bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT-077 Two Cases of Hypoparathyroidism Due to Activating Calcium Sensing Receptor Mutation
Authors: Badran Ahmed , Chin Vivian 
Published: May 2020

Abstract
Introduction
The extracellular calcium-sensing receptor (CaSR) expressed mainly in the parathyroid gland and kidneys regulates calcium (Ca+2) homeostasis through parathyroid hormone (PTH) secretion. Activating mutations of CaSR can lead to autosomal dominant hypocalcemia and severe congenital hypoparathyroidism. Constitutively activated CaSR receptors blocks PTH release leading to hypocalcemia, hyperphosphatemia and decreased Ca+2 reabsorption from the kidney.
Case 1:
14 year old male presented for an evaluation of hypocalcemia and hyperphosphatemia found on routine blood work. He denied symptoms of hypocalcemia. He had normal vital signs, positive Chovstek sign but rest of exam was unremarkable. His lab results showed low Ca+2 8.1 mg/dl (8.6–10 mg/dl), high phosphorus 6 mg/dl (2.7–4.5 mg/dl) and inappropriately normal PTH 26.8 pg/ml (10–65 pg/ml). FISH was negative for DiGeorge. Genetic testing showed heterozygous CaSR gene mutation I822T, variant of uncertain significance. His father with primary hypoparathyroidism has the same CaSR gene mutation; mother is healthy and tested negative for this variant. Given the inheritance pattern of the mutation, it is likely a pathologic mutation. He is maintained on Calcium (1500 mg BID) and Calcitriol (0.5 mcg PO BID) and is doing well.
Case 2:
One day old premature 32-week old infant girl was found to have early onset neonatal hypocalcemia 6.1 mg/dl (6.2–11 mg/dl) during NICU admission for respiratory distress, inappropriately normal PTH 18.5 pg/ml and high phosphorus 8.8 mg/dl (4.6–7.9 mg/dl). She had no symptoms of hypocalcemia in the NICU or at home. She did not have any dysmorphic features. FISH was negative for DiGeorge. Genetic testing to sequence genes including AIRE, AP2S1, CASR, GNAS, HADHA, HADHB, PTH1R, SOX3, STX16, TBCE was done and revealed a novel heterozygous mutation in the CaSR gene for a missense variant c.2495T&gt;C
(p.lle832Thr) and STX16 c.644A&gt;T, possibly benign variant. Unfortunately, the parents have not consented to testing yet. Further familial and functional characterization of this new variant is necessary to confirm its possible pathogenetic role in this hypocalcemic patient. Currently she is maintained on ergocalciferol 800 IU, calcitriol 0.25 mcg and sevelamer 3 packets daily and is doing well.
Conclusion:
In the workup for primary hypoparathyroidism without dysmorphic features and tests negative for DiGeorge, CaSR mutations should be investigated as part of the differential as we have identified variants in the CaSR gene in 2 children with asymptomatic hypocalcemia, one of which is a novel mutation which has never been reported before.
SAT-057 A Novel IGSF1 Variant in a Boy with Central Hypothyroidism and Epiphyseal Dysplasia
Authors: Laurenzano Sarah , Bird Lynne , Demeterco-Berggren Carla 
Published: May 2020

