellanki Priyathama
Published: May 2020

Title: Dissociation of Clinical Course of Coexisting Autoimmune Hepatitis and Graves Disease

Introduction: The association between Graves’ disease and coexisting autoimmune hepatitis is well known. Treatment of autoimmune hepatitis with glucocorticoids can concurrently lower thyroid hormone levels. Additionally, recurrence of hyperthyroidism has been shown to be associated with recurrence of autoimmune hepatitis. We present a case of a patient with autoimmune hepatitis and Graves’ thyrotoxicosis, which initially improved with prednisone therapy, but thyrotoxicosis recurred during the prednisone taper while hepatitis stayed in remission.

Clinical Case: A 47-year old female initially presented with fatigue, nausea, and jaundice. Liver enzymes showed elevated AST (1634 U/L) and ALT (1956 U/L) with total bilirubin 15.1 mg/dL. Liver biopsy was consistent with autoimmune hepatitis. Treatment was initiated with ursodiol 300 mg TID and liver enzymes improved to ALT 579 IU/L and AST 544 IU/L with total bilirubin 1.9 mg/dL. Nine months later, she presented with worsening upper and lower extremity weakness, slurred speech, abdominal pain, and nausea and vomiting. AST and ALT were again elevated to >1,000 U/L. TFTs were checked due to symptoms of palpitations and heat intolerance. TSH was 0.024 uIU/mL with elevated free T4 of 3.74 ng/dL and TSI of 435%. She was treated with prednisone, cholestyramine, and propranolol and discharged with a one-month prednisone taper starting at 60 mg daily. LFTs and TFTs normalized after one month. Cholestyramine was discontinued and prednisone was tapered to 5 mg daily. Seven months later, she had symptoms of palpitations and heat intolerance. TFTs were consistent with hyperthyroidism (TSH 0.049 uIU/mL, free T4 3.96 ng/dL). LFTs remained in normal range. Since thionamides have relative contraindications in patients with liver disease, prednisone was increased from 5 mg to 20 mg daily and cholestyramine was resumed to treat hyperthyroidism. After five months, TSH remained suppressed to 0.019 uIU/mL however free T4 improved to 1.74 ng/dL. The patient was referred for total thyroidectomy.

Conclusion: This case illustrates an example of the rarely reported occurrence of thyrotoxicosis recrudescence despite initial improvement with treatment of underlying autoimmune hepatitis. Recognition of recurrence of hyperthyroidism independent of recurrence of autoimmune hepatitis indicates the need for early definitive therapy for hyperthyroidism.
SUN-521 Hyperemesis Gravidarum Resulting in Wernicke’s Encephalopathy and Abnormal Thyroid Function Tests
Authors: Merrill Jennifer D , Roomiany Pahresah , Wachter Adam , Setji Tracy Lynn
Published: May 2020

