bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-721 Implementation of Whole Exome Sequencing for Clinical Diagnostics: A Prospective Busan Kyung-Sang Regional Co-Work Team Experience
Authors: Lee Jeong Eun , Chung WooYeong , Lee BoLyun , Ku SooHyun , Jeon Ga Won , Park JiKyung , Kim TaeHee , Eom MiJa , Huh YoonJung , Park Jinse , Kwak MinJung , Kim JinKyung , Kang Seok-Jin , Jang Kyung-mi , Park Jung-young , Seo GoHun , Keum Changwon , Jun KyungRan , Oh SeungHwan 
Published: May 2020

Abstract
Purpose: Next Generation Sequencing (NGS) technology is a highthroughput method for genome sequencing which assists clinicians with diagnosis of patients with suspected genetic disorders. This study was to investigate diagnostic yield and clinical utility of whole exome sequencing prospectively in the rare genetic diseases. Method: WES was performed a total of 178 patients with suspected genetic disorder. Buccal swab samples were collected from the patients to extract genomic DNA. WES and variant interpretation was conducted in 3 Billion Inc (Seoul, Republic of Korea), based on their own software. Patients’ phenotype was interpreted by clinical geneticists. Results: WES reported 117 variants (66.7%). According to the ACMG/AMP guidelines, there were 25 pathogenic variants (14%), 37 likely pathogenic variants (32%), and 55 VUS (31%). Among the 117 patients who detected variants, genotype-phenotype correlation was analyzed and resulted that 44 (38%) were found to be apparently causal mutation of the disease, 37 (32%) were not considered the cause of the disease, and 36 (31%) were withheld judgement. Of the VUS variants, 13% were likely to be the causal variants of the disease considering phenotype of patients. Conclusion: This study showed 38% of diagnostic yield in patients with unidentified genetic condition by using prospective WES based on automating variant interpretation system. In the diagnosis of rare genetic disease, we identified the need for a multi-disciplinary team to select appropriate subjects and interpret the clinical significance of the found genetic variants.
SUN-476 Risk of Thyroid Cancer in McCune-Albright Syndrome
Authors: Bick Sarah L , Steinkrauss Linda J , Thacker Mihir M , Berman Loren , Gannon Anthony W 
Published: May 2020

Abstract
Background: McCune-Albright syndrome (MAS) is a well described genetic syndrome characterized by café-au-lait spots, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies. Hyperthyroidism is a common endocrine manifestation of MAS, but thyroid nodules are less frequently observed. Thyroid cancer is generally considered uncommon in patients affected by MAS.
Clinical Case: A 15-year-old male was referred to endocrinology for evaluation of polyostotic fibrous dysplasia with onset at 6 years old. He had no café-au-lait spots and initial labwork revealed no endocrine abnormalities. Subsequent labwork revealed non-autoimmune hyperthyroidism, leading to a diagnosis of MAS. Repeat clinical assessment revealed a goiter. 123-I uptake and scan revealed diffusely increased uptake throughout the gland with increased intensity in two regions of the right lobe separated by a region of photopenia. Ultrasound demonstrated three right-sided thyroid nodules – two correlating with the areas of increased iodine uptake and one with the area of photopenia. The left lobe of the thyroid was normal. FNA biopsy was performed and cytopathology was consistent with Bethesda II and III for the hyperfunctioning nodules and Bethesda VI for the cold nodule.
The patient received total thyroidectomy with right-sided central neck dissection, and he was found to have multiple foci of papillary thyroid carcinoma with central neck metastases. The largest hyperfunctioning thyroid nodule was benign. He received radioactive iodine ablation which demonstrated no distant metastases and has had no evidence of recurrent disease.
Conclusions: Hyperthyroidism is a common manifestation of MAS, but thyroid nodules are much less frequently observed, and thyroid cancer is considered quite rare. This patient developed TSH-independent hyperthyroidism in normal thyroid cells as well as in two hyperfunctioning thyroid nodules. He developed two contemporaneous classical papillary thyroid cancers – one manifesting as a nonfunctioning thyroid nodule and one manifesting as a thyrotoxic nodule with lymphatic invasion.