Abstract
Background: IGSF1 deficiency syndrome, also known as X-linked central hypothyroidism and testicular enlargement (CHTE) syndrome, is caused by mutations in the immunoglobulin superfamily, member 1 gene. Recently recognized as the most common genetic cause of isolated central hypothyroidism (CH), its cardinal features include CH and adult macroorchidism. We describe a boy with CH and epiphyseal dysplasia found to have a novel IGSF1 variant.
Clinical case: A male with attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, obsessive compulsive disorder and obesity was evaluated at age 9y for high total and LDL cholesterol and low T4 with normal TSH. He had short stature for family, high BMI, high sitting height ratio, and short arm span. Laboratory investigation revealed persistently mildly high total and LDL cholesterol, low T4, normal cortisol response to low-dose Cortrosyn stimulation, and normal IGF-1 and IGF-BP3. Bone age at 9y1m chronological age was 8y0m. Skeletal survey showed abnormal epiphyses of the femoral heads, knees, and humeral capitella suggesting primary epiphyseal dysplasia; he was referred to genetics. Growth improved after starting levothyroxine for CH. Multiple epiphyseal dysplasia gene panel (with reflex to clinical exome) did not find any variants known to be pathogenic for his condition. He was found to be a carrier of autosomal recessive Bartter syndrome. Heterozygous variants of unknown significance were found in RMRP, FGFR1, CDT1 and APOB. Whole exome sequencing showed hemizygosity for the p.Q743X (c.2227C&gt;T) variant in IGSF1.
Discussion: The p.Q743X IGSF1 variant has not been reported in the literature and is not present in population databases. It is predicted to cause loss of normal protein function and is considered pathogenic. CH is found in all males with IGSF1 deficiency syndrome. Macroorchidism, another defining feature, develops in adulthood; age of testicular growth onset is normal, but pubertal testosterone rise is delayed. Our patient remains prepubertal at age 11y. Other features sometimes present include hypoprolactinemia (which was found in this child) and transient partial GHD (not seen in this case). Overweight and the metabolic syndrome are common; this child’s cholesterol abnormalities may be due to weight and/or APOB variant found on genetic testing. ADHD has been seen in some patients with this syndrome; this child also has extensive psychiatric/behavioral problems, which have not been described. The skeletal findings in this case have not been previously noted in IGSF1 deficiency syndrome; whether this is a rare feature of IGSF1 deficiency syndrome or a separate entity is unclear. This case adds to the growing list of disease-causing variants in IGSF1. Endocrinologists should consider IGSF1 deficiency syndrome when diagnosing isolated CH in boys, as the characteristic macroorchidism is not present in childhood.
SUN-309 Interleukin-2 Administration in Healthy Men Activates Cortisol Secretion in an Age-, Dose-, and Body Composition-Dependent Way
Authors: Roelfsema Ferdinand , Liu Peter Y , Yang Rebecca , Takahashi Paul , Veldhuis Johannes D 
Published: May 2020

Abstract
Context. Interleukin-2 (IL2), a proinflammatory cytokine, is used for treatment of malignancies. Increased cortisol and ACTH were noted, but not investigated in detail. This is the first study in healthy men which uses moderate high IL2 doses as used in cancer treatment.
Objective. The goal of this study was to quantify cortisol secretion after a single sc injection of IL2 at 1900 h in young and older healthy men in relation to dose, age and body composition. Design. This was a placebo-controlled, blinded, prospectively randomized cross-over study in 17 young subjects (mean age 24.1 yr, range 19–30 yr) and 18 older subjects (mean age 63.9 yr, range 60–75 yr). The subjects underwent 24 h of blood sampling at 10-min intervals, starting at 1800 h. At 2000 h IL2 (3 or 6 million units per m2 body surface) or saline was injected sc. Lights were off between 2300 and 0700 h.
Setting. The study was performed in a Clinical Translational Research Unit.
Outcome measures. Mean concentrations of cortisol, deconvolution analysis, and approximate entropy. Abdominal visceral fat (AVF) and total abdominal fat (TAF) were calculated from single slice CT.
Results. Cortisol concentrations started to rise at 2300 h. The AUC’s during the lights-on periods were unchanged by IL2. Therefore, most analyses were restricted to the 8 h lights-off period. In young volunteers pulsatile cortisol secretion increased from 52.9±5.8 to 77.0±8.0 µg/L/8h and in older subjects from 60.6±3.8 to 70.6±4.6 µg/L/8h (GLM: treatment P &lt;0.0001, treatment x age: P=0.02, mean ± SEM). Thus, the effect was smaller in older subjects. Increasing the IL2 dose increased cortisol secretion in young subjects (P= 0.001), but not in older subjects (P=0.90). In addition, the slopes (mean ± SE) of the linear part of the concentration curves after IL-2 were steeper than after placebo, pointing to accelerated release (young 1.40±0.13 to 3.76±0.11, P&lt;0.0001, in older 1.27±0.04 to 3.28±0.15, P&lt;0.0001).The incremental nocturnal pulsatile cortisol secretion after IL2 was negatively related to body composition (AVF: R= ̶ 0.41, P=0.019; TAF R= ̶ 0.41, P=0.043). Nocturnal ApEn-cortisol did not increase after low dose IL2 (0.981± 0.099 to 0.991±0.046, P=0.92). After high-dose, ApEn increased from 0.877±0.041 to 1.024±0.049, P=0.008, not correlated with body composition, nor with age. The ApEn increase points to decreased secretory regularity imposed by enhanced CRF signaling, rather than diminished cortisol feedback, which leads to greater secretory regularity.
Conclusion. Il2, a paradigm for inflammation, increased pulsatile cortisol secretion, more in young than in older subjects. Higher IL2 doses in young subjects amplified cortisol secretion, but not in older subjects. Cortisol secretion exhibited an advance (earlier) time shift, accompanied by accelerated secretion. Incremental nocturnal cortisol secretion was negatively related to fat mass.
SUN-642 Paracetamol May Increase Cardiac Congenital Malformations Risk in Prediabetic Pregnancy Women
Authors: Guerrero Juan Ariel Jara 
Published: May 2020