Background: Wernicke’s encephalopathy (WE) is a potentially fatal consequence of thiamine deficiency that must be considered in patients with poor nutrition and altered mentation. We report a case of a female with hyperemesis gravidarum (HG), nystagmus, clonus, and abnormal thyroid function tests associated with WE. Clinical Case: A 23 year-old healthy G2P0010 woman was admitted for rehydration at 15 weeks gestation after four weeks of intractable vomiting. She denied medications, supplements and alcohol use. Vitals were normal. Exam showed a fatigued ill appearing female with no thyromegaly, tremor, lid lag, or stare. She had a gravid uterus but otherwise normal exam. Fetal heart rate was normal. Laboratory findings included hyponatremia, hypokalemia, elevated creatinine and transaminases, and normocytic anemia. Hepatitis panel, vitamin B12, ammonia, urinalysis and ultrasound of the appendix and gallbladder were unremarkable. She was treated with intravenous fluids and potassium. Electrolyte abnormalities and renal dysfunction resolved. On hospital day three, she became lethargic, tachycardic, unable to follow commands, and exhibited nystagmus and clonus. Thyroid studies showed TSH 0.06 uIU/mL (0.34 - 5.66 µIU/mL), and free T4 3.59 ng/dL (0.52 - 1.21 ng/dL). Methimazole and propranolol were started while awaiting repeat thyroid studies. MRI brain was not obtained due to aspiration risk. EEG showed diffuse slowing but no epileptiform activity. She returned to baseline mentation within hours of intravenous thiamine, with resolution of dysphagia and nystagmus. Thiamine level returned low (51 nmol/l; normal 67–200 nmol/L). Methimazole and propranolol were stopped and thyroid function tests normalized. She was discharged and delivered a healthy baby at term. Conclusion: WE is an acute neuropsychiatric condition caused by thiamine deficiency. Early recognition and treatment are critical to prevent irreversible damage; the classic signs are ataxia, ophthalmoplegia, and encephalopathy. Historically considered in patients with a history of alcohol use, WE is increasingly recognized in other conditions associated with dietary deficiency, since body stores of thiamine last only 18 days. WE has been reported in HG due to prolonged vomiting and increased thiamine requirements in pregnancy. WE has been associated with thyrotoxicosis, possibly due to increased metabolic demands. Both gestational transient thyrotoxicosis and HG are associated with markedly elevated HCG and present in the first 16 weeks of pregnancy. Initial thyroid studies were concerning for thyrotoxicosis, but normal repeat studies argue against that as a contributor. WE is a life threatening complication of poor oral intake, which should be empirically treated with thiamine prior to glucose. WE may be associated with thyrotoxicosis.
SUN-910 High Enhancement Washout by CT Imaging Does Not Exclude Pheochromocytoma/Paraganglioma: Review of Two Cases
Authors: Erenler Feyza , Lechan Ronald M
Published: May 2020

Background:

It is well known that delayed images from contrast-enhanced CT are useful in distinguishing adrenal adenomas from non-adenomas, with an absolute washout that exceeds 60% being most consistent with a lipid rich adenoma. We present two cases of an adrenal mass that met the criteria for a lipid rich adenoma by CT imaging, but found to be a pheochromocytoma (PCC) and paraganglioma (PGL).

Clinical Case

Case#1

An 82 yo woman presenting with tachycardia was found to have a 2.4 cm heterogeneously attenuating, left adrenal nodule with an absolute washout of 61% and a relative washout of 45%. The right adrenal was normal. Urinary catecholamine levels were elevated with an epinephrine (E) 38 mcg (2–24), norepinephrine (NE) 388 mcg (15–100), dopamine (DOPA) 175 mcg (52–480), metanephrine (MN) mcg 620 (90–315), normetanephrine (NMN) 1553 mcg (122–676) and vanillylmandelic acid 12.5 mg (< 6) on a 24h collection. Due to a cardiac resynchronization therapy device, an MRI could not be obtained. MIBG imaging was obtained and showed increased uptake in left adrenal gland, corresponding to the lesion identified on CT. The patient underwent laparoscopic adrenalectomy and the pathology confirmed a PCC.

Case#2:

A 74 yo man was found to have an incidental right adrenal nodule on CT imaging measuring 2.4 cm. Absolute washout was 83% and relative washout 68%. The left adrenal gland was normal. A follow up MRI obtained showed slight increase in T2 weighted images and no drop out on out of phase imaging, raising concern for a PCC. Urinary catecholamines were elevated including E 12 mcg (2–24), NE 280 mcg (15–100), DOPA 246 mcg (52–480), MN 175 mcg (90–315) and NMN 1298 mcg (122–676) on a 24-hr. collection. MIBG imaging further confirmed the diagnosis with increased uptake in the right adrenal gland. The patient underwent laparoscopic adrenalectomy then, converted to open right adrenalectomy through an anterior approach due to adherence of the tumor to the renal vein. The pathology revealed a PGL.

Conclusion:

PCC/PGL are rare but life-threatening neuroendocrine tumors that require early detection to reduce associated morbidities and mortality and improve surgical outcomes. CT is commonly used to characterize adrenal lesions and an absolute washout of >60% is most consistent with an adenoma. However, as demonstrated by these two cases, washout exceeding 60% can also be seen in non-adenomas, perhaps secondary to degeneration of the nodule causing necrotic or cystic changes or uncommonly, the presence of a high lipid content in the tumor [1]. Thus, when clinical suspicion is strong and/or there is a positive biochemical workup, confirmatory imaging should be considered to establish the diagnosis.

