bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-516 Quantitative Analysis of Differential Enigma/PDLIM7 Gene Expression in Thyroid Cancer vs. Benign Nodules
Authors: Roberts Kari , Choi Sang Hee K , Frank Ethan , Foulad David , Mirshahidi Saeid , Perez Mia C , Simental Alfred A , Khan Salma
Published: May 2020

Thyroid cancer incidence is rising worldwide. Although fine-needle aspiration biopsy (FNAB) is an accurate modality for evaluating thyroid nodules, up to 25% of FNABs still yield indeterminate results. There is a considerable number of diagnostic thyroidectomies for benign disease as a result of indeterminate FNAB. A more accurate and time-efficient diagnostic approach for analyzing indeterminate thyroid nodules may reduce diagnostic thyroidectomy. Recently, the osteogenic protein, Enigma, has been associated with different cancer types, including thyroid cancer progression and calcification through its interaction with bone morphogenic protein-1 (BMP-1), and tyrosine kinases linked to mitogenic signaling pathways [1, 2]. Our published data on Enigma protein analysis with immunohistochemistry showed promising results in discriminating between malignant versus benign thyroid nodules and demonstrated a correlation with thyroid cancer staging [3]. In this study, we are investigating Enigma at a gene expression level by real-time (RT-qPCR), which is a quantitative and more time-efficient method that requires smaller samples (FNA) than immunohistochemistry. We analyzed Enigma mRNA expression levels to determine if Enigma-qPCR could be used as a diagnostic tool to improve the accuracy of FNAB in both malignant and benign thyroid tissues. We extracted mRNA/DNA/proteins from fresh malignant and benign thyroid nodules using a QIAGEN DNA/RNA/Protein Kit. We ran isolated pure mRNA through Enigma-qPCR. The results showed that the Enigma-mRNA expression was 3-fold higher in malignant as compared to benign thyroid tissues. This finding supports our previous Enigma immunohistochemistry data and shows a relative quantitative difference in Enigma-mRNA expression level between malignant and benign thyroid nodules. We conclude that Enigma-RT-qPCR can be used to effectively determine malignancies in FNAB samples derived from thyroid nodules. This method could potentially enhance the diagnostic accuracy of indeterminate nodules and decrease diagnostic thyroidectomies and associated morbidity.

[1] C.R. Jung, J.H. Lim, Y. Choi, D.G. Kim, K.J. Kang, S.M. Noh, D.S. Im, Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice, The Journal of clinical investigation 120(12) (2010) 4493-506.

[2] Y.J. Kim, H.J. Hwang, J.G. Kang, C.S. Kim, S.H. Ihm, M.G. Choi, S.J. Lee, Enigma Plays Roles in Survival of Thyroid Carcinoma Cells through PI3K/AKT Signaling and Survivin, Anticancer research 38(6) (2018) 3515-3525.

[3] A.A. Firek, M.C. Perez, A. Gonda, L. Lei, I. Munir, A.A. Simental, F.E. Carr, B.J. Becerra, M. De Leon, S. Khan, Pathologic significance of a novel oncoprotein in thyroid cancer progression, Head & neck 39(12) (2017) 2459-2469.
SUN-089 Novel Genetic and Biochemical Findings of DLK1 Deficiency in Children with Central Precocious Puberty - a Collaborative Brazilian-Spanish Study
Authors: Montenegro Luciana Ribeiro , Labarta José , Piovesan Maiara , Canton Ana Pinheiro Machado , Collado Raquel Corripio , Soriano-Guillén Leandro , Barrios Vicente , Seraphim Carlos Eduardo , Brito Vinicius Nahime , Latronico Ana Claudia , Argente Jesus
Published: May 2020

