bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT592 Sexually Dimorphic Modulation Of Arcuate Kisspeptin Neurons Activity In Response To NPY
Authors: da Silva Mansano Naira , Frazao Renata
Published: October 2023

Disclosure: N.D. Mansano: None. R. Frazao: None.

Kisspeptin neurons are part of an intricate brain circuit that receives neuronal inputs related tonutritional status from at least three neuronal populations, including NPY/AgRP and POMC neurons of the arcuate nucleus of the hypothalamus (ARH) and cells in the ventral premammillary nucleus. Its well-known action on the HPG axis, hypothalamic kisspeptin neurons also modulate the activity of specific neurons of the paraventricular and the dorsomedial nuclei of the hypothalamus, regions involved in the regulation of appetite and energy expenditure. However, it is not completely elucidated if NPY can influence the HPG axis through the modulation of kisspeptin neuron activity. To determine the NPY effect in the hypothalamic kisspeptin neurons we performed whole-cell patch-clamp recordings. The hypothalamic slices were obtained from the adult Kiss1/hrGFP female (diestrus-stage) or male mice. Kisspeptin cells located in the arcuate nucleus of the hypothalamus (ARHkisspeptin) and at the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeNkisspeptin) were recorded. On female mice, ARHkisspeptin neurons exhibited a rest membrane potential (RMP) average of -52.5±2.5 mV (-40 to -62 mV) and 1.3±0.2 GΩ input resistance (IR). NPY induced the hyperpolarization of 45% of the ARHkisspeptin neurons (n= 9 of 20 cells, out of 9 mice). ARHkisspeptin neuron’s RMP hyperpolarization was followed by a significant decrease in IR and frequency of action potentials (fAPS). In the AVPV/PeNkisspeptin neurons showed RMP average of -69.6±1.9 mV (-51 to - 88 mV) and IR of 0.8±0.09 GΩ (n=18 cells out of 9 mice). No significant NPY-induced effect was noted when recordings were performed on AVPV/PeNkisspeptin cells from female mice. To elucidate if the ARHkisspeptin neuron’s hyperpolarization depends on action potentials (APs) mediated by synaptic transmission we further evaluated NPY effects in the presence of TTX and amino acid receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10μM), DL-2-amino-5-phosphonopentanoic acid (AP5, 50μM), and picrotoxin (50μM). NPY induced no effect on ARHkisspeptin neuron’s RMP, and IR in the presence of TTX and amino acid receptor antagonists. Suggesting that NPY-induced hyperpolarization of ARHkisspeptin neurons is an indirect effect. To further verify whether sex must be considered as a biological variable to study the NPY effect, we recorded ARHkisspeptin cells from male mice. ARHkisspeptin neurons recorded from male mice exhibited RPM average of -55.6±1.5 (-45 to -66 mV) and IR of 1.5±0.15 GΩ (n= 13 cells out of 10 mice). Interestingly, NPY induced no effect on RMP, IR, or fAPs in male animals. In conclusion, our results suggest that NPY-induced hyperpolarization of ARHkisspeptin cells depends on AP’s mediate synaptic transmission, as a sex-specific effect.

Presentation: Saturday, June 17, 2023
SAT598 7mg-dexamethasone Suppression Test For The Differential Diagnosis Of Cushing’s Syndrome
Authors: Ramos Daniel Cuevas , García Gabriela Garza , Hernández Núñez Wellbert Elías , Gómez Pérez Francisco Javier
Published: October 2023

Disclosure: D. Cuevas Ramos: None. G. Garza García: None. W. Hernández Núñez: None. F.J. Gómez Pérez: None.