References:

[1] Blake, M. A., Kalra, M. K., Maher, M. M., Sahani, D. V., Sweeney, A. T., Mueller, P. R., ... & Boland, G. W. (2004). Pheochromocytoma: an imaging chameleon. Radiographics, 24(suppl_1), S87-S99.
SUN-247 GABA Receptor-Dependent Inhibition and Excitation of GnRH Neuron Dendrons near the Median Eminence in Mice
Authors: Liu Xinhuai , Porteous Robert , Herbison Allan Edward
Published: May 2020

The gonadotrophin-releasing hormone (GnRH) neuron cell bodies are scattered throughout the basal forebrain but funnel their projections to the median eminence to control fertility in all mammals. In mice, these long projections, termed “dendrons”, have characteristics of both dendrites and axons and are found to receive large numbers of synaptic inputs just prior to entering the median eminence. While the effects of many neurotransmitters have been documented at the GnRH neuron cell body, very little is known about the neural control of the distal dendron.

To examine the role of amino acid neurotransmitters in the regulation of the thin GnRH neuron distal dendrons, we used confocal microscopy in combination with real-time GCaMP6 calcium imaging in acute horizontal brain slices. Adult male and female GnRH-Cre mice were given stereotaxic injections of a Cre-dependent AAV expressing GCaMP6s and, > 3 weeks later, the brain removed and a single thick horizontal brain slice prepared that included the base of the brain and median eminence. The intracellular calcium levels of multiple dendrons were monitored simultaneously while puffs of amino acid receptor agonists were applied. Surprisingly, GABA exhibited a dual action on calcium concentrations with an initial transient increase followed by a prolonged decrease and subsequent rebound. The administration of GABAA and GABAB receptor agonist and antagonists revealed that the transient increase resulted from a quickly desensitizing activation of GABAA receptors while the decrease and subsequent rebound was dependent upon the slower kinetics of the GABAB receptor. Kisspeptin exerts a potent long-lasting elevation of calcium levels in GnRH dendrons and this was robustly inhibited by subsequent GABAB receptor activation. In contrast to GABA, glutamate was not found to have any impact on intracellular calcium levels in the distal dendrons and, similarly, the activation of NMDA or AMPA receptors was found to be ineffective.

The results show that GABA exerts particularly potent modulatory actions upon basal and evoked calcium concentrations within the GnRH neuron distal dendron. This suggests that acute brief activation of the dendron by GABA would facilitate GnRH release through GABAA receptor activation whereas prolonged GABA release would suppress activity through the GABAB receptor. As such, GABA inputs to the distal dendron appear likely to play a major role in the control of GnRH secretion in the mouse.
MON-483 Familial Dysalbuminemic Hyperthyroxinemia with False Hypercortisolemia
Authors: Chiba Koki , Kameda Hiraku , Nomoto Hiroshi , Cho Kyu Yong , Nakamura Akinobu , Jin Shigeki , Matoba Kotaro , Miyoshi Hideaki , Atsumi Tatsuya
Published: May 2020

Background: Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant disease characterized by hyperthyroxinemia without symptoms of thyrotoxicosis, due to a high affinity of mutant albumin for thyroxine. No report has described cortisol-albumin binding in FDH patient, and here we present a case of FDH presenting with false hypercortisolemia.

Clinical Case: A 46-year man, previously diagnosed with FDH by genetic test (1), was pointed out hypercortisolemia with normal ACTH level (ACTH 64.7 pg/mL, Cortisol 34.7 μg/dL) during the investigation for Parkinson’s syndrome and referred to our department for further examination. Cortisol was 7.1 μg/dL at midnight, 14.9 μg/dL after low dose dexamethasone overnight test, and DDAVP test was positive. ACTH and cortisol responded to CRH load, although basal and peak cortisol levels were high (35.4 and 53.9 μg/dL, respectively). High dose dexamethasone overnight test showed suppressed ACTH and cortisol, and MRI showed no obvious pituitary adenoma.

