bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-055 A De Novo 1p13.2 Deletion Related to Short Stature, Hypothyroidism and Mild Developmental Delay
Authors: Vlachopapadopoulou Elpis Athina , Dikaiakou Eirini , Panagiotopoulos Ioannis , Papoulidis Ioannis , Manolakos Emannouil , Michalacos Stefanos
Published: May 2020

Background: Chromosomal deletions may lead to variable phenotypic alterations, depending on which loci and genes are deleted. We present the case of a boy with a de novo 1p13.2 deletion which was diagnosed by array-CGH analysis.

Clinical Case: A Greek boy, who was referred for evaluation of growth failure, was investigated. He was delivered at term by cesarean section, with normal birth weight (3.060 kg), birth length (51 cm) and head circumference (35.5 cm). There was no positive family history for short stature. Target height was on the 25th percentile. He presented with growth deceleration since the age of 12 months leading to stature lower than the 3rd percentile at the age of two years, while his weight was at the 3rd percentile. Macrocephaly was appreciated (53 cm, >95th percentile). Dysmorphic facial features resembling Noonan syndrome, such as frontal bossing, depressed nasal bridge and low-set ears were recognized. His motor development was normal. Laboratory examination revealed hypothyroidism and treatment with L-thyroxine was initiated. He had regular follow-ups at 6 months intervals. A mild delay in speech development and motor skills was appreciated. At the age of five years old, as his growth rate remained slow, growth hormone (GH) stimulation tests were performed. GH had a borderline normal peak of 9.9 ng/ml. IGF-1 levels were also within normal range (123.7 ng/ml). Magnetic Resonance Imaging (MRI) of the pituitary gland and the brain was normal. Array-CGH analysis detected a loss of approximately 800 Kb on chromosome 1p13.2; these alterations affect 8 genes in the OMIM database. The deleted segment was mapped at chr1: 115,186,092_115,977,647 region. The genomic coordinates are listed according to genomic build GRCh37/hg19. The genetic material analysis did not show the presence of a deficit in chromosomal region 1p13.2 (chr1: 115,186,092_115,977,647) in neither of the parents, indicating that this finding was created de novo.

Conclusion: We describe a patient with a Noonan like phenotype, due to a 1p13.2 deletion. In the international literature and databases of Database of Genomic Variants and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensemble Resources there are no reports of normal individuals or patients with a similar finding in chromosomal region 1p13.2. Regular follow up of the patient is needed in order to better understand the evolution of the phenotype.
OR22-06 Bone Outcomes Following Sleeve Gastrectomy in Adolescents and Young Adults with Obesity Versus Non-Surgical Controls
Authors: Misra Madhusmita , Singhal Vibha , Carmine Brian , Bose Amita , Kelsey Megan Moriarty , Stanford Fatima Cody , Bram Jennifer , Aidlen Jeremy , Inge Thomas , Bouxsein Mary L , Bredella Miriam
Published: May 2020

Background: Sleeve gastrectomy is the most commonly performed weight loss surgery in adolescents with moderate-to-severe obesity. While studies in adults have reported on the deleterious effects of gastric bypass surgery on bone structure and strength estimates, data are lacking for the impact of sleeve gastrectomy on these measures in adolescents.

Objective: To evaluate the impact of sleeve gastrectomy on bone outcomes in adolescents and young adults over 12 months using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT).

Participants and Methods: We enrolled 33 youth 14-22 years old with moderate to severe obesity; 17 underwent sleeve gastrectomy and 16 were followed without surgery. DXA was used to assess areal bone mineral density (aBMD). HRpQCT was used to assess bone geometry, microarchitecture and volumetric BMD (vBMD) and finite element analysis to assess strength estimates (stiffness and failure load) at the distal tibia and distal radius at baseline and 12 months. 25(OH) vitamin D (25OHD) levels were obtained at baseline and follow-up.

Results: The surgical group lost 28.2% of total body weight compared to 1.4% in the non-surgical group. The groups did not differ for changes in 25OHD levels (P=0.181). After controlling for age and sex, compared to the non-surgical group, the surgical group had reductions in aBMD Z-scores at the femoral neck and total hip (p≤ 0.0005). At the distal tibia, there were reductions in cortical thickness and trabecular number, and increases in trabecular separation and cortical vBMD, without changes in strength estimates in the surgical group vs. controls (p≤0.043). Changes were less marked at the distal radius. While sleeve gastrectomy resulted in deleterious effects on most bone parameters, there was an increase in cortical vBMD at both sites, possibly from a decrease in cortical porosity. Most differences were attenuated after adjusting for changes in BMI over 12 months.

Conclusions: Over 12 months, weight loss associated with sleeve gastrectomy in adolescents had deleterious effects on areal BMD, bone geometry and trabecular microarchitecture at weight-bearing sites. However, strength estimates did not decrease, possibly because of a simultaneous increase in cortical volumetric BMD. Additional research is necessary to determine the relative contribution(s) of weight loss and the metabolic effects of surgery, and whether the observed effects on bone stabilize or progress over time.
SUN-101 Support for a New Therapeutic Approach of Using a Low-Dose FGFR Tyrosine Kinase Inhibitor (Infigratinib) for Achondroplasia
Authors: Demuynck Benoit , Filipo Justine , Li Gary , Dambkowski Carl L , Legeai-Mallet Laurence
Published: May 2020