Abstract
ABSTRACT
Hyperglycemia can influence the development of the fetal heart, affecting both its structure and its function. Prospective and retrospective cohort studies have demonstrated an increased risk of congenital abnormalities with gestational diabetes. This observation is probably related to the inclusion of women with unrecognized type 2 diabetes (Allen, 2007, Pasarella, 2013).
Substantial literature indicates that diabetes in pregnant rats and mice induces embryo lethality, growth retardation, and a variable incidence of birth defects. Then, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy.
Acetaminophen overdose is the most often cause of acute liver injury and obese women are in particular risk, because is able to induce mitochondrial oxidative stress (Rousar, 2012). Acetaminophen (Paracetamol) over doses decreased embryonic low-molecular-weight thiols (glutathione and cysteine), compounds that play a vital role in the detoxication of exogenous and endogenous chemicals (Mitchell, 1973, Beck, 2001, Rousar, 2012, rev).
The apparent safety of Paracetamol drug, a useful analgesic only (with no anti-inflammatory properties) (Neto, 2004; Hamlyn, 1978, Ucheya, 2006, Bessems, 2001) is compromized by its widespread and extensive chronic use, particularly in Peruvian population- Paracetamol though considered safe at a considerable low dose, especially in women, could cause kidney derangement and cardiac malformations during pregnant state (Ucheya, 2006), if the drug is ingested in the first trimester. Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers (Pinter, 2001). Thus, there is an overcome potential maternal acetaminophen (paracetamol) toxicity (Horowitz, 1997).
MON-043 Sleep Disturbances in Women with and Without Polycystic Ovary Syndrome (PCOS) and Their Association with Lifestyle Factors (Diet, Physical Activity and Sitting Time)
Authors: Bennett Christie , Mansfield Darren , Mo Lin , Hodge Allison , Joham Anju , Cain Sean , Blumfield Michelle , Teede Helena , Moran Lisa J 
Published: May 2020

Abstract
Sleep disturbances in women with and without polycystic ovary syndrome (PCOS) and their association with lifestyle factors (diet, physical activity and sitting time)
Bennett C1, Mansfield DR2, Mo L2, Hodge A3, Joham A4, 5, Cain SW6, Blumfield M1, Teede H4, 5, Moran LJ4
1. Be Active Sleep and Eat (BASE) Facility, Department of Nutrition and Dietetics, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria
2. Monash Lung and Sleep, Monash Health, Clayton, Victoria
3. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria
4. Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria
5. Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Victoria
6. Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, Victoria
Sleep disturbances are a risk factor for poorer lifestyle behaviours. While PCOS is associated with a higher prevalence of sleep disturbances, the relationship between sleep and lifestyle behaviours is unknown in PCOS. Self-reported data from the Australian Longitudinal Study on Women’s Health young cohort (31–36 years, n=6067, n=464 PCOS, n=5603 non-PCOS) were collected on PCOS, anthropometry, physical activity, sedentary behaviour, diet (74-item validated food frequency questionnaire) and sleeping behaviour (sleep quantity and adverse sleep symptoms). Multivariate regression models controlled for sleeping behaviour, BMI, age, marital status, education, income and area of residence. Women with PCOS reported greater adverse sleep symptoms, higher energy intake, diet quality (dietary guidelines index (DGI)), fibre intake and sedentary time and lower glycaemic index, compared to women without PCOS. This was not maintained for energy intake and sedentary behaviour on adjustment for confounders. For diet quality, there was an interaction between PCOS and sleep disturbances. Only for women with fewer sleep disturbances (~8 hours sleep/no adverse sleep symptoms) was PCOS associated with better diet quality (DGI higher by 3.14±0.86, p&lt;0.001), with no differences in diet quality for women with poorer sleep. Lifestyle behaviours in women with PCOS appear to be influenced by sleep quality and quantity.
Nothing to disclose: CB, DM, LM, AH, AJ, SC, MB, HT, LM
SUN-430 A Prospective Clinical Trial on the Efficacy of Lithium as Adjuvant Therapy to Radioiodine in the Treatment of Hyperthyroidism (Railit Study)
Authors: Dharan Shalini Sree , Dharan Shalini Sree 
Published: May 2020