In spite of significant high cortisol level, no Cushing sign’s or metabolic abnormalities were observed and urinary free cortisol was within the normal range (30.7 μg/day), suggesting the presence of factors affecting the laboratory testing. We removed albumin from serum with immunoprecipitation using anti-albumin antibody and measured cortisol with LC-MS/MS. The decrease of cortisol was 4% in control serum but 38% in the patient serum after removing albumin, suggesting the binding rate of cortisol to mutant albumin in the patient was increased, leading to false hypercortisolemia.

Conclusion: This is the first case demonstrating the false hypercortisolemia in a FDH patient. Clinicians should consider the possibility of the abnormal cortisol binding to albumin in differential diagnosis of hypercortisolemia with normal ACTH level.

Reference: (1) Norio Wada, et al: A Novel Missense Mutation in Codon 218 of the Albumin Gene in a Distinct Phenotype of Familial Dysalbuminemic Hyperthyroxinemia in a Japanese Kindred. Journal of Clinical Endocrinology and Metabolism 1997;82;3246–3250
MON-060 P-450 Oxidoreductase Deficiency with Antley Bixler Phenotype: A Novel Mutation
Authors: Kumar Anshul , Mathur Sandeep Kumar , Sharma Balram , Purwar Naincy , sharma Himanshu , Saran Sanjay
Published: May 2020

Introduction

We present first case of 46 XY Disorder of Sex Development (DSD) from India due to P-450 Oxidoreductase Deficiency with Novel variant (p.Ala541Thr) in a heterozygous state.

Case Discussion

6 months old boy presented with ambiguous genitalia since birth. No history of neonatal crisis, failure to thrive and pigmentation of skin, maternal virilisation or drug ingestion during pregnancy. On examination: weight 6.2 Kg (3rd centile), height 64 cm (3rd centile), MPH-170 (25-50th centile), head circumference 38 cm (−2.7 SD), vitals stable, trigonocephaly with fused anterior and posterior fontanelle, prominent pointed forehead, midfacial hypoplasia, up slanting eyes, hypertelorism and low set ears were present. Genitalia: 1.5 cm phallus like structure with foreskin, chordee, single perineal opening in form of peno-scrotal hypospadias, bifid scrotum with poor rugosity and poor pigmentation and both gonads (1 ml) were palpable in labio-scrotal fold with external masculinization score (EMS), 6/12 and Prader stage 4.

Investigations showed normal electrolytes and blood sugar, High basal ACTH, post stimulation cortisol 14mcg/dl, Basal 17-OHP was 8.6 ng/ml and post stimulation 12ng/ml, with low DHEAS 36.4 mcg/dl and androstenedione 0.42 ng/ml, LH 16.09 mIU/ml (elevated), FSH 2.97 mIU/ml (normal) and low Testosterone for his age. T/DHT 9.6 (normal<10) and Testosterone /Androstenedione ratio 0.95 (normal >0.8). Abdominal and Pelvic imaging showed normal adrenal glands and absent female internal genitalia, bilateral testis in labio-scrotal fold (right testis-6x6.5x11 mm, left testis-6.6x7x10 mm), corpora cavernosa and bifid scrotum. NCCT Head showed metopic craniosynostosis with trigonocephaly and hypotelorism. Skeletal survey showed bowing of femora. 20 cell Karyotype of peripheral blood lymphocyte was 46 XY. NGS was done of the POR gene, which revealed a heterozygous missense variation in exon 13 of the POR gene variant (p.Ala541Thr) which has not been reported yet.

The patient was initiated hydrocortisone, fludrocortisone, DHT gel and corrective surgery is planned.