Background: Delta-like 1 homolog (DLK1), also known as pre-adipocyte factor 1 (Pref-1), is part of the Notch signaling pathway that controls many developmental processes. Loss-of-function mutations of DLK1 have been identified in children with central precocious puberty (CPP), as well as in women who had precocious menarche (≤ 9 years) with an unfavorable metabolic profile. Objective: To investigate genetic and biochemical aspects of DLK1 in a cohort of children with CPP. Patients: A large cohort of Spanish children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic DNA was obtained from 444 individuals, including 168 index cases with CPP and their close relatives. Automatic sequencing of the coding region (5 exons) of DLK1 was performed in all index cases. Serum DLK1 levels were measured by using a soluble DLK1 enzyme-linked immunosorbent assay (ELISA). Results: A rare allelic deletion (c.401_404 + 8del) of a splice site junction of DLK1 was identified in a girl with sporadic CPP. Pubertal signs appeared at 5.7 years of age with progressive puberty (basal LH: 1.7 mIU/mL, peak LH: 32.77 mIU/mL; basal FSH: 6.32 mIU/mL, peak FSH: 19.89 mIU/mL), BA/CA 1.7 years; normal cranial MRI). She received LHRH analogues (6.3 - 10.1 years of CA) with no side effects. At 14.9 years of age height and BMI are 152.9 cms and 18 kg/m2, respectively, presenting regular menses. Familial segregation analysis showed that the affected child was the only carrier of this deletion characterizing a de novo mutation (biological paternity and maternity were confirmed by microsatellite analysis). Serum DLK1 levels were undetectable (<0.4 ng/mL) in this girl, supporting that the deletion lead to complete lack of DLK1 production. Her father, mother and sister had normal serum DLK1 levels (ranged 6.36 ng/mL to 8.98 ng/mL). Two rare consecutive nucleotide changes in the promoter region of the DLK1 gene (c.-222 C>A and c.-223 G>A) were also identified in an adopted child with CPP. They are located in a transcription factor binding site for SP1 (a zinc finger transcription factor). Pubertal signs appeared at 6.7 years of age with progressive puberty (Basal LH: 0.5 mIU/mL, peak LH: 15.9 mIU/mL, basal FSH: 1.52 mIU/mL, peak FSH: 6.56 mIU/mL, BA/CA 1.4 years; normal cranial MRI). She is under therapy with LHRH analogues with no side effects. Conclusion: Novel DLK1 findings were identified in the Spanish cohort of children with CPP, reinforcing a significant role of this factor in human pubertal timing.
MON-703 Injection Technique over Insulin Dose - Nuances in Diabetes Therapy
Authors: Mehrotra Neha , Kotok Daniel , DeJesus Carla J , Korytkowski Mary T , Mon Sann Yu
Published: May 2020

Introduction

Optimal insulin injection technique is crucial for therapeutic success in patients with diabetes who require insulin therapy for glycemic control. One of the causes for failure to reach glycemic goals can be attributed to improper injection technique. Problems related to poor injection technique may arise at a later stage and hence, may lead to a major barrier to intended glycemic control. We present a patient with worsening glycemic control and significant insulin requirement due to ineffective injection technique. Our case highlights the importance of direct observation of the patient injecting insulin, even for those who have been on insulin therapy for years.

Case Presentation

A 55-year-old woman with T2DM and Class III obesity was referred for endocrine consultation with HbA1c >12% for 9 months despite adhering to 4.7 unit/kg/day basal bolus daily Insulin, Metformin 1000 mg twice daily and liraglutide 1.8 mg daily. Secondary causes of insulin resistance were ruled out. Initial review of injection technique on an insulin-injection pad failed to identify the error. However, a leakage was observed when patient was asked to demonstrate injection technique on herself, using the BD AutoShield Duo needle, which she was using at that time. Patient was advised to switch to BD nano needles and given proper training. Following this adjustment, her HbA1c improved to 6.9% within 3 months with a decrease in daily insulin requirement to 1 unit/kg/day.

Discussion

In optimizing glycemic control, proper insulin injection technique is as essential as the appropriate type and dose of insulin; however, this is often overlooked. Studies assessing proper insulin injection technique by direct observation are limited. Problems experienced by patients are rarely brought up and often neglected during the follow-up visits. Supervision of injection technique periodically can help identify injection errors.

The BD AutoShield Duo offers the distinct advantages of concealing the needle which benefits those who have an aversion to needles and reduces the risks of accidental needlesticks. The force required to deliver a successful injection of insulin using this needle is greater in comparison to traditional needles. Such force and lack of direct visualization may potentially lead to failure of insulin delivery. Such challenges may be more obvious in patients with obesity.

Our case highlights the importance of periodic review of insulin injection technique, particularly when glycemic control is suboptimal, and emphasizes the correct choice of insulin pen needle.