Abstract
Background: Radioactive Iodine (RAI) is one of the main treatment modalities of hyperthyroidism. However, its success rate differs between centres. One of the determining factors of RAI success is its intrathyroidal persistence. Lithium has been said to improve efficacy of RAI but it remains debatable till today. Objective: To assess the efficacy and safety of lithium carbonate as an adjuvant therapy to RAI in the treatment of hyperthyroidism. Methods: This is a prospective, interventional, 2 arm parallel-group, open label single centre study carried out in the Endocrinology Unit, Department of Medicine and the Radionuclear Department of Penang General Hospital. The study period was from 30th August 2015 to 30thAugust 2016. The interventional medication is lithium carbonate 300mg twice daily for fourteen days starting on the day of RAI therapy. Lithium carbonate 300mg twice daily was given on the day of RAI (at least 2 hours prior to RAI) to 40 subjects and no added medication to the standard RAI therapy in 40 subjects in the control group. Subjects were followed up for 24 weeks with 6 study visits to assess side effects to medication, compliance to medication, determining cure with adjustments to medications as deemed needed by the study doctors during these study visits. There were 3 drop-outs in the RAI plus Lithium group and 2 drop-outs in the RAI alone group. Results: There were no significant difference in the clinical, demographic and biochemical profile of the two groups. Dose of RAI was a standard 15mCi in both groups. The cure rate in RAI plus lithium group was 62.2% and the cure rate in RAI alone group was 63.2% (p=0.932). Mean time to cure in RAI plus Lithium versus RAI alone group were similar 13.6±6.1weeks vs 13.2±6.5 weeks (p=0.841). There was numerically higher cure rate in Toxic Multinodular goitre in the RAI plus lithium group 10 out of 14 (71.3%) versus RAI alone group 8 out of 15 (53.3%)(P=0.316) though this was not statistically significant. Lithium however was able to prevent thyroid hormone surge 2 weeks post RAI as the median Free T4 was lower at week 2 post RAI compared to baseline (P=0.004) Conclusion: Lithium carbonate does not improve the efficacy of RAI significantly in hyperthyroid patients in our study. Its role in improving efficacy of RAI in toxic multinodular goitre needs further investigations. Lithium is able to prevent thyroid hormone surge post RAI therapy.
SUN-691 Type 2 Diabetes Management in the Context of Smith-Magenis Syndrome: Case Report
Authors: Mulvaney Kylie Tamm , Sathananthan Airani 
Published: May 2020

Abstract
Background: Smith-Magenis syndrome (SMS) is a rare condition caused by microdeletion chromosome 17p11.2 via RAI1 gene mutations, causing disrupted circadian sleep-wake patterns. Characteristic behaviors include: sleep disturbance, anxiety, maladaptive habits with self-injury (biting, picking, self-hugging, page-flipping) and outbursts. Characteristic features include: craniofacial abnormalities, short stature, 2/3 toe syndactyly, scoliosis, cardiac and genitourinary defects, hypotonia, peripheral neuropathy, epilepsy, childhood-onset truncal obesity, toileting difficulties. Management of adults with SMS span multiple disciplines: otolaryngology, audiology, ophthalmology, assessments of scoliosis, seizures, familial psychosocial health, sleep and behavioral changes with each medication. Annual assessments include: fasting lipids, thyroid panel, screening urinalysis. Patients should receive standard treatment for comorbid endocrine conditions, classically: hypercholesterolemia, hypothyroidism, growth hormone deficiency.
Clinical Case: 49-year-old Hispanic female with history of SMS who presented to endocrinology for type 2 diabetes mellitus (T2DM) management. Past medical history includes T2DM with peripheral neuropathy, hypertension, hypercholesterolemia, intellectual disability, anxiety, recurrent genitourinary infections, sleep apnea. Physical exam is remarkable for macroglossia, truncal obesity, scoliosis, extremity excoriations evident of skin picking and xerosis, syndactyly of 2nd-3rd toes. Patient exhibited maladaptive behaviors like page-flipping, self-hugging, tantrums. Over the past 3 years, BMI remained in the obese range (&gt;30 kg/m2) and A1c fluctuated from 7.0 to 10.6% averaging 8.8% (&lt;5.7%). Patient is currently managed on insulin glargine, pioglitazone and liraglutide. She did not tolerate metformin due to dose-dependent diarrhea. Patient’s mother chose against SGLT2 inhibitors due to diminished genitourinary hygiene. T2DM management was complicated by patient behaviors, including nocturnal consumption of fructose-containing food and beverages, exercise intolerance, and associated caregiver fatigue.
Conclusion: This case describes a patient managed for metabolic dysfunction in conjunction with a rare microdeletion disorder causing neurobehavioral disturbance with disrupted circadian sleep-wake patterns. The most difficult aspects of diabetes management included difficulty implementing lifestyle modifications to control the patient’s hyperglycemia.
SAT-286 TSH Synthesis and Secretion Are Unperturbed in Male IRS4 Knockout Mice
Authors: Brule Emilie , Boelen Anita , Bernard Daniel J 
Published: May 2020