We conclude that individuals with MAS may be at an increased risk for thyroid nodules and thyroid cancer, although the data are not well established. Clinicians should have a low threshold for thyroid ultrasound in patients with MAS and goiter.
Reference: (1) Collins, M. T., Sarlis, N. J., Merino, M. J., Monroe, J., Crawford, S. E., Krakoff, J. A., Guthrie, L. C., Bonat, S., Robey, P. G., & Shenker, A. (2003). Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gsα mutations. The Journal of Clinical Endocrinology & Metabolism, 88(9), 4413-4417.
(2) Hannon, T. S., Noonan, K., Steinmetz, R., Eugster, E. A., Levine, M. A., & Pescovitz, O. H. (2003). Is McCune-Albright syndrome overlooked in subjects with fibrous dysplasia of bone?. The Journal of pediatrics, 142(5), 532-538.
SAT-262 A Case of Pseudotumor Cerebri After Removal and Recurrence of ACTH-Producing Tumor
Authors: Andre Karla Bermudez Saint , Petak Steven , Tabatabai Laila 
Published: May 2020

Abstract
Introduction: Pseudotumor cerebri also known as idiopathic intracranial hypertension (IIH) is a condition of elevated cerebrospinal fluid pressure which as a result causes headaches and vision problems. Several case reports and studies have reported a relation of IIH with Cushing’s disease (CD) in adults and children, particularly after surgical or medical therapy. We describe a very uncommon presentation of persistent intracranial hypertension (ICH) in a patient with recurrence of cushing’s disease after her initial surgical resection.
Case presentation:38-year-old African-American female with a BMI of 45, type 2 diabetes, HTN and history of Cushing’s syndrome from an ACTH-producing pituitary macroadenoma. She initially presented with increasing weight gain and features of Cushing’s syndrome including hypertension, hyperglycemia, truncal obesity and moon facies. Imaging studies showed a 2 cm intrasellar mass with suprasellar extension without compression of the optic chiasm. Hormonal evaluation confirmed Cushing’s syndrome from an ACTH-producing pituitary macroadenoma. Patient underwent initial trans-sphenoidal hypophysectomy (TSR) and was tapered down to physiologic doses of glucocorticoids.
Post-operatively she started complaining of significant headaches and transient vision loss. She followed up with neuro-ophthalmology and was diagnosed with papilledema that was not present in the pre-operative examination. An LP (lumbar puncture) was recommended to assess for ICH, however patient declined the procedure. A year after, a second surgery had to be performed for recurrent pituitary adenoma. Unfortunately, a repeat MRI pituitary shortly after her second surgery revealed recurrent pituitary macroadenoma of 2.2 cm. Patient continued with headaches and underwent an LP with an opening pressure of 28 cm H20 (ICH &gt; 26 cm H2O). She underwent a third TSR with follow up MRI showing gross total resection of the previously seen pituitary mass. For her ICH she was started on acetazolamide but was not able to tolerate due to paresthesias and metallic taste. Her symptoms have improved after her last resection and last MRI brain shows no residual tumor. She is currently on furosemide and focusing on weight loss.
Conclusion: Our patient’s presentation is an interesting and unusual case because we believe she had both pseudotumor cerebri (IIH) and real tumor cerebri from the complications of her ACTH-secreting macroadenoma. The cause of IIH after treatment of cushing’s disease is believed to be mostly due to steroid withdrawal after surgical resection or medical treatment comprising hormonal control of cerebrospinal fluid production and absorption. In our patient we suppose that the persistent weight gain caused by the recurrence of her CD could also contribute to her IIH. The treatment in general is the same with physiologic doses of corticosteroids, diuretics and weight loss.