References

1.King, Laila. “Subcutaneous insulin injection technique.” Nursing Standard, vol. 17, no. 34, 2003, p. 45+. Academic OneFile, https://link.galegroup.com/apps/doc/A130629162/AONE?u=googlescholar&sid=AONE&xid=5f28fd49. Accessed 18 Nov. 2018.
OR16-06 Age-Associated Local GH Promotes Colon Neoplasia
Authors: Chesnokova Vera M , Zonis Svetlana , Apostolou Nasia , Hannah Estrada Q , Knott Simon , Wawrowsky Kolja , Ben-Shlomo Anat , Barrett Robert , Gorbunova Vera , Karalis Katia , Melmed Shlomo
Published: May 2020

Colon polyp and cancer frequency increase with age, yet little is known about age-related mechanisms underlying development of these neoplasms. Defective DNA damage response and accumulation of unrepaired DNA damage can trigger genomic instability and cellular transformation.

Patients with acromegaly have a higher prevalence of colon polyps and, arguably, colon adenocarcinoma, while those with GH signaling deficiency do not develop cancer. We showed that APC+/- mice that all develop colon adenomas exhibit a significant decrease in the number and volume of colon tumors with deletion of the GH transcription factor Prop1. Further, DNA damage response triggered GH expression in colon cells, and GH, in turn, altered DNA damage repair, resulting in DNA damage accumulation and cell transformation both in vitro and in vivo. These findings prompted us to hypothesize that accumulated DNA damage in aging colon induces local GH, suppressing DNA damage repair and creating a milieu consistent with genomic instability favoring neoplastic development.

In human colon tissue we now show increased expression of γH2AX, a marker of DNA breaks, associated with increased GH transcription (detected by RNA scope) and translation (assessed by immunohistochemistry) as well as GH induction in both human and murine colon after DNA damaging radiotherapy. In vitro studies support these results, showing GH induction in normal human colon epithelial cells, fibroblasts, and 3D human intestinal organoids after DNA damage. Of note, local GH was secreted in the medium, indicating a paracrine effect. Paracrine/autocrine GH expression in these cellular models resulted in suppression of p53, induction of EMT, and attenuation of DNA damage response, and accumulated unrepaired DNA damage in human colon cells and in human intestinal organoids. In vivo, colon cells infected with lentivirus expressing GH generated more metastases than did cells expressing control vector. Co-culturing of human normal colon fibroblasts expressing GH together with normal human colon cells led to increased motility and accumulation of DNA damage as well as increased proliferation of epithelial cells on a gut-on-a-chip microfluidic device, confirming paracrine GH effects. In an in vitro model of aging, culturing human intestinal organoids for up to 2 months resulted in decreased telomere length and increased GH mRNA and protein expression associated with suppressed DNA damage response evident by decreased phosphorylation of ATM and DNA-PKcs, both kinases involved in DNA repair, and DNA damage accumulation assessed by Comet assay. Suppression of GH in these aging organoids led to increased phospho-p53 and reduced DNA damage. Although somatotroph axis endocrine activity decreases with age, local GH induced in response to age-related DNA damage may trigger a “field change,” creating a milieu favorable for colon neoplastic development.
MON-589 Studying Mechanisms of Satiety in the Human Ileum and Colon
Authors: Ramgulam Anya , Tashkova Martina , O’Driscoll Maeve , Becker Georgia Franco , Stephens Hannah , Blanco Jesus Miguens , Holmes Elaine , Marchesi Julian R , Blunt Dominic , Perez Isabel Garcia , Frost Gary , Murphy Kevin Graeme
Published: May 2020