Background: Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia. Fibroblast growth factor receptor 3 (FGFR3) plays a crucial role in bone elongation, demonstrated by FGFR3 gain-of-function mutations in individuals with ACH and hypochondroplasia. Multiple therapeutic strategies have been considered for ACH, the most advanced is to employ an analog of C-type Natriuretic Peptide (CNP), which antagonizes the MAP kinase (MAPK) pathway. Here, we evaluated a therapeutic strategy that targets all pathways downstream of FGFR3 (e.g., STAT1), not just MAPK. We hypothesized that a very low dose of the oral selective FGFR1-3 tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) would be able to improve defective bone elongation. We also hypothesized that infigratinib would have greater potency at lower concentrations in an ACH cell line than a CNP analog (e.g., vosoritide) given its effects on multiple downstream pathways. Methods: A mouse model (Fgfr3Y367C/+) mimicking ACH was treated with subcutaneous injections of infigratinib daily (0.2 or 0.5 mg/kg/day) or intermittently (1 mg/kg, every 3 days) for a treatment duration of 15 days (PND1-15). In vivo results were compared with vehicle-treated mutant mice. TAN 4-18-chondrocytes, a human chondrocyte line expressing a heterozygous Y373C FGFR3 mutation, were treated with multiple concentrations of infigratinib and vosoritide and MAPK levels were measured. Results: We observed a significant improvement of the upper (humerus +7%, ulna +11%) and lower (femur +11%, tibia +16%) limbs at 0.5 mg/kg/day, and improvement in the foramen magnum. The effect of infigratinib on bone elongation was reduced with a lower dose (0.2 mg/kg), confirming a dose-response relationship. With intermittent injections of infigratinib (1 mg/kg, every 3 days), gain of growth was significant for all the long bones (+7%) and the size of the foramen magnum was increased. Modification of the growth plate structure, displaying better organization, was also seen. In cell line data, compared with FGF18-treated TAN 4-18-chondrocytes, concentrations of 10-6M to 10-10M infigratinib led to statistically significant (p<0.05) improvements. With vosoritide treatment, a concentration of 10-4M led to statistically significant improvements compared with FGF18-treated chondrocytes (p<0.05), although this was not seen at 10-5M. Conclusions: Preclinical ACH mouse model data indicate that low, as well as intermittent, doses of infigratinib promote growth and can improve the foramen magnum. No apparent toxicity of infigratinib was observed, suggesting that TKI therapy has the potential to be a valuable and relevant option for children with ACH. Furthermore, cell line data indicate that infigratinib showed superior potency over a CNP analog, suggesting that inhibition of multiple FGFR3-related pathways vs MAPK inhibition alone may lead to increased efficacy.
SUN-611 Impact of Existing Heart Failure on Outcomes of Hospitalization of Hyperosmolar Hyperglycemic State. From the National Inpatient Sample
Authors: Ahmed Fatima , Abugroun Ashraf , Elhassan Manar , Seyoum Berhane
Published: May 2020

Introduction: Patients with underlying heart failure (HF) are at increased risk for hyperosmolar hyperglycemic state (HHS). However, no studies have investigated whether the presence of existing HF would impact the outcomes of HHS. Objective: we aimed to study the impact of heart HF on outcomes of HHS among adult patients hospitalized for HHS. Methodology: The National Inpatient Sample (NIS) was queried for all patients who were admitted with a diagnosis of hyperosmolar hyperglycemic state during the years 2005-2014. The primary outcomes of the study were all-cause mortality, acute myocardial infarction (MI), acute stroke. The secondary outcomes were acute kidney injury (AKI), rhabdomyolysis, acute respiratory failure (ARF), need for mechanical ventilation (MV), length of stay (LOS), and total cost of stay. Results: Overall, 188,725 patients were admitted for hyperosmolar hyperglycemic state. Mean age was 55.9 (SEM: 0.1). Females were (43.9%), Caucasians were 37.4% while African American were 35.2%. Total mortality was 1.1%, MI was 1.3% and stroke was 1.1%. Most common secondary outcome was AKI seen in 31.3% followed by ARF seen in 2.9% of total. The mean cost was 7887 $ (SEM: 84.6) and mean LOS was 4.1 days (SEM: 0.03). Patients with heart failure had higher rates for mortality 2% vs 0.9%, p<0.001, MI 3.1% vs 1.1 % p<0.001 and stroke 1.6% vs 1%, p<0.001. In addition, they had higher rates for AKI, ARF, need for mechanical ventilation, length of stay and cost. No significant difference on risk for rhabdomyolysis. On multivariable analysis, patients with heart failure had higher odds for mortality adjusted odd’s ratio (a OR) 1.58 [95%CI: 1.15-2.17] p<0.01 and higher risk for stroke a OR 1.43 [95%CI:1.04-1.95] p=0.03. In addition, presence of heart failure significantly correlated with ARF, need for mechanical ventilation, higher cost and longer LOS. No significant association was demonstrated between heart failure and risk for Rhabdomyolysis, MI and AKI. Conclusion: Diabetic patients with heart failure who develop hyperosmolar hyperglycemic state are at higher risk for stroke and mortality and respiratory failure. Particular attention on fluid balance as well as early recognition for signs of stroke is warranted.
SUN-361 Cultured Murine Osteoblasts Convert DHEA to Testosterone
Authors: Clines Katrina L , Moon Henry H , O’Day Patrick J , Farber Charles R , Auchus Richard Joseph , Clines Gregory A
Published: May 2020