Clinical learning

Although in PORD classically the inheritance is generally autosomal recessive, but manifesting heterozygotes are not uncommon1. This case also shows the value of Next gen sequencing and the role it can play in DSD

1. Scott RR, Gomes LG, Huang N, Van Vliet G, Miller WL. Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2007;92:2318–2322
OR12-05 MDC1 Is a Novel Estrogen Receptor Co-Regulator in Invasive Lobular Carcinoma of the Breast
Authors: Bordeaux Evelyn K , Sottnik Joseph L , Goodspeed Andrew E , Ferrara Sarah E , Costello James C , Sikora Matthew J
Published: May 2020

Invasive Lobular Carcinoma (ILC) is the 2nd most common histotype of breast cancer, but is critically understudied. ~95% of ILC are estrogen receptor (ER) positive, and previous studies demonstrate the importance of estrogen in ILC etiology. However, retrospective studies show that anti-estrogens are substantially less effective in ILC than in ER+ Invasive Ductal Carcinoma (IDC). This strongly suggests that regulation of ER function is unique in ILC, and we hypothesize that this is due to an ILC-specific cohort of ER co-regulators. We performed Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) to determine ILC-specific ER-interacting proteins, and identified Mediator of DNA Damage Checkpoint 1 (MDC1) as a novel ER co-regulator in ILC cells. We confirmed ER:MDC1 interaction by co-immunoprecipitation and proximity ligation assays (PLA); interaction was specifically observed in ILC cell lines but not IDC cell lines. Consistent with co-regulator function, we found MDC1 is essential for ER-driven proliferation of ILC cells. MDC1 knockdown dysregulates transcription of ER target genes in ILC cells (e.g. IGFBP4, WNT4). Moreover, RNA-seq analysis showed that in ILC cell line MDA MB 134VI, >50% of ER target genes require MDC1 for their regulation. To understand how MDC1 controls ER transcriptional activity, we performed ChIP-qPCR and found that MDC1 controls ER binding to DNA in ILC cells. Further, MDC1 controls binding of the pioneer factor FOXA1 to DNA, and Dual PLA studies of ER:MDC1 and ER:FOXA1 interaction revealed that MDC1 knockdown decreased ER:FOXA1 interaction. MDC1 canonically functions in DNA damage response, but our preliminary data suggest MDC1 is decoupled from its canonical role in DDR in the context of ER co-regulator activity in ILC cells. Together, these data suggest MDC1, independent of its role in DDR, acts as a novel ER co-regulator in ILC and regulates ER:DNA binding and ER transcriptional function to drive ILC cell proliferation and survival.
MON-011 NALCN Expression Is Regulated by Progesterone and Estrogen in Human Myometrial Smooth Muscle Cells
Authors: Amazu Chinwendu , Ma Xiaofeng , Henkes Clara , Ferreira Juan J , Santi Celia , England Sarah
Published: May 2020

During pregnancy, the uterus transitions from a quiescent state to a highly contractile, excitable state. Both ion channels and hormones are essential for this transition. We recently identified that the Na+ leak channel, non-selective (NALCN) contributes to a leak current in human MSMCs and mice lacking NALCN have prolonged and dysfunctional labor. Additionally, NALCN levels change throughout mouse pregnancy suggesting regulation by hormones of pregnancy, specifically estrogen and progesterone. Here, we tested the hypothesis that P4, a pro-quiescent hormone, and E2, a pro-contractile hormone, regulate NALCN expression and current in the myometrium. In a human immortalized myometrial cells (HM6ERMS2), using qPCR we measured a 2.3 fold decrease and a 5.6 fold increase in NALCN mRNA expression in the presence of E2 and P4, respectively. These findings were also confirmed when NALCN protein expression were measured by immunoblot. Conversely, treatment with the ER antagonist, ICI 182,780, significantly increased NALCN mRNA expression, while treatment with the PR antagonist RU486 significantly decreased NALCN mRNA expression suggesting E2 and P4 work through their respective receptors to regulate NALCN. P4 differentially regulates myometrial activity depending on which progesterone receptor is activated: PRA, promotes contractility, whereas PRB promotes quiescence. Thus to study the effect of each PR, we used a human myometrial cell line stably expressing PRA or PRB, and measured similar increases in NALCN mRNA expression in both cell lines treated with P4. To determine the functional consequences of E2 and P4, we measured NALCN-dependent leak current in MSMCs using whole cell patch clamping. We observed that E2 significantly inhibited while P4 significantly enhanced NALCN current. Finally, we identified estrogen response and progesterone response elements (ERE and PRE) in the NALCN promoter and showed that the PREs contributed to P4 regulation while the ERE did not contribute to the regulation of NALCN expression using luciferase based promoter assays. Overall, our findings show that NALCN is upregulated by P4, the pro-quiescent hormone, and downregulated by E2, the pro-contractile hormone. This data reveals a new mechanism by which NALCN is regulated in the myometrium and may suggest a novel role for NALCN during pregnancy. Further investigation into these novel roles can provide an insight into potential targets to modulate uterine quiescence and contractility.
SUN-928 Adrenal Plasmacytoma in Multiple Myeloma Patient-An Unusual Presentation
Authors: Mathew Jeena , Lubitz Sara , Zaidan Julie
Published: May 2020