Background The gut-brain axis plays important roles in the regulation of appetite and glucose homeostasis. The presence of nutrients and their digestive products in specific regions of the gastrointestinal tract modulates neuronal and hormonal signalling, including the release of the appetite-suppressing gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). While there has been significant research into the upper gut mechanisms behind satiation, i.e. the termination of meal, the role of the ileum and colon in satiety, i.e. the process which delays a subsequent meal, has been relatively little investigated, particularly in humans. Methods Ten healthy volunteers attended our Clinical Research Facility for two visits of four days each. At each visit they had either a nasoileal or a nasocolonic tube inserted under fluoroscopy. They were then provided a diet rich in protein and fibre to promote satiety. Gut contents and blood samples were taken before and during test meals at the start and end of the visit, and visual analogue scales were used to measure subjective feelings of appetite. Metabonomic analysis of gut fluid was carried out using a combination of in-house NMR and LC-MS-based methods. 16S rRNA gene sequencing was used to investigate effects on the colonic microbiome. Circulating levels of glucose, the gut hormones GLP-1 and PYY, and the pancreatic hormones insulin and glucagon were measured. Results and discussion The test meals resulted in sustained suppression of appetite and release of GLP-1 and PYY. Ileal and colonic microbial profiles were distinct from those identified in stool samples, and changed with adaptation to the high protein and fibre diet. Integrating hormonal, metabonomic and bacterial datasets from these human studies gives insight into how nutrient and metabolite sensing in the gastrointestinal tract regulates appetite and glucose homeostasis, and may suggest novel therapeutic targets for metabolic disease.
SAT-732 Historical Occurrence of Intersex in Largemouth Bass (Micropterus Salmoides) and Smallmouth Bass (Micropterus Dolomieu)
Authors: Norris David O , Geiger Angela , Vajda Alan Milan
Published: May 2020

The widespread occurrence of gonadal intersex (presence of testicular oocytes) has been recently reported in populations of Largemouth Bass (Micropterus salmoides) and Smallmouth Bass Micropterus dolomieu) from populations across North America. To evaluate the historical occurrence of intersex in bass species, gonads were examined visually and histologically from Largemouth Bass and Smallmouth Bass from museum specimens collected from 16 States. These fishes were collected between 1823-1965, before the widespread discharge of estrogenic chemicals to surface waters via wastewater effluents. All females examined had normal ovaries. Intersex gonads were identified in 17.8 % of male Largemouth Bass, and in 14.2% of male Smallmouth Bass. The intensity of testicular oocytes in some males was as great as observed since 2000. These results indicate that the occurrence of this form of intersex in these bass species is not a recent phenomenon.
SUN-587 IDH1-Dependent Alpha-KG Regulates Brown Fat Differentiation and Function by Modulating Histone Methylation
Authors: Kim Won Kon , Han Baek-Soo
Published: May 2020

Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. These results suggested that the IDH1–α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.
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

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

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

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 > 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

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 < 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

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

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

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

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.
MON-252 Pituitary Tumor Apoplexy Presenting with Acute Psychosis
Authors: Pineyro Maria Mercedes , Agüero Patrica , Irazusta Florencia , Brun Claudia , Duarte Paula , Ems Vanessa
Published: May 2020

Background: Pituitary tumors (PT) can present with neuropsychiatric symptoms. It has been associated with hormonal changes, as well as extension of the tumor to the diencephalon. Psychopathology has been reported in up to 83% in Cushing Disease (CD) and 35% in acromegaly (ACR). Psychiatric disorders (depression, anxiety and psychosis) have been reported up to 77% in CD and 63% in ACR. We present a rare case of a patient presenting with acute psychosis and a PT apoplexy. Case: A 27 year-old Caucasian female with a PMH of primary hypothyroidism presented with a 15-day history of delusions. She had delusional ideas on the subject of harm and prejudice, persecutory and mystical-religious. The mechanism was mainly intuitive and interpretive with false acknowledgments. She also had sleep disturbance, death ideation and subacute alteration of consciousness. There was no history of substance abuse or psychiatric disorders. She did not report headaches, visual disturbances, symptoms of hormone hypersecretion or hypopituitarism. She had regular menses on BCP. She had no family history of mental illnesses. Physical exam revealed reluctance, latency in responses and bradypsychia. She did not have acromegalic or cushingoid features. She was diagnosed with acute psychosis with atypical features so a brain CT was performed, which showed a sellar mass. Pituitary MRI revealed a sellar mass measuring 15x12x13 mm, with suprasellar extension, optic chiasm compression, hyperintense on T1- and hypointense on T2-weighted imaging compatible with subacute hemorrhage. She was treated with neuroleptics and benzodiazepines. Lab work revealed high prolactin (PRL) (114ng/dl), and normal 8 AM cortisol, FT4, LH, FSH and IGF-1 levels. Repeated PRL was 31,6 ng/dl after changing psychiatric treatment to aripiprazole. Her psychiatric symptoms improved. We postulate a diagnosis of PT apoplexy that presented with acute psychosis. In relation to the nature of the PT we postulate a non functioning pituitary adenoma (NFA) or a partial resolution of a prolactinoma after apoplexy. A follow up MRI is pending. Discussion: Infrequently, psychiatric symptoms may be the primary manifestation of brain tumors. Patients with PT have been reported to have altered quality of life, reduced coping strategies, increased prevalence of psychopathological alterations and maladaptive personality disorders. In addition, they can present with psychotic symptoms, mostly reported with hormone excess (GH and cortisol). Psychiatric symptoms such as anxiety and neurosis have been reported in NFA and prolactinomas. However, it is not clear a higher prevalence of psychiatric illnesses in these tumors. To our knowledge this is the first case of a pituitary tumor apoplexy presenting with acute psychosis. Conclusion: Psychiatric symptoms can be the first manifestation of PT, so atypical presentations should warrant further workup with brain imaging.
SAT-071 Autoimmune Polyglandular Syndrome Type 1 with Common Variable Immunodeficiency
Authors: Shikdar Yasamen Abdulmannan , Almazrooa Abdullah , Samargandy Shaza
Published: May 2020