Androgens have complex effects on the skeleton. Besides gonadal testosterone (T), the adrenal produces the androgen precursor dehydroepiandrosterone (DHEA), using 3β- and 17β-hydroxysteroid dehydrogenases (3βHSD & 17βHSD) to convert to T in target tissues. Microarray analyses of murine calvarial osteoblasts, RT-PCR of long bone osteoblasts, and RNA-Seq of human bone biopsies confirmed that each of the enzyme families is expressed in osteoblasts, suggesting osteoblasts can generate androgens from the adrenal-derived androgen precursor DHEA. Activation of osteoblast androgen receptor (AR) signaling by DHEA was detected using an AR reporter construct, providing evidence that active androgens are generated. To understand how DHEA is converted to T, we treated murine primary osteoblasts with 100 nM and 1 μM DHEA, or vehicle control. Conditioned media were collected 1, 2, and 3 days after DHEA treatment and assayed for intermediate and active androgens by tandem mass spectrometry with two-dimensional chromatography. As DHEA was consumed, the androgen intermediates androstenediol (A5) and androstenedione (A4) were generated and subsequently converted to T. The peak concentrations of T generated by DHEA 100 nM and 1 μM were 22 and 101 pg/ml, respectively. The equilibrium dissociation constant of the AR for T is ~0.2 nM (57.7 pg/ml), indicating sufficient T production to activate AR in androgen-sensitive osteoblasts. Cultured osteoblasts preferentially converted DHEA to A5, via 17βHSD, rather than to A4, signifying that in the conversion of DHEA to T, 3βHSD is the rate-limiting step. Of the 13 17βHSD isoforms, 7 were expressed in these samples. In contrast, only a single gene isoform of Hsd3b—Hsd3b7—was abundantly expressed in mouse osteoblasts and human bone. We investigated the effects of 3βHSD7 in osteoblasts. An Hsd3b7 shRNA knocked-down mRNA and protein expression by >85%, and caused an osteoblast growth defect compared to an shRNA control. 3βHSD7 has known functions in bile acid synthesis, converting 7α-hydroxycholesterol to 7α-hydroxycholestenone (7HC). Treatment of Hsd3b7 knockdown osteoblasts with 7HC rescued the growth defect suggesting that osteoblasts might generate 7HC or a subsequent metabolite as a trophic factor. We now report an unreported function of bone as a source of T, by conversion of the adrenal androgen precursor DHEA, using 3βHSD7 as a common enzyme for androgen and bile acid synthesis, and leading to the activation of osteoblast AR signaling. These data suggest that the skeleton has evolved protective mechanisms against hypogonadal bone loss that exploits the continued production of adrenal DHEA. This concept is especially important in men with prostate cancer bone metastasis undergoing testicular-targeted therapies whereby adrenal DHEA may continue to fuel cancer growth, and in bone maturation during adrenarche before the pubertal rise in gonadal androgens.
SUN-522 A Case of Diabetic Ketoacidosis Associated with Thyroid Storm
Authors: Watanabe Yui , Matoba Keiichiro , Yamazaki Hiroyuki , Nishimura Rimei
Published: May 2020

Background: Thyrotoxic crisis is a rare complication of diabetic ketoacidosis (DKA). We herein report a case of DKA and subsequent thyroid storm which required emergent tracheostomy possibly due to large goiter and post-intubation obstruction.

Clinical Case: A 26-year-old woman was admitted to our emergency department complaining fever (38.2℃) and palpitation. There was no history of autoimmune disease. Physiological examination revealed tachycardia (pulse rate 164/min), tachypnea (55/min), impaired consciousness with a GCS score of 13 (E3V4M6) and goiter. Endotracheal intubation was performed. Her laboratory tests showed metabolic acidosis (pH 7.255), marked high plasma glucose of 1,672 mg/dL, elevated HbA1c of 9.2%, elevated FT3 and FT4 with suppressed TSH. She scored 55 on the diagnostic criteria for thyroid storm of Burch & Wartofsky. Based on these findings, she was diagnosed as having DKA and thyroid crisis. The patient responded well to standard treatment which involves intravenous insulin infusion with pump, correction of electrolyte disturbances, use of methimazole, as well as propranolol. Meanwhile, the patient was positive for anti-glutamic acid decarboxylase (GAD) antibody, TSH receptor antibody, as well as thyroid stimulating antibody, indicating type 1 diabetes and Graves’ disease. She underwent extubation on day 5, however, she developed wheezing around day 30. Imaging analysis demonstrated remarkable tracheal stenosis that is possibly due to large goiter and airway injury by intubation. Emergent tracheostomy was performed on day 50, because the dyspnea became progressively worse. Later, she was successfully treated by tracheal stent placement. At the follow-up period, the patient was found to be doing well, with no severe hyperthyroidism or changes in bronchoscopic findings.

Conclusion: Thyroid storm is a rare but serious complication of DKA. Our report highlights the importance of considering airway obstruction due to large goiter especially in patients with a past history of prolonged ventilation.
MON-270 Diagnostic Value of Copeptin in Central Diabetes Insipidus
Authors: Boehm Emma , Sherfan Julie , Smith Joel , King James , Wentworth John , Chiang Cherie
Published: May 2020

Background: The diagnosis of diabetes insipidus (DI) relies on indirect measurement of serum and urine sodium and osmolality. Since the diagnosis can only be made when an inappropriately dilute urine is paired with a significantly concentrated serum, the process is tedious for the clinician and uncomfortable for the patient. Copeptin is the C-terminal portion of the anti-diuretic hormone (ADH) prohormone which correlates with the less stable ADH, therefore providing a direct measurement of posterior pituitary response to hyperosmolar stress. (1,2)

Aim: This study aims to assess the diagnostic accuracy of copeptin in patients with central DI compared with subjects who underwent pituitary surgery without developing DI.

Methods: Serum samples from subjects with central DI, control subjects post pituitary surgery with no DI (NDI) and control subjects with SIADH were collected and analysed on the BRAHMS KRYPTOR copeptin assay. Groups were compared using unpaired T-test and Levene’s test for equal variance.