MON-076 Adrenal Hypoplasia Congenita - Is It Possible to Make This Diagnose in Previous “Idiopathic” Adrenal Insufficient Patients? Series of Cases
Authors: Paula Leila Pedroso de , Gomes Nathalia Lisboa , Czepielewski Mauro Antonio , De Mendonca Berenice Bilarinho 
Published: May 2020

Abstract
Background: Adrenal hypoplasia congenita (AHC) is a rare disease (1:70.000 men) characterized by reduction in all cortical adrenal hormones and also by hypogonadism. NR0B1 -related AHC includes both X-linked AHC and Xp21 deletion. AHC gene mutation was first described in 1994 and occurs in less than 1% of adrenal insufficiency (AI) cases and it is imperative that clinical endocrinologists increase their knowledge on this condition to recognize it as promptly as they were used to do so in other causes of pediatric AI.Clinical Cases: We describe here two sporadic cases and three familial cases from one family, all of them attending at our Endocrine Unit at HCPA, in the South of Brazil. The median age of AI first symptoms was 1 month old in two patients (acute infantile onset due to a salt wasting crises), and eleven years old in the remaining patients (childhood onset). Their exams confirmed the clinical suspicion of primary AI because of low plasma cortisol (from &lt; 0.5 to 4 mcg/dl - reference range from 7-24 mcg/dl), as well as all adrenal steroids levels, high ACTH levels (from 672 to 2225 pg/ml - reference range from 7-63 pg/ml) and high plasmatic renin (from 92 to 448 mcUI/ml - reference range from 2.8-39.9 mcUI/ml). They were also extensively investigated searching for the AI pathophysiology. After some years of lost follow-up, one of the familial cases that had first been seen in 1993, returned to our hospital and was diagnosed with hypogonadism, leading to NR5OB1 gene evaluation.Regarding the genetic etiology, one of the sporadic cases developed a clinical picture including profound developmental delay, seizures and strabismus suggestive of a contiguous gene syndrome that involves Duchenne muscular dystrophy, glycerol kinase deficiency and AHC. A CGH array was performed and identified a Xp21.3-p21.1 deletion. The affected family had an extensive history suggestive of a genetic disease with X-linked inheritance pattern, as shown by the premature death of 3 uncles and a male cousin. A deleterious variant (c.131_212delinsTGAGACCTGTACCGT) in NR5OB1 gene was identified by Sanger sequencing in hemizygous state in the 46,XY affected patients.Conclusion: Albeit a rare disease, it is crucial that endocrinologist all around the World could be aware about clinical characteristics of this condition in order to properly diagnose it. And it is even possible, as it occurred with one of our patient, to make a late pathophysiologic diagnosis, making possible to treat the associated hypogonadism. Reference: Acherman JC, Vilain EJ. NR0B1- related adrenal hypoplasia congenita. GeneReviews 1993-2019.
OR32-06 Opportunistic Assessment of Pituitary Gland with Routine MRI and PET/CT Can Guide in Earlier and Increased Identification of Hypophysitis in Patients Treated with Combination Checkpoint Inhibitors
Authors: Galligan Anna , Iravani Amir , Lasocki Arian , Wallace Roslyn , Weppler Alison , Au-Yeung George , Sachithanandan Nirupa , Chiang Cherie Ying , Wentworth John , Colman Peter Grahame , Kay Thomas William , Krishnamurthy Balasubramanian , Sandhu Shahneen 
Published: May 2020

Abstract
Background: Hypophysitis is one of the commonly reported adverse events related to immune checkpoint inhibitors (ICI), and the incidence is expected to rise with increased use of combined programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4) blockade. The clinical diagnosis can be delayed due to non-specific symptoms. At our centre, subjects undergo periodic imaging to assess tumour response to ICI. We reviewed whether neuroimaging studies can guide us in the diagnosis of hypophysitis and whether early changes can be detected before the onset of the clinical syndrome. Methods: We retrospectively reviewed the medical charts, biochemistry, structural brain imaging and whole-body positron emission tomography (PET) with specific reference to hypophysitis in 162 patients treated with combination ICI at a tertiary melanoma referral centre. Suspected cases were identified based on meeting one or more of the following criteria: 1) A documented diagnosis of hypophysitis or pituitary dysfunction found on chart review, 2) A relative change in pituitary size or appearance from baseline on neuroimaging studies, or 3) An increase in pituitary maximum standardized uptake value (SUVmax) greater than 25% from baseline on 18F-FDG PET. Results: 58/162 patients (36%) met criteria for suspected hypophysitis. Only 4 patients were identified on routine screening of early morning cortisol. 14 patients presented with symptoms leading to biochemical work up. A further 40 patients were found to have suspicious imaging changes, 13 of which went on to receive a formal diagnosis of hypophysitis. Of the remaining 27 patients, 23 were receiving high dose glucocorticoids for concomitant immune related adverse events at the time of the abnormal imaging study.Conclusion: We report the highest incidence to date of suspected hypophysitis in cohort of patients treated with combination ICI. This study highlights the important role of structural and functional neuroimaging in the early recognition of hypophysitis. Imaging may also play a role when the clinical syndrome is masked by concurrent glucocorticoid use.