Abstract
It was recently reported that mutations in the insulin receptor substrate 4 (IRS4) gene cause a novel form of X-linked congenital central hypothyroidism (OMIM 300904). To date, four different mutations, three frameshift and one nonsense, have been reported, with two affected male patients showing decreased basal, pulsatile, and total thyroid-stimulation hormone (TSH) secretion (PMID 30061370).
Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and their downstream effectors. IRS4/Irs4 expression is enriched in the pituitary; however, its role in the hypothalamic-pituitary-thyroid (HPT) axis has not been studied in detail.
We generated novel whole-body Irs4-knockout mouse lines using CRISPR-Cas9. A specific guide RNA was used to target the Cas9 enzyme to the 5’ end of the single exon Irs4 gene. A two-nucleotide deletion was introduced into Irs4, resulting in a frameshift and premature stop codon. We hypothesized that like IRS4 deficient patients, these mice would exhibit central hypothyroidism. Given that Irs4 is X-linked, we focused our initial characterization on males.
Under normal laboratory conditions, Irs4 knockout mice do not exhibit differences in pituitary expression of Tshb, which encodes one of the subunits of the TSH heterodimer. Expression of the gene encoding the thyrotropin-releasing hormone (TRH) receptor, Trhr1, is also unperturbed in these knockout mice. Additionally, there are no differences in their serum thyroid hormones, T3 (triiodothyronine) and T4 (thyroxine). When Irs4 knockout males were placed on a low-iodine diet supplemented with propylthiouracil (PTU) for 3 weeks and rendered hypothyroid, their serum TSH increased similarly to wild-type males. Overall, Irs4 knockout males do not exhibit central hypothyroidism or phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these mice.
SUN-372 Deterioration of Bone Microarchitecture in Prediabetes Is Partly Mediated Through Fibroblast Growth Factor 21
Authors: Lui David T W , Lee Chi Ho , Chau Vicky W K , Fong Carol H Y , Yeung Kristy M Y , Lam Joanne K Y , Lee Alan C H , Chow Wing Sun , Tan Kathryn C B , Woo Yu Cho , Lam Karen S L 
Published: May 2020

Abstract
Introduction: Prediabetes has been reported to be associated with a worse trabecular bone score (TBS). Fibroblast growth factor 21 (FGF21) levels are raised in prediabetes and other insulin-resistant states, and FGF21 has been reported to be implicated in bone metabolism. We compared the bone mineral density (BMD) and TBS between prediabetes and normoglycemia, and studied the correlation of FGF21 with BMD and TBS. Method: Chinese postmenopausal women aged between 55 and 80 and without type 2 diabetes were recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study between November 2016 and October 2018. Participants were excluded if they were already on anti-osteoporosis therapy, had secondary causes of osteoporosis, had body mass index (BMI) &lt;15 or &gt;37 kg/m2 (when TBS measurement may not be accurate), or had an estimated glomerular filtration rate (eGFR) &lt;30mL/min. They were divided into prediabetes (defined by fasting glucose ≥5.6mmol/L or HbA1c ≥5.7%) and normoglycemia. BMD and TBS were measured by dual-energy X-ray absorptiometry. Serum FGF21 levels were measured with an in-house ELISA kit. Results: 258 participants were included (130 prediabetes and 128 normoglycemia), with a mean age of 61.5±5.1years and mean BMI of 24.2±3.7kg/m2. BMD over lumbar spine, femoral neck and total hip were all comparable between prediabetes and normoglycaemia, while TBS was lower in prediabetes (1.27±0.07 vs 1.30±0.07, p=0.007), which remained significant after adjustment for age and BMI. Serum FGF21 levels did not correlate with BMD but inversely correlated with TBS. On multiple linear regression models, serum FGF21 levels showed an independent inverse correlation with TBS (standardized beta -0.13, p=0.031), which remained significant with the inclusion of homeostasis model assessment of insulin resistance (HOMA-IR) in the model. Conclusion: Among Chinese postmenopausal women, bone quality was worse in prediabetes despite comparable bone density. Serum FGF21 levels showed a significant independent correlation with TBS, suggesting the potential impact of FGF21 on the deterioration of the bone microarchitecture in prediabetes.