Results: 56 samples from 22 subjects (13 females, 9 males, mean age 53.9 ± 15.5 y.o.) were analysed. Two subjects had resolved DI (RDI) after copeptin analysis and were successfully weaned off DDAVP and reclassified as NDI. Of the DI subjects, 1 had acute and 5 had chronic DI. Copeptin was lower in DI compared to NDI group (p = 0.013), while serum sodium, osmolality, urine osmolality were similar. Copeptin did not differentiate between the SIADH and NDI groups. After exclusion of NDI samples with serum sodium ≤ 140 mmol/L, the area under the curve was 0.97 (95% CI 0.9 to 1.0), a copeptin cut-off of 2.9 pmol/L predicts DI with a sensitivity of 92% and a specificity of 90%.

Conclusion: Copeptin concentration of < 3.0 pmol/L concurrently with serum sodium concentration of > 140mmol/L predicted central DI when using post pituitary surgery subjects without DI as controls.

1. Winzeler, B., Zweifel, C., Nigro, N., Arici, B., Bally, M., Schuetz, P., Blum, C., Kelly, C., Berkmann, S., Huber, A., Gentili, F., Zadeh, G., Landolt, H., Mariani, L., Müller, B. and Christ-Crain, M. (2015). Postoperative Copeptin Concentration Predicts Diabetes Insipidus After Pituitary Surgery. The Journal of Clinical Endocrinology & Metabolism, 100(6), pp.2275-2282.

2. Fenske, J., Refardt, I., SchnyderI., Winzeler, B., Drummond J., Ribeiro-Oliveira, Jr. A., Drescher, T., Bilz S., Vogt, D.R., Malzahn, U., Kroiss, M., Christ, E., Henzen, C., Fischli S., Tönjes, A., Mueller, B., Schopohl, J., Flitsch, J., Brabant, G., Fassnacht M., Christ-Crain, M. (2018). Copeptin in the Diagnosis of Diabetes Insipidus. New England Journal of Medicine, 379(18), pp.1784-1786.
MON-672 Progesterone Receptor Membrane Component 1 Suppresses Lipid Accumulation and Lipotoxicity in Animal Model of Diabetic Cardiomyopathy (DCM)
Authors: Lee Sang R , Hong Eui-ju
Published: May 2020

Diabetic cardiomyopathy (DCM) is one of the complications triggered by type II diabetes (T2D) (1). When free fatty acids (FFA) are abundant in insulin resistant pre-diabetic patients because of adipose lipolysis, FFA tends to move toward heart (2). Lipid accumulation can cause cardiac lipotoxicity and exacerbate DCM (3). In previous study, Pgrmc1 has been identified to associate with fatty acid synthesis (4). Therefore, we assumed that Pgrmc1 will associate with DCM. By feeding high-fat diet for 8 weeks and injecting streptozotocin (30mg/kg), T2D and DCM were induced. The lipid accumulation was exacerbated in T2D-induced Pgrmc1 KO heart, and FFA level was also high. Levels of lipid metabolic genes showed the tendency for lipid accumulation and lipotoxicity, and glycolysis was induced in T2D-induced Pgrmc1 KO heart. Though glycolysis presents higher efficiency for energy production in cardiomyopathy (5), it did not compensate the impairment of mitochondrial respiration in Pgrmc1 KO heart. High-fat diet and streptozotocin could not be the interfering factors, because suppression of fatty acid oxidation, induction of glycolysis, and impairment of mitochondrial respiration were observed similarly in post-prandial mice which were fed with normal chow. Insulin was excluded for interfering factor as cell line with serum starvation showed mitochondrial suppression and glycolytic induction in flux analyzer analysis in Pgrmc1 knockdown. Conversely, induction of fatty acid oxidation and suppression of glycolysis were observed in 72 h fasting of Pgrmc1 KO heart, suggesting the nutrition is closely associated with the metabolic modulation of Pgrmc1 on heart. This metabolic phenotype of Pgrmc1 KO heart consequently exacerbated DCM by showing high levels of fibrosis, inflammation, endoplasmic reticulum stress, and oxidative stress.

References: (1) Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circulation research. 2018;122:624-38. (2) Noll C, Carpentier AC. Dietary fatty acid metabolism in prediabetes. Current opinion in lipidology. 2017;28:1-10. (3) Goldberg IJ, Trent CM, Schulze PC. Lipid metabolism and toxicity in the heart. Cell metabolism. 2012;15:805-12. (4) Lee SR, Kwon SW, Kaya P, Lee YH, Lee JG, Kim G, et al. Loss of progesterone receptor membrane component 1 promotes hepatic steatosis via the induced de novo lipogenesis. Scientific reports. 2018;8:15711. (5) Nagoshi T, Yoshimura M, Rosano GM, Lopaschuk GD, Mochizuki S. Optimization of cardiac metabolism in heart failure. Current pharmaceutical design. 2011;17:3846-53.
SAT-164 Pattern and Spectrum of Adrenal Disorders Seen Among Adults in Southern Iraq. A Tertiary Center Experiences
Authors: Mansour Abbas Ali , Ali Alhamza Ali Hussain , Abdullah Almomin Ammar Mohammed Saeed , Zaboon Ibrahim Abbood , Alibrahim Nassar Taha Yaseen , Hussein Rudha Naser , Kadhim Muayad Baheer , Mohammed Adel Gassab , Al-Waeli Dheyaa Kadhim Jabbar , Nwayyir Hussein Ali , Alidrisi Haider Ayad Yassin , Hussein Ibrahim Hani , Odhaib Samih Abed , Altemimi Mahmood Thamer Jallod , Imran Husam Jihad
Published: May 2020

Background: Adrenal disorders is rare life-threatening conditions needed high awareness for earlier diagnosis. The aim of this study is to see the pattern and spectrum of adrenal disorders in Southern Iraq.

Methods: Retrospective electronic database analysis of Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah, the largest tertiary referring Center in the Southern Iraq. Only adults 18 years and above analysed.