Introduction: Establishing the cause of Cushing’s syndrome remains challenging. Bilateral Inferior Petrosal Sinus Sampling (BIPSS) is the gold standard for distinguishing between Cushing's disease (ACHT-secreting pituitary adenoma) and an ectopic source of ACTH. However, BIPSS is an invasive test and is not widely available. Therefore, we sought to explore the diagnostic efficacy of the 7 mg dexamethasone suppression test (7mg-dexa) for establishing the diagnosis of Cushing's disease (CD). Methods: We reviewed 1375 cases with pituitary adenomas. From them, 191 cases had confirmed diagnosis of CD from 1999 to 2022. Of these, 25 patients underwent 7 mg dexamethasone suppression test together with BIPSS during their diagnosis workup. A diagnosis of CD was established in 21 patients, confirmed after neurosurgery, with a pathology report of ACTH+ secreting pituitary adenoma, and a biochemical resolution of CS. The additional 4 cases showed an adrenal source of CS. Suppression of 50% or more in the afternoon (of day 1 after 7 mg-dexa IV infusion by 7h starting at 7:00 hrs at 1 mg/hr) was considered consistent with CD. A central-to-peripheral plasma ACTH gradient of ≥2 before and after desmopressin stimulation was also considered consistent with CD during the BIPSS. We calculated kappa index to evaluate concordance between diagnostic test. Also, sensitivity (S), specificity (E), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were calculated. Results: The mean age was 43±12.1 years, with a BMI of 30±5.6 kg/m2, 86% females. For the basal ACTH values during BIPSS, the S=76%, E=75%, PPV=94%, NPV=37%, LR+=3, LR-=0.3. For the post-stimulation BIPSS, the S=95%, E=75%, PPV=95%, NPV=75%, LR+=3, LR-=0.06. Using the 7mg-dexa, a S=91%, E=75%, PPV=95%, NPV=60%, LR+=3.6, LR-=0.12. Kappa between test was 0.6 before stimulation, and 0.7 after desmopressin stimulation showing acceptable concordance. Conclusion: The 7 mg-dexa showed similar and acceptable diagnostic performance in comparison with basal or stimulated BIPSS. Since 7mg-dexa inhibition test is less invasive and less expensive, further clinical research to evaluate its utility in CD diagnostic approach is in order.

Presentation: Saturday, June 17, 2023
SAT612 Granulomatous Mastitis: An Unusual Presentation Of Prolactinoma
Authors: Alkaissi Hussam R , Kim Emily , McFarlane Samy
Published: October 2023

Disclosure: H.R. Alkaissi: None. E. Kim: None. S. McFarlane: None.

Background: Granulomatous mastitis (GM) is a rare, benign inflammatory breast disease of unclear etiology with clinical presentation that is similar to inflammatory breast cancer and periductal lobular mastitis. It occurs mainly in younger females and during the postpartum period. Prolactin (PRL) is an essential hormone of pituitary and extrapituitary origin that promotes lactation and the development of mammary glands within breast tissues. In addition to its lactogenic effect, it has over 300 other effects, several of which are immunomodulatory, including the expression and secretion of proinflammatory cytokines from macrophages. Clinical Case: A 37-year-old African American woman presented with right breast pain and swelling for a few weeks. Her medical history includes amenorrhea for five years. She is gravida 1, para 1 with normal spontaneous vaginal delivery at the age of 20. Physical exam showed non-bloody, non-purulent nipple discharge bilaterally, otherwise unremarkable. A breast ultrasound showed a 1 cm complex cystic mass. Biopsy showed benign breast tissue, with noncaseating granulomas formed by macrophages (CD68 positive on immunohistochemistry). Ziehl-Neelsen staining for acid-fast bacilli was negative. Staining for fungi was also negative. Prolactin level was 237 ng/mL. TSH, IGF-1, and ACTH were within normal. Pituitary MRI showed a focus of abnormal signal and diminished enhancement measuring 2.8x3.2x4.2 mm within the left side of the pituitary gland is compatible with a microadenoma. The patient was started on bromocriptine 2.5mg daily. Discussion: Our patient represents a rare case of granulomatous mastitis in the setting of microprolactinoma, likely long-standing, given the five years history of amenorrhea. The immunomodulatory effect of PRL on several immune system cells, including B-cells, T-cells, and macrophages, might be an underlying mechanism. In a recent study of 25 samples of GM, metagenomics studies identified unusual organisms in 68% of the samples. Of these, Corynebacterium kroppenstedtii was the most common (60%), followed by Pseudomonas oleovorans (16%), Epstein-Barr virus (4%), Acinetobacter baumannii (4%), and Tepidiphilus thermophilus (4%). In addition, 50% of the patients had elevated PRL, and elevated immunological markers, such as C3 and IgA [1]. This suggests that GM results from an interaction between the presence of certain pathogens in a host with elevated PRL that mediates proinflammatory response.