Introduction:

Extramedullary plasmacytomas are plasma cell tumors that arise outside of the bone marrow. They are solitary lesions, and are most often located in the head and neck region, mainly in the upper aerodigestive tract. However, involvement of adrenal gland is extremely rare, with only nine case reports published to date. A mass in the adrenal gland carries a broad differential, and identification is important, as diagnosis drives treatment options. CT imaging with attenuation, timing of contrast medium washout, size, and shape, with biopsy is necessary for diagnosis of a high Hounsfield unit mass. Ruling out pheochromocytoma before biopsy of the adrenal glands is crucial.

Clinical Case:

A 64-year-old female was diagnosed with multiple myeloma after presenting with back pain and altered mental status. Imaging revealed diffuse lytic lesions in clavicles, pelvis, calvarium, long bones, ribs, and compression fractures of T8, T10, and T12 vertebral bodies. A 1.5 cm left adrenal nodule was also noted. She was treated with bortezemib, cyclophosphamide, lenalidomide, and dexamethasone, and clinically improved. Four months after initial presentation, patient was to undergo chemotherapy with melphalan and autologous stem cell transplantation. Further imaging was performed, and CT Chest revealed an enlarging left adrenal mass measuring 3.0 x 3.2 cm with increased attenuation at 37 Hounsfield units and lobulated borders with no invasion of adjacent structures. The endocrinology team was consulted for evaluation of the adrenal mass, as patient’s disease from multiple myeloma was presumed to be in remission. Differential for the adrenal mass included pheochromocytoma, primary adrenal carcinoma, and metastatic disease from multiple myeloma vs other primary. Plasma fractionated metanephrines and DHEAS were within normal range. CT guided core biopsy was performed. Cytology revealed diffuse infiltrate of atypical plasma cells. IHC studies were positive for CD138, CD56, and showed lambda light chain restriction. Cyclin D1 stain was negative, consistent with plasmacytoma. Clinically, the patient started developing progressive disease, including cutaneous plasmacytomas, and she was treated with additional chemotherapy.

Conclusion:

Adrenal plasmacytoma is extremely rare, and in a patient with multiple myeloma, should be considered in the differential diagnosis of a rapidly enlarging adrenal mass with high CT attenuation. CT guided biopsy is the definitive test for diagnosis.

References:

Li Y., Guo Y.-K., Yang Z.-G., Ma E.-S., Min P.-Q. Extramedullary plasmacytoma involving the bilateral adrenal glands on MR imaging. Korean Journal of Radiology. 2007;8(3):246–248. doi: 10.3348/kjr.2007.8.3.246.
SAT-370 Novel CASR Gene Mutation as a Cause of Familial Isolated Primary Hyperparathyroidism
Authors: Juneau Andrea K , Opoku-Boateng Adwoa , Uwaifo Gabriel Ikponmosa
Published: May 2020