Results: The total referred patients for presumed adrenal disorders were 5064(6%) of 83473 new patients seen over 11 years for the period of August 2008 to August 2019.The commonest adrenal disease were due to glucocorticoids misuse in 2407/5064 (47.5%),followed by adrenal endocrine hypertension in 883/5064 (17.4%),than adrenal insufficiency in 340/5064 (6.7%), hirsutism in 264/5064 (5.2%), hypopituitarism 85/5064 (1.6%) and congenital adrenal hyperplasia in 78/5064 (1.5%).Rare causes of adrenal disorder were primary aldosteronism in 30/5064 (0.5%), Addison disease in 26/5064 (0.5%), pheochromocytoma in 19/5064 (0.4%), autoimmune polyendocrine syndromes in 19/5064 (0.4%), ACTH independent Cushing syndrome in 17(0.3%), ACTH dependent Cushing syndrome in 4(0.07%), subclinical Cushing syndrome in 4(0.07%), ectopic ACTH syndrome in 1(0.01%), adrenal cyst in 9(0.1%), adrenal myelolipoma in 5(0.09%), adrenocortical carcinoma in 3(0.05%),and paraganglioma in 2(0.04%).One of the paraganglioma were secretory. Patients characteristics for those with glucocorticoids misuse showed that female forming the bulk of cases in 1708/2407 (70.9%), and mean age of 39.5±12.3 years. Urban constitutes 1306/2407 (54.3%),and 629/2407 (26.1%) were illiterates. There were 706/2407 (29.3%) with established type 2 diabetes mellitus(with all the risks of loss of glycemic control) and glucocorticoids misuse causes 105/2407 (4.3%) incident diabetes.

Conclusion: Glucocorticoids misuse constituted the bulk of referral for adrenal disorders in Basrah. A lot of work needed to reduce the prevalence of this new high-risk iatrogenic disease.
SUN-084 A Quantitative-PCR Based Rapid and Cost-Effective Diagnostic Method for Turner Syndrome and Its Variants
Authors: Mondal Sunetra , Saha Chinmay , Bhattacharyya Nitai P , Mukhopadhyay Satinath
Published: May 2020

Turner’s syndrome (TS) is a common aneuploidy diagnosed by peripheral blood karyotyping in patients. Karyotyping involves manual labour, time and costs. Quantitative real-time PCR (qPCR) is a rapid molecular diagnostic test for TS that yields results of upto 48 samples within two hours at low cost with reasonable accuracy. To assess the sensitivity and specificity of qPCR in the rapid diagnosis of TS, genomic DNA was isolated and estimated from peripheral blood from 50 TS patients(45,XO-23, XO/XX mosaics - 10, Isochromosome Xq-12, XO/XY mosaics - 5), 25 normal females(46,XX) and 5 normal males(46,XY). qPCR was done using 96 well plates, fast real-time PCR. 4 primers were used - two on Xp [SHOX and ARSE] and two on Xq (VAMP7 and XIST). Autosomal gene HBB was used as housekeeping gene. The ΔΔ CT method was used for calculation of the ‘X gene dose’ with respect to the housekeeping gene and X genes from normal females. Differences of doses of the four X-chromosomal primers in different karyotypes were analysed. ROC curves were plotted to determine cut-offs to discriminate the different karyotypes of TS from normal females. qPCR could distinguish classical TS from normal females with >95% sensitivity and specificity. SHOX gene primer was the best to diagnose TS of all karyotypes combined and also classical TS(XO) from normal females. qPCR could also identify non-classical TS with >92% sensitivity and specificity,the best primer being ARSE, for detecting both mosaics and isochromosomes. The cut-offs determined from our study corroborates with past similar studies.1,2 qPCR using an appropriate panel of primers on the short and long arms of X chromosomes can be a rapid and cheaper alternative to karyotyping to diagnose TS of different karyotypes. The choice of primers should be guided by the need for a more sensitive or specific test depending on the clinical scenario. If used as a neonatal screening test, SHOX should be the best primer. For diagnostic purposes, when the pre-test probability is low, a more specific primer like SHOX would be more appropriate. However, when the pre-test probability is high, a sensitive primer for ruling out TS like VAMP7 is better. In case there is a high pre test probability of the patient having a non-classic TS rather than classic TS, ARSE should be used. This is the first study to show good sensitivity of qPCR in detecting non-classic TS of different karyotypes in addition to classic TS. References: 1. Ibarra-Ramírez M, Martínez-de-Villarreal LE. Clinical and genetic aspects of Turner’s syndrome. Medicina universitaria. 2016 Jan 1;18(70):42-8. 2 .Rocha MN et al. Applicability of real-time PCR methodology in the neonatal detection of Turner syndrome. Hormone and metabolic research. 2010 Aug;42(09):677-81.
SUN-239 Effects of High-Fat Diet-Induced Obesity on Pulsatile LH Secretion and Hypothalamic KISS1 Expression in Female Rats
Authors: Minabe Shiori , Iwata Kinuyo , Watanabe Youki , Ozawa Hitoshi
Published: May 2020