References: 1. Bi J, Li Z, Lin X, et al. Etiology of granulomatous lobular mastitis based on metagenomic next-generation sequencing. Int J Infect Dis. 2021 Dec;113:243-250. doi: 10.1016/j.ijid.2021.10.019. Epub 2021 Oct 19. PMID: 34673215.

Presentation: Saturday, June 17, 2023
SAT619 Post-operative Fluid Restriction Prevents Hyponatremia And Readmissions After Pituitary Surgery
Authors: Chang Julia J , Veruttipong Darlene , Chu Olivia , Erin Wipff , Gates-Bazarbay Victoria , Kling Samantha , Vinluan Khristine , Chittum Shelli , Alhadha Mohamed , Fernandez-Miranda Juan
Published: October 2023

Disclosure: J.J. Chang: None. D. Veruttipong: None. O. Chu: None. W. Erin: None. V. Gates-Bazarbay: None. S. Kling: None. K. Vinluan: None. S. Chittum: None. M. Alhadha: None. J. Fernandez-Miranda: None.

Background: Delayed hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion is the most common cause of readmission after pituitary transsphenoidal surgery (TSS). Post-operative fluid restriction (FR) after discharge may effectively reduce hyponatremia and related readmissions. Methods: Our aim was to assess the effectiveness of FR after TTS. We compared post-operative day (POD) 8 hyponatremia and related readmission rates pre- and post- FR protocol implementation at our institution. Pre-FR (July 1, 2018-March 15, 2020) post-TSS patients were instructed to drink ad lib or to thirst on discharge. Post-FR (March 16, 2020-December 31, 2020), post-TSS patients were routinely provided education and documentation on the outpatient protocol that recommended 1 liter/day FR from POD 3-5 to POD 8-10. Serum sodium was assessed at POD-8 for all patients. Patients hospitalized for more than 5 days after surgery, had untreated adrenal insufficiency, or had pre-existing AVP deficiency were excluded. Results: The average POD-8 sodium level was lower in the 115 patients in the pre-FR cohort than the 216 patients in the post-FR cohort (135.8±6.7 vs. 138.1±4.4 mEq/L; Wilcoxon-Mann-Whitney test p=0.0081). POD-8 hyponatremia (Na ≤134 mEq/L) occurred in a lower proportion of patients post-FR (15.0%; 32/214) than pre-FR (28.9%; 30/104) (Chi-Square test p=0.0033). Similarly, severe hyponatremia (Na ≤124 mEq/L) occurred in a lower proportion of patients post-FR (1.4%; 3/214) than pre-FR (8.7%; 9/104) (Fisher test p= 0.01). Only 1.4% (3/216) of patients were readmitted post-FR compared to the 8.7% (10/115) pre-FR (Fisher test p=0.0020). Conclusions: Our retrospective evaluation showed that implementation of post-TSS FR protocol significantly decreased hyponatremia by nearly 50% and readmissions by over 80% compared to the prior standard of care of drink ad lib or to thirst. FR should be considered standard-of-care for eligible patients without ongoing AVP deficiency to reduce hyponatremia and readmission burden to both patient and healthcare system.

Presentation: Saturday, June 17, 2023
OR2801 Novel Cis-Regulatory Mechanisms Of Lhb Transcription By Non-Coding RNAs And Non-Canonical DNA Structures
Authors: Refael Tal , Gruber Hadas , Golan Gil , Pnueli Lilach , Melamed Philippa
Published: October 2023

Disclosure: T. Refael: None. H. Gruber: None. G. Golan: None. L. Pnueli: None. P. Melamed: None.