BACKGROUND: Primary hyperparathyroidism (pHT) is one of the most common causes of hypercalcemia. About 10% of these patients have a familial cause of which MEN and the hyperparathyroid-jaw tumor syndrome (HJTs) are most common. Familial hypocalciuric hypercalcemia (FHH) due to loss of function mutations of the calcium sensing receptor (CASR) gene is an important familial mimic of this that needs to be distinguished. Beyond this are still a group of patients with familial isolated primary hyperparathyroidism (FIpHT). Recognition of this entity is important because of the different prognostic and surgical treatment strategy for their management compared to regular sporadic pHT. Clinical Case: A 58 yr old postmenopausal lady on topical HRT was referred for thyroid nodular disease. Her initial lab tests showed primary hyperparathyroidism with mild hypercalcemia. Her initial neck sonogram showed multiple benign appearing nodules that did not warrant biopsy. There was a history of hypothyroidism in her mother and thyroid cancer in a maternal cousin. In addition, her father and two sons have history of hypercalcemia that required repeated hospital admissions for treatment. Her two daughters to date have had no hypercalcemia, nephrolithiasis nor thyroid problems. There was no family history of jaw, renal nor brain or pituitary tumors and no history of severe dyspeptic disease nor familial cancers. She had hypercalciuria, normal bone density and non-obstructive nephrolithiasis. MEN-1 gene testing was normal. Parathyroid scan suggested a possible right sided parathyroid lesion and she had elective parathyroidectomy of an ectopic right parathyroid that was hypercellular on histology. The intra-operative PTH dropped following the lesion extraction by ~ 51%. Post operatively the patient’s mild pHT and hypercalcemia persists but imaging studies have been unrevealing. Further genetic testing for other possible etiologies of familial pHT were -ve for HJTs but revealed a novel somatic mutation of the CASR gene; c.1868G>A (p.Gly623Asp) whose present significance is unclear. This variant has been described in one family with FHH but In silico predictive analyses of the mutation suggests a possible deleterious effect. Given her known family history of symptomatic hypercalcemia this novel mutation appears to be a hitherto unrecognized cause for FIpHT. The patient is presently being conservatively managed and monitored. Conclusion: While familial pHT is relatively uncommon its recognition is important as it can inform planned surgical intervention and expected prognosis for anticipated cure. While MEN and HJTs are the most common etiologies for familial pHT other possibilities need to considered when the history suggests possible FIpHT and our case highlights a novel CASR mutation as diagnostic consideration.
MON-274 Analysis of Perioperative Prophylactic Steroid for Pituitary Surgery Using a National Inpatient Database in Japan
Authors: Hattori Yujiro , Tahara Shigeyuki , Aso Shotaro , Matsui Hiroki , Fushimi Kiyohide , Yasunaga Hideo , Morita Akio
Published: May 2020

BACKGROUND: There is not enough evidence regarding the need for perioperative prophylactic steroid at the time of transsphenoidal pituitary surgery [1], and it is currently administered empirically. In patients with normal preoperative adrenal function, the meta-analysis of nonrandomized studies [2] and only two randomized controlled studies [3,4] suggested no necessity to routine steroid administration, but the number of the studies subjects was small. Analysis using big data has not been performed. Therefore, this study examined the relationship between perioperative steroid administration and complications using a nationwide Diagnosis Procedure Combination database in Japan.

Method: We performed a retrospective study on patients who had undergone pituitary surgery (excluding meningiomas, Cushing’s disease, and preoperative steroid administration) between July 2010 and March 2016. To this end, a nationwide inpatient database in Japan was used, and the patients were divided into a prophylactic steroid-administered group and a nonadministered group. Patients’ complications, including hypopituitarism, diabetes insipidus, meningitis, hyponatremia, and hypokalemia, and discharge status were examined by inverse probability of treatment weighting using propensity score.

Result: A total of 7,725 inpatients received prophylactic steroids, whereas 864 did not. The inverse probability of treatment weighting using propensity score revealed that the incidence of hypopituitarism and diabetes insipidus was significantly higher in the prophylactic steroid group than in the nonsteroid group (3.5% vs. 0.5%, P 0.001 and 9.6% vs. 6.0%, P = 0.001, respectively). There were no significant differences in the incidences of meningitis, electrolyte abnormalities, and length of hospital stay.

This study using big data suggests that prophylactic steroid administration may not be necessary in patients with an intact adrenocortical function undergoing transsphenoidal pituitary surgery.

1. Fleseriu M, et al. J Clin Endocrinol Metab. 101:3888–3921 (2016)

2. Tohti M, et al. PLoS One 10: e0119621 (2015)

3. Sterl K, et al. Neurosurgery 85: E226-e232 (2019)4. Lee HC, et al. Neurosurg (2020, in press)