Female obesity is associated with menstrual dysfunction leading to anovulation and infertility. It has recently been reported obesity-induced infertility is involved in the dysfunction of a kisspeptin neuron, a key player in reproduction via direct stimulation of gonadotropin releasing hormone (GnRH) and subsequent gonadotropin release in mammalian species. Previous studies reported that obesity due to high-fat diet (HFD) for 8 months induced a disruption in estrous cyclicity, caused by a decrease in Kiss1 (coding kisspeptin) expression in the hypothalamic arcuate nucleus (ARC) in female rodents. Here we showed the effects of shorter-term (4 months) HFD on pulsatile LH secretion and hypothalamic Kiss1 expression to show pathogenic mechanism underlying obesity-induced infertility. Female Wistar-Imamichi strain rats (7 weeks old) fed on either a standard diet (10% calories from fat) or a high-fat diet (45% calories from fat) for 4 months. Estrous cyclicity and body weight were monitored regularly. All animals were implanted with a jugular catheter and collected blood samples to analyze pulsatile LH secretion, after a week of the ovariectomy with low-dose replacement estradiol to negate influence of changes in ovarian steroid levels and mimic diestrous levels of plasma estrogen. On the next day of the blood sampling, rats were perfused with 0.05 M PBS followed by 4% paraformaldehyde and their brains were collected for in situ hybridization of Kiss1 and Gnrh1. The HFD-fed rats showed progressive increases in body weight, along with hyperphagia and adipose tissue accumulation, compared with control animals. Fifty-eight percent of the HFD-fed rats exhibited irregular estrous cycles, whereas remaining HFD-fed rats showed regular cycles. Two out of 7 rats showing HFD-induced irregular estrous cycles exhibited profound suppression of the LH pulse frequency and the number of Kiss1-expressing cells in the ARC, whereas remaining HFD-fed rats showed normal LH pulses and ARC Kiss1 expressions. The number of Kiss1-expressing cells in the ARC had close positive correlation with LH pulse frequency (R2=0.6872, P<0.001) in both groups. Additionally, the number of Kiss1- or Gnrh1-expressing cells in the anteroventral periventricular nucleus or the preoptic area, were comparable between groups. Taken together, our finding reveals the possibility that irregular menstruation was also induced by changes in the kisspeptin-GnRH independent pathway during the incipient stage of obese infertility.
SAT-187 Altered Mental Status in a Patient with Bilateral Adrenal Masses
Authors: Mathews Sherin Elsa , Castellanos-Diaz Jessica , da Silva Alexis , Donahoo William Troy , Ghayee Hans Kumar , Barb Diana
Published: May 2020

Introduction

Primary adrenal lymphoma (PAL) is a very rare and aggressive form of Non-Hodgkin’s lymphoma originating from the adrenal glands and with no prior history of lymphoma. It can present with symptoms related to adrenal insufficiency due to tumoral destruction of normal adrenal tissue. Hypercalcemia has also been previously reported as a less common presentation of PAL. We describe here a case of PAL presenting with severe hypercalcemia and adrenal insufficiency.

Clinical Case

75 year male presented with 50 pound weight loss, fatigue and anorexia for several months. On admission, patient had altered mental status. Further investigation revealed severe hypercalcemia (corrected calcium for albumin =15mg/dl) and AKI (serum creatine=3.45mg/dl, blood urea nitrogen=89). He was started on IV fluids for the hypercalcemia and AKI. Additional work up revealed suppressed parathyroid hormone (PTH) levels of 9 (12 - 88 pg/mL), high normal PTH-related peptide 22 (14-27), low 25-OHD 7.34 (20-120 ng/ml), high normal 1,25-(OH)2-D 63.0 (19.9-79 pg/mL). His ACTH level was elevated ~159 (7.2-63.3 pg/ml) with low normal morning cortisol levels ~10 mcg/dl. Patient was started on IV stress dose steroids for concerns of adrenal insufficiency and calcitonin was also initiated for the treatment of hypercalcemia. CT of the abdomen showed bilateral adrenal masses, measuring 9.8 x 6.4 x 10.8 cm on the right and 9.3 x 5.2 x 9.6 cm on the left with marked retroperitoneal lymphadenopathy. After ruling out pheochromocytoma with negative plasma and urine metanephrines, biopsy of the adrenal mass revealed a highly aggressive diffuse B large cell lymphoma, with BCL2 and MYC overexpression. Concurrent flow cytometric analysis also identified an abnormal population of medium to large B cells expressing bright CD20, CD19, CD38, CD45 without CD10, CD5, CD23 or overt kappa or lambda expression. His calcium levels improved with hydration and steroids. Chemotherapy was later initiated.

Conclusion

Primary adrenal lymphoma is rare and aggressive type of NHL. While adrenal insufficiency is expected in this clinical scenario, hypercalcemia from 1,25-(OH)2-D excess is a relatively uncommon presentation. Adrenal insufficiency should be ruled out in bilateral infiltrative adrenal masses. Likely etiologies for hypercalcemia in our case appeared to be secondary to elevated 1,25-(OH)2-D production, humoral hypercalcemia of malignancy and worsened by untreated clinically evident adrenal insufficiency.

References

(1) Laurent C, Casasnovas O, Martin L, et al. Adrenal lymphoma: presentation, management and prognosis. QJM. 2017 Feb 1;110(2):103-109. doi: 10.1093/qjmed/hcw174

(2) Masood A, Tumyan A, Nussenzveig D R., Wakefield D N., Barb D, Ghayee H K., Maalouf N M. The Diverse Clinical Presentations of Adrenal Lymphoma. AACE Clinical Case Reports: Autumn 2017, Vol. 3, No. 4, pp. e307-e312. doi: 10.4158/EP161595.CR
MON-218 Clinical and Genetic Aspects of Pediatric Pheochromocytomas and Paragangliomas
Authors: Petenuci Janaina , Guimaraes Augusto , Benedetti Anna Flavia Figueredo , Fagundes Gustavo Freitas Cardoso , Pereira Maria Adelaide , D’Eur Joya Emilie Correa , Zerbini Maria Claudia , Siqueira Sheila , Yamauchi Fernando , Soares Silvia , Srougi Vitor , Tanno Fabio Y , Chambo Jose L , Denes Francisco T , Hoff Ana O , Latronico Ana Claudia , Mendonca Berenice Bilharinho , Fragoso Maria Candida B V , Almeida Madson Q
Published: May 2020