Expression of the Lhb gene was shown previously to be directed by synergistic actions of lineage-specific transcription factors at conserved regions of the proximal promoter. However extensive genomic analysis during the last few decades has expanded the repertoire of factors we now know to be involved in transcriptional regulation, revealing roles for distal transcriptional enhancers and long non-coding RNAs (lncRNAs), whose modes of action are only beginning to be elucidated1. Recently it has also become evident that regulatory regions of the genome are enriched with non-canonical DNA structures. These include G-quadruplexes (G4s) which form on guanine-rich stretches of single-stranded DNA and iMotifs (iMs) on the complementary strand, and are reported to bind various proteins which presumably regulate and mediate their actions. We identified in available mice pituitary scATAC-seq data a region of gonadotrope-specific open chromatin upstream of the Lhb gene, and chromatin conformation capture (3C) in murine gonadotrope cell lines indicated the distal sites that are in physical proximity to the Lhb promoter. Further, we show by chromatin immunoprecipitation (ChIP) a peak of H3K4 monomethylation (H3K4me1) ∼3 kbp upstream of the Lhb TSS, and transcription of two bi-directional non-coding enhancer RNAs (eRNAs), both of which are characteristic of transcriptional enhancers. One of the eRNAs was found to direct open chromatin at the Lhb promoter and is required for Lhb transcription, while guide RNA-mediated recruitment of dCas9- KRAB or dCas9-VP64 to this locus altered Lhb mRNA levels accordingly, confirming its functional enhancer activity. However this enhancer activity is not sufficient for optimal Lhb transcription, and we found that splicing in situ of a distinct downstream lncRNA is also required. The DNA at the central non-coding region of the enhancer, and at the promoter of this lncRNA, forms G4 and iM structures, seen by circular dichroism and ChIP. These DNA structures are affected differentially by local conditions including changes in pH or hormonal treatments, and appear to have diverse effects. HMGB2, which is known to bind structured DNA, was found to bind the enhancer iM in cells and in vitro. Further, HMGB2 knockdown reduced the iM signal and Lhb mRNA, eRNA and lncRNA expression levels quite dramatically. We thus present novel elements involved in the regulation of Lhb transcription through various classes of non-coding RNAs and DNA structures, while emphasizing the complexity of transcriptional regulation via context-dependent cis-acting elements. References: 1. Refael T, Melamed P. (2021). Enhancing gonadotrope gene expression through regulatory lncrnas. Endocrinol. (United States) 162, bqab116.

Presentation: Sunday, June 18, 2023
THU580 A Subset Of Migrating Cells Co-express Gonadotropin Releasing Hormone And Prokineticin Receptor 2 During Embryonic Development
Authors: Danku Antoinette Eyram , Elias Carol F
Published: October 2023

Disclosure: A.E. Danku: None. C.F. Elias: None.

A subset of migrating cells co-express gonadotropin releasing hormone and prokineticin receptor 2 during embryonic development Antoinette Danku and Carol F Elias. Neuroscience Graduate Program and Department of Molecular & Integrative Physiology, University to Michigan. Reproductive vitality in humans is strongly influenced by developmental foundations. The successful migration of GnRH cells and the pulsatile secretion of gonadotropin releasing hormone (GnRH) drives pubertal onset and dictates long-term fertility outcomes. During development, GnRH neurons migrate from the nasal placode to the basal forebrain to reach their destination in the medial preoptic area (MPOA). Aberrant GnRH migration causes redirection of axonal projections to atypical brain regions and dysregulated GnRH secretion. Disruption of GnRH neuronal function causes infertility or reproductive dysfunction. These etiologies are grouped as isolated gonadotropin deficiencies (IGD). Kallmann’s syndrome (KS) is a pediatric IGD that manifests as anosmia and hormonal dysfunction that can result in pubertal delay or infertility. Children with KS often have mutations in prokineticin 2 (Prok2) or the cognate receptor (ProkR2).Prok2 and ProkR2 are required for the formation of the olfactory bulb in rodents and humans. Loss-of-function mutations in these genes also disrupts GnRH cell migration, but whether the activation of ProkR2 regulates the guidance of GnRH neurons to their final destination has not been defined. Previous studies suggested that GnRH and ProkR2 are expressed in distinct cells, but how the prokineticin system may alter GnRH migration is largely unknown. To gain insights into the underlying mechanisms associated with ProkR2-GnRH interaction and migration, we conducted single nuclei RNA sequencing in nasal-forebrain junction of embryos at embryonic day 16 (E16) and fluorescent in situ hybridization in three developmental time points: E14, E16, and E18 for validation and spatial evaluation. Using these methods, we were able to isolate GnRH and ProkR2 cells and sort their cell types into clusters. While these cells differ in their expression profiles, they both express genes associated with migration at E16. Our findings suggest that ProkR2 cells in the nasal-forebrain junction migrate along with GnRH cells. Additionally, a subset of these migrating cells co-express ProkR2 and GnRH mRNA. Further studies are needed to determine whether this subset of cells take on specialized roles in GnRH cell migration and maturation.