MON-258 Hyperprolactinemia: An Unusual Initial Presenting Manifestation of Multiple Sclerosis
Authors: Hodge MaKenzie , Ganta Vijaya A , Nunlee-Bland Gail Louise , Odonkor Wolali Akua-Sabia , Zenebe Anteneh Woldetensay , Folawewo, MbChB Kehinde Matilda , Osman Nada 
Published: May 2020

Abstract
Hyperprolactinemia and multiple sclerosis (MS) have a direct relationship and hyperprolactinemia may precede clinical signs of MS as a heralding manifestation of disease. Prolactin has significant pro-inflammatory effects in addition to its lactotrophic properties and can also lower the body’s immune tolerance, inducing autoimmunity. High levels of prolactin have been thought to contribute to the inflammation of multiple sclerosis. However, elevated levels of prolactin, especially in pregnant women, can be protective for MS patients and induce remission. Prolactin is neuroregenerative and stimulates the precursors for oligodendrocytes, the cells responsible for myelination. Our hypothesis is that an elevated prolactin level detected during an MS flare should not be treated with dopamine agonist, but rather allowed to decrease as the MS improves with treatment.
Case Presentation
A 24 year old woman with a history of marijuana use is referred to our clinic for elevated prolactin levels associated with galactorrhea for 3 months duration. In addition to marijuana use, patient was also sexually active and having regular menses, with menarche at age 11 years old. On physical exam, the patient was found to have bilateral nipple discharge with stimulation, and visual fields were intact to confrontation. At the time of referral, the patient’s prolactin was 92.3 ng/dL (4.8−23.3 ng/mL) TSH was normal, and pregnancy test negative.An MRI showed multiple areas of enhancement compatible with active demyelination, concerning for multiple sclerosis. The pituitary gland was enlarged, without evidence of adenoma. A follow up prolactin level was 101 ng/dL and upon further discussion, patient also admitted to some “funny feeling” and weakness in her right hand and a feeling of being “off balance” diagnosed as a left ear infection. Patient was advised to seek urgent treatment for multiple sclerosis. She was admitted, where she was seen by neurology and diagnosed with relapsing remitting multiple sclerosis. She was initially treated with a course of IV methylprednisolone. She was discharged after this course and followed with neurology as an outpatient. For a few months our patient went into remission and her prolactin improved to 24 ng/dL. A few months later, she had a significant increase in her prolactin to 71.5 ng/dL accompanied by evidence of disease progression on MRI and symptoms of weakness and falls. Neurologists changed her medication from Copaxone to Tecfidera and patient improved clinically and has not had any further flares. Notably, she never received any dopaminergic agent to treat her prolactin level, which improved significantly.Our case illustrates that prolactin may be a disease marker in the acute phase of MS and can be restorative. Further more it will improve when the MS is treated and we should not use any dopamine agonist.
SUN-670 P300 and CBP Are Necessary for Skeletal Muscle Insulin-Stimulated Glucose Uptake
Authors: Martins Vitor Fernandes , LaBarge Samuel , Svensson Kristoffer , Cunliffe Jennifer M , Banoian Dion , Ciaraldi Theodore P , Hetrick Byron , Meyer Gretchen A , Philp Andrew , David Larry L , Henry Robert R , McCurdy Carrie E , Aslan Joseph E , Schenk Simon 
Published: May 2020

Abstract
Introduction: Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity.