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin cells. At least 30% of PPGL patients have hereditary predisposition. PPGLs in children are more often hereditary, multiple and extra-adrenal. To date, more than 14 tumor-susceptibility genes have been reported: Cluster 1 or hypoxic (VHL, SDHB, SDHD, SDHC, SDHA, SDHAF2, FH, ENGL1 and HIF2A) and cluster 2 (RET, NF1, TMEM127 and MAX). The aim of this study was to evaluate clinical and molecular aspects of a Brazilian cohort of pediatric patients with PPGLs. Out of 262 patients with PPGLs, 26 (9 %) were diagnosed before 19 yrs of age (16 males and 10 females), with a median age of 14.5 yrs (range, 4 to 18). Genetic investigation was performed in 19 patients: 14 by automated Sanger sequencing (VHL, SDHB, SDHD and RET genes) and 5 by a custom next-generation sequencing (NGS) panel including all genes previously associated with germline mutations in PPGLs. Median tumor size was 5.5 cm (1.7 to 16). Pheochromocytomas (PHEOs), paragangliomas (PGLs) or both were diagnosed in 46%, 31% and 23% of the patients, respectively. Bilateral PHEOs were diagnosed in 61% of the cases, most of them asynchronous (75%). Genetic diagnosis was confirmed in 14 out of 19 (74%) patients and all variants were found in heterozygous state: 8 VHL missense mutations from 6 kindreds (p.R167W in 2 kindreds, p.R167Q in one and p.G114S in 3); 3 SDHB mutations (p.C98Y, c.201-2A>G and p.L180L); 2 SDHD mutations (p.Y144_H145del and p.Q121*); and one RET mutation (p.C634R). All 8 VHL patients had bilateral PHEOs and 3 of them had also abdominal PGLs. All patients with SDHB mutations had abdominal PGLs. Two patients with SDHD mutation had head and neck paraganglioma (one of them had unilateral PHEO). Genetic investigation by NGS Panel was negative in all 5 cases: 2 malignant PPGLs (one PHEO and one PGL) and 3 PHEOs. Four out of 26 (15%) pediatric PPGLs were malignant: 2 with SDHB mutation and 2 with negative screening (one PHEO and one PGL). In conclusion, the majority of pediatric PPGLs (74%) were hereditary and almost exclusively caused by mutations in hypoxic genes. VHL (PHEOs) and SDHB (only PGLs) were the most frequent affected genes in this cohort of pediatric PPGLs. Support: CAPES grant to Petenuci J.
SUN-668 Elevated Osmolal Gap in Long-Term Complication of Type 2 Diabetes
Authors: Klimek Monika , Wojtysiak-Duma Beata , Duma Dariusz , Solski Janusz
Published: May 2020

Osmolal gap (OG) is the difference between the measured osmolality and calculated osmolality estimated by using the mathematical equation. Elevated OG indicates the presence of osmotically active particles undetected in the plasma of healthy individuals. Elevated OG has been observed in multiorgan trauma as a useful prognostic factor of patient survival [1, 2]. We hypothesized that elevated OG may occur in patients with type 2 diabetes (T2D) and may become a useful indicator of unmeasured endotoxins. One of the major mechanisms of this phenomenon may be non-enzymatic glycation of proteins in hyperglycemia, in which the osmotic active carbonyl compounds such as glyoxal, methylglyoxal, and 3-deoxyglucosone, are formed. Testing was performed for participants with T2D, aged 18 to 85. The osmolality measurement was performed with venous blood using the osmometer. The concentration of individual osmols (sodium, potassium, glucose, urea) was determined and on this basis, osmolality was calculated using the Dorwart-Chalmers formula: osmolality (mOsm/kg H2O) = 1.86 x [Na+] + glucose + urea + 9 (Dorwart, 1975). The clinical profile of patients was established based on history and physical examination (age, sex, age, duration of T2D, complications of T2D, HbA1c, LDL-cholesterol, triglyceride, BMI, coexisting diseases, medication). Data were analyzed using descriptive statistics. This study is currently ongoing, but preliminary data from the pilot study suggest an increased mean measured osmolality as well as elevated OG in patients with T2D compared to the reference values for healthy adults. These values differed depending on the type of long-term complications and the duration of the disease. In the pilot study, the highest OG was reported in diabetic retinopathy. A follow-up study with a larger sample may have a better ability to detect the statistical significance of the association of OG and complications of T2D. The association of the osmolal gap and complication of type 2 diabetes is poorly understood, and further investigation is warranted.

References:

[1] Inaba, H., Hirasawa, H., Mizuguchi, T. (1987), Serum Osmolality Gap In Postoperative Patients In Intensive Care. Lancet, 329 (8546): 1331-1335.

[2] Hirasawa, H., Odaka, M., Sugai, T., Ohtake, Y., Inaba, H., Tabata, Y., Kobayashi, H. and Isono, K. (1988), Prognostic Value of Serum Osmolality Gap in Patients with Multiple Organ Failure Treated with Hemopurification. Artificial Organs, 12: 382-387.
MON-711 Induction of Apolipoprotein A1 Gene Expression by the Rare Sugar Allulose
Authors: Parekh Shrina
Published: May 2020