BACKGROUND:

Autoimmune polyglandular syndrome (APS) is a rare disorder. It’s co-existence with common variable immunodeficiency (CVID) was reported in 5 cases before but, none of them was APS type 1up to our knowledge. The overlap between the 2 conditions indicates a possible association between Autoimmunity and immunodeficiency.

CLINICAL CASE:

A 21-year-old lady was diagnosed to have CVID since infancy, as she was presenting to the hospital with recurrent infections and sepsis. At the age of 7 months, she was diagnosed with type 1 diabetes and was started on insulin. Furthermore, at 2 years of age she was found to have primary hypothyroidism and in her teenage she was diagnosed with primary adrenal insufficiency. Her history became more complicated when she also started to develop recurrent oral and esophageal candidiasis that required systemic anti-fungal therapy. Later in her life, she was incidentally found to have hypoparathyroidism when her labs showed hypocalcemia with inappropriately normal parathyroid hormone. She had chronic diarrhea which was thought to be due to celiac disease based on intestinal biopsy showing villous atrophy. With her IgA deficiency, her Tissue transglutaminase IgA antibodies were not reliable. Splenic atrophy was also detected on abdominal imaging. She never reached puberty and elected with her parents to not start combined hormonal therapy.

With the constellation of these features, we concluded that she has type 1 APS along with CVID.

CONCLUSION:

Autoimmunity and immunodeficiency might be interconnected. Early diagnosis will affect the quality of life and early targeted treatment will prevent morbidity and early mortality.

KEY WORDS: Autoimmune Polyglandular Syndrome, Common Variable Immunodeficiency.
SAT-636 The Fast-Evolving Connected Diabetes Care Landscape: Transforming Diabetes Care with Telehealth and Technology
Authors: Levine Brian , Close Kelly , Gabbay Robert Abraham
Published: May 2020

Background and Aims

Recent years have brought about a new form of “connected diabetes care,” defined as digital diabetes management systems based around (1) smartphone apps, (2) devices with built-in connectivity, and (3) remote human and automated coaching and support. Given their potential to help improve health outcomes, the rapid pace of innovation, and the dearth of information about them to guide patients, providers, and payers, we provide an update on the landscape of and trends in connected diabetes care offerings.

Methods

Prominent connected diabetes care providers that have published results are categorized and characterized. Similarities and differences are identified and the state of available evidence is evaluated.

Results

Connected diabetes care offerings were analyzed for items including: health conditions managed, care team composition, connected medical devices, and evidence. We expect these players will further expand offerings across chronic conditions, strive to integrate more deeply with the traditional healthcare system, deploy greater automation to promote scalability, and find clever ways to promote and support the use of continuous glucose monitoring in type 2 diabetes. Future evidence generation for this field should have more standardized methodology.

Conclusions

The field of connected diabetes care has tremendous potential to improve outcomes, but it is in its infancy in terms of awareness, uptake, and effectiveness. Further, questions regarding offerings’ abilities to support most people with diabetes sustainably remain. However, existing evidence is sufficient to support further exploration and refinement of the model as the next step in team-based diabetes care.