Presentation: Thursday, June 15, 2023
THU607 Improving Screening For Primary Aldosteronism Among People With Apparent Treatment Resistant Hypertension
Authors: Zekarias Kidmealem , Tessier Katelyn , Kohlenberg Jacob
Published: October 2023

Disclosure: K. Zekarias: None. K. Tessier: None. J. Kohlenberg: None.

Introduction: The screening rate for primary aldosteronism (PA) is low among people with resistant hypertension. People with PA experience significantly more cardiovascular complications than those with primary hypertension and an equivalent degree of blood pressure control1. Therefore, identification of people with PA for early-directed therapy is crucial. Objective: We aimed to improve the screening rate for PA among people with apparent treatment resistant hypertension (aTRH), defined as blood pressure >140/90 despite the concurrent use of three antihypertensive drug classes or any person with hypertension on >4 antihypertensive medications. Methods: Using an electronic medical record (EMR) best practice alert (BPA), we implemented a quality improvement (QI) program from 9/17/2022-3/16/2023. We included adults ≥18 years of age with aTRH, who were identified using ICD codes, the last three blood pressure measurements and the antihypertensive medication list. During office visits with nephrologists, cardiologists, endocrinologists, family medicine physicians, and internists, a BPA notified providers if the person with aTRH had not been previously screened for PA with plasma aldosterone and plasma renin activity. The alert defined aTRH, suggested that screening be performed regardless of active medications, and contained an order set for plasma aldosterone, plasma renin activity, and plasma potassium. Furthermore, the BPA suggested referral to an endocrinologist if the patient fulfilled criteria for positive case detection for PA, defined as plasma renin activity < 1 ng/mL/hour and plasma aldosterone concentration (PAC) > 10 ng/dL or the plasma aldosterone to renin ratio (ARR) > 30 with PAC > 10. We compared the PA screening rate after the implementation of the BPA to the PA screening rate over the 1 year prior to the BPA implementation (9/16/2021-9/16/2022). Results: Plasma aldosterone lab orders were placed for 3.4% (179/5,261) of people with aTRH post-BPA implementation compared to 1.9% (211/10,944) pre-BPA implementation (p<0.01). Positive case detection for PA occurred in 25% (38/152) of people screened post -BPA implementation compared to 27% (47/173) pre-BPA implementation (p=0.66). People with aTRH who were younger (p<0.01) were more likely to be screened for PA pre-BPA implementation and this did not change post-implementation. Conclusion: Implementation of a QI program employing a BPA with an embedded order set in the EMR improved the screening rate for PA among adults with aTRH. Reference 1. Monticone S, D'Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F, Mulatero P. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018 Jan; 6 (1):41-50.

Presentation: Thursday, June 15, 2023
THU130 Long Term Tracking Of HbA1c Levels Across The Life Span In Type 1 Diabetes: From Infants To Young Adults
Authors: Kim Sujin , Song Kyungchul , Lee Myeogseob , Seo Junghwan , Chae Hyun-wook , Kim Ho-Seong , Kwon Ahreum
Published: October 2023

Disclosure: S. Kim: None. K. Song: None. M. Lee: None. J. Seo: None. H. Chae: None. H. Kim: None. A. Kwon: None.

Objectives HbA1c is the most important monitoring value and generally used in diabetes. However, HbA1c may change across the life span according to growth and puberty. This study explores the long-term tracking of HbA1c from infants to young adults diagnosed with Type 1 Diabetes mellitus (T1DM) and analyzes the effects of HbA1c according to life span on complications. Method This retrospective study, included 289 patients (M, 43.0%; mean first visit age, 7.39±3.94 years old; mean followed up periods, 4.32±3.15 years) diagnosed with T1DM. The total of 6368 HbA1c values were analyzed. The distribution of HbA1c values according to age and life period was evaluated. In addition, the differences in mean HbA1c values according to sex and the use of continuous glucose monitoring (CGM) were analyzed. Furthermore, it was analyzed which HbA1c of life period has the most influence on occurrence of complications. Result The level of HbA1c was relatively high at the age of 1- to 2-years, and then decreased between 4 to 5-years. After 5 years of age, HbA1C gradually escalated and peaked at the age of 12- to 15-years, during puberty. Especially for girls, HbA1c increased dramatically during puberty between the age of 10- to 13-years, which was consistent with the physiologic insulin resistance. During in childhood to young adulthood, the mean HbA1c of CGM users was lower than that of non-users. The higher mean HbA1c during all ages affected the occurrence of complications. Intriguingly, the HbA1c level during adolescence was important for the occurrence of diabetic retinopathy. Conclusion HbA1c level change across life span, and peaked at pubertal stage, which consistent with physiologic insulin resistance during puberty. In addition, good glycemic control in adolescence may reduce the occurrence of diabetic retinopathy. Therefore, using CGM in adolescence may be helpful for glycemic control and prevention of diabetic complications.

Presentation: Thursday, June 15, 2023
THU143 A Novel Maternally Inherited GNAS Variant In A Family With Hyperphagia And Obesity
Authors: Purushothaman Preetha , Ramakrishnan Anand , Gevers Evelien F
Published: October 2023

Disclosure: P. Purushothaman: None. A. Ramakrishnan: None. E.F. Gevers: None.

Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP) characterized by developmental delay, short stature, obesity, hormone resistance and bone abnormalities. Recently, GNAS variants were also described in 1% of patients in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling. Here, we report another novel GNAS variant in family with hyperphagia and obesity and only mild features of PHP. Case: The proband presented at 6 years with hyperphagia and obesity from age 3 years. BMI was 30.4 (4.1 SDS) with height +1.9 SDS, and head circumference (HC) + 3.0 SDS. She had subtle brachydactyly, short toes and a café au lait patch. Developmental milestones and cognitive achievements were mildly delayed. Her 12-year-old brother [ height +2.1 SDS, weight +3.1 SDS, BMI 29.55 (2.9 SDS), HC +3.6 SDS] had been followed in an obesity clinic for a few years with hyperphagia, obesity, delayed developmental milestones and a recent diagnosis of autism. He also had subtle brachydactyly, as did the mother who was also obese (BMI 38.9) with a normal height but had normal cognition. Results: In the proband, initial investigations did not suggest hormone resistance. However, at 8.7 years, PTH was high [9.5 pmol/L (0.7-5.6)] with normal calcium and Vitamin D; TSH 6.6 mU/L (<6), FT4 11.8 pmol/L (10.8 - 19.0). She had hyperlipidaemia and fatty liver. X-ray hand showed generalised mild brachydactyly with a short right fifth metacarpal. In the brother, PTH tested for the first time at 12.9 years was 18.4 pmol/L (1.6-6.9), calcium and vitamin D were normal; TSH 4.04 mU/L (<4.2) and FT4 13.4 pmol/L. Next Generation Sequencing using the Cambridge Obesity gene panel detected a novel heterozygous (c.791A>C, p.(Asn264Thr) variant in exon 10 of GNAS in the proband and subsequently in the mother and brother confirming maternal inheritance. This variant has not been reported in control databases (1000 Genomes, ESP, ExAC and gnomAD, Human Gene Mutation Database and ClinVar). The variant is in a highly conserved region susceptible to missense mutations and has been classified as pathogenic using ACMG and ACGS guidelines. Discussion: In conclusion, we describe a novel heterozygous inactivating GNAS variant c.791A>C, p.Asn264Thr resulting in hyperphagia, obesity, developmental delay, macrocephaly, mild brachydactyly, tall stature and variable biochemical mild hormone resistance in 2 siblings and resulting in obesity, mild brachydactyly without cognitive impairment in the mother. These cases demonstrate the clinical heterogeneity of the monogenic disease. Clinical and biochemical screening for PHP and genetic screening for GNAS variants should be performed in patients presenting with obesity, even in the