Methods: We used Cre-LoxP methodology to generate mice with a tamoxifen-inducible, conditional knock out of Ep300 and/or Crebbp in skeletal muscle. At 13-15 weeks of age, the knockout was induced via oral gavage of tamoxifen and oral glucose tolerance, ex vivo skeletal muscle insulin sensitivity, and microarray and proteomics analysis were done.
Results: Loss of both p300 and CBP in adult mouse skeletal muscle rapidly and severely impairs whole body glucose tolerance and skeletal muscle insulin sensitivity. Furthermore, giving back a single allele of either p300 or CBP rescues both phenotypes. Moreover, the severe insulin resistance in the p300/CBP double knockout mice is accompanied by significant changes in both mRNA and protein expression of transcript/protein networks critical for insulin signaling, GLUT4 trafficking, and metabolism. Lastly, in human skeletal muscle samples, p300 and CBP protein levels correlate significantly and negatively with markers of insulin resistance.
Conclusions: p300 and CBP are jointly required for maintaining whole body glucose tolerance and insulin sensitivity in skeletal muscle.
SUN-016 Mendelian Randomization Reveals That Polycystic Ovary Syndrome Is Not a Causal Risk Factor for Type 2 Diabetes, Coronary Heart Disease, or Stroke
Authors: Zhu Tiantian , Goodarzi Mark O 
Published: May 2020

Abstract
Polycystic ovary syndrome (PCOS) is now recognized not only as a cosmetic and reproductive disorder, but also as a metabolic disorder with important consequences. The balance of the literature suggests that PCOS increases the risk of future type 2 diabetes (T2D); however, whether PCOS increases the risk of coronary heart disease (CHD) and/or stroke is more controversial. Despite a high burden of cardiovascular risk factors (which suggests a high risk of events), the mostly small and retrospective cohort studies have yielded conflicting results. Meta-analyses of these studies suggested at best a 1.4 to 2-fold increased risk of CHD and stroke, which attenuated to 1.2-1.6 when accounting for body mass index (BMI) (1,2). Given that observational studies may be biased by confounders between the risk factor and outcome (in this case, elevated BMI often present in PCOS), we performed Mendelian randomization (MR) analyses to examine the possible causal effect of polycystic ovary syndrome (PCOS) with T2D, CHD and stroke. MR uses genetic variants as instruments to represent exposures of interest to assess causality between exposures and outcomes (3). It is increasingly being used because it overcomes confounding and reverse causation, which often plague observational studies. The instrument variables for PCOS were constructed based on 14 SNPs derived from a published GWAS meta-analysis for PCOS conducted in European cohorts (10,074 cases and 103,164 controls) (4). The SNP to outcomes estimates were obtained from the DIAMANTE T2D GWAS (74,124 T2D cases and 824,006 controls) (5), the CHD GWAS meta-analysis of the UK Biobank plus CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) (6) and the MEGASTROKE consortium GWAS (67,162 cases and 454,450 controls) (7). MR analyses were conducted using three methods: inverse variance weighted (IVW) (primary method), weighted median and MR Egger (sensitivity analyses). In our study, no significant association of genetically predicted PCOS with T2D (OR 0.97, CI 0.91-1.02), CHD (OR 0.99, CI 0.95-1.03) or stroke (OR 0.98, CI 0.93-1.02) was observed. Our findings suggest that PCOS is not a causal risk factor for T2D, CHD or stroke. The observed associations of PCOS with these three diseases from observational studies are likely due to confounding factors and small sample sizes. Given that MR has found that increasing BMI is causal for PCOS as well as T2D and CHD, overweight/obesity is the likely confounding variable. These results suggest a critical revision of how we counsel and manage women with PCOS.
Reference:
1. Zhou Y, et al. Gynecol Endocrinol 2017; 33:904-910
2. De Groot PC, et al. Hum Reprod Update 2011; 17:495-500
3. Davey Smith G, et al. Hum Mol Genet. 2014; 23:R89-R98.
4. Day F, et al. PLoS Genet. 2018;14(12).
5. Mahajan A, et al. Nat Genet. 2018;50(11):1505-1513.
6. van der Harst P, et al. Circ Res. 2018;122(3):433-443.
7. Malik R, et al. Nat Genet. 2018;50(4):524-537.