Apolipoprotein A-I (apo A-I) is the primary protein component of high-density lipoprotein (HDL) and has many well documented properties which promote cardiovascular health. However, clinical trials designed to increase HDL levels by preventing its catabolism have failed in their primary endpoints in decreasing the risk of cardiovascular disease. Alternative strategies to increase de-novo apo A-I production may be more attractive. We recently demonstrated that the rare sugar allulose decreases oxidative stress and endoplasmic reticulum stress in both endothelial cells and hepatocytes. During these studies we demonstrated that allulose also induces apo A-I secretion by HepG2 cells. Apo A-I, albumin, and SP1 levels were measured by Western blot. Apo A-I and glyceraldehyde-3-phosphate (GAPDH) mRNA levels were measured by quantitative real-time polymerase chain reaction. The effect of allulose on apo A-I promoter activity was measured using transient transfection assays with several plasmids containing various segments and mutations in the apo A-I gene promoter. Apo A-I protein and mRNA levels in cells treated with allulose increased more than two-fold in a dose-dependent manner. These changes were due to the ability of allulose to induce apo A-I gene promoter activity. Using a series of deletion constructs, an allulose-response element was identified in the apo A-I gene promoter which was previously shown to confer induction of apo A-I gene expression by insulin and epidermal growth factor (EGF), the insulin response core element (IRCE). Mutation of the IRCE decreased the ability of allulose and insulin to induce apo A-I promoter activity. Allulose treatment also increased expression of the transcription factor SP1, which had been shown previously be essential for the effects of insulin and EGF on apo A-I promoter activity. In conclusion, allulose increased apo A-I gene expression in HepG2 hepatocytes. This effect was mediated by the IRCE in the apo A-I gene promoter and the transcription factor SP1. The rare sugar allulose may have novel anti-atherogenic properties, in part, by increasing HDL levels.
SUN-902 Bradycardia as a Presentation of Malignant Pheochromocytoma
Authors: Saleem Marwa , Vargas-Jerez Julia , Zahra Tasneem
Published: May 2020

Introduction

Pheochromocytoma usually presents with tachycardia, hypertension and other symptoms related to catecholamine release. Bradycardia has been reported in up to 10% of patients and is due to an unusual reflex to cathecolamine surge.

Case Report:

57-year-old morbidly obese female with a history of COPD, hypertension, paroxysmal bradycardia, and urinary incontinence was referred to endocrinology clinic after an adrenal mass was found incidentally as part of a work-up for microscopic hematuria and urinary incontinence. CT abdomen showed unilateral 3.3 x 3.9 cm left lobular adrenal mass. Family history was negative for malignancies or pheochomocytoma. Patient denied substance abuse or ethanol use. Her medications include amlodipine, hydrochlorothiazide and albuterol. Physical exam was remarkable for a BMI of 51.6 and bradycardia of 50 bpm and well controlled blood pressure. On further review of her history, patient had prior visits to outpatient and emergency department for chronic headaches, insomnia, palpitations and sweating. Patient had a previous admission 13 years prior for chest pain and hypertensive urgency associated with headache and junctional bradycardia.

Laboratory workup was significant for serum metanephrine levels of 749 pg/ml (normal <42), serum normetanephrine 185 pg/ml(normal <145), serum chromogranin A 130 ng/L(normal <39) and 24hr urine metanephrine of 1340 ug/24hr (normal <96) and urine normetanephrine of 357 ug/24hr (normal <80). Previous ECG showed sinus bradycardia. Echo-cardiogram revealed normal ejection fraction with left atrial enlargement.

MIBG showed large focal area of intense radio-tracer accumulation in left mid abdomen and small focal lesions in the liver. Diagnosis of malignant pheochromocytoma was made and patient was referred to another institution for further management.

Conclusion:

Malignant pheochromocytoma is a rare neuroendocrine tumor that usually presents with tachycardia and hypertension. 10% of patients with malignant pheochromocytoma can debut with bradycardia due to sinus arrest. Although malignant and benign pheochromocytoma share the same clinical and histological features, the presence of metastasis is the main clue to differentiate them. Surgery remains the main treatment option even if complete debulking cannot be achieved. Nuclear radiation therapy or chemotherapy are two other therapeutic options that can be considered alone or in combination with surgery depending on the patients’ comorbidities. Lifetime surveillance is recommended as recurrence can occur up to 40 years after original resection.

References -Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010 Aug;39(6):775-83.
SAT-374 The Many Faces of Parathyroid Carcinoma in the Philippines: A Case Series
Authors: Encarnacion Margaret C , Ramos Celeste O , Aquino Eduardo Thomas M , Mirasol Roberto C , Villa Michael L
Published: May 2020

Introduction: Parathyroid carcinoma is rare, affecting less than 1% of patients with primary hyperparathyroidism (PHPT). 1 Parathyroid carcinoma with concomitant papillary thyroid carcinoma is also rare, and the etiology is not fully defined.

Clinical Case: We present 3 patients with parathyroid carcinoma and discuss their presenting symptoms, characteristics, and treatment. Two women and 1 man (2 Filipinos and 1 Marshallese) with age range 53-68 years old had parathyroid carcinoma. Two had primary hyperparathyroidism, one had non-functioning type of parathyroid carcinoma. Two had concomitant bone or renal disease. All three had concurrent thyroid disease- 2 had papillary thyroid microcarcinoma, one had colloid goiter. Because each one had different indications for neck surgery, different surgical techniques were done. Parathyroid cancer size ranged from 2.0-5.2 cm, with capsular and vascular invasion in all three. One case had double parathyroid carcinoma. No lymph node metastasis was identified. On follow up, the patient with the largest tumor size had tumor recurrence within 1 year from surgery.

Conclusion: To the best of our knowledge, this is the first case series on parathyroid carcinoma in the Philippines, and includes the 7th case of double parathyroid carcinoma worldwide. Parathyroid carcinoma is a rare condition, and coupled with its highly variable presentation, as seen in the 3 cases, presents clinicians with a difficulty in arriving at a diagnosis. Histopathology remains the gold standard in diagnosis and is a key in guiding management. Since coexisting thyroid and parathyroid disease may occur, thyroid pathology should be evaluated in the presence of PHPT.

References:

1. Elizabeth Shane; Parathyroid Carcinoma, The Journal of Clinical Endocrinology & Metabolism, Volume 86, Issue 2, 1 February 2001, Pages 485-493, https://doi.org/10.1210/jcem.86.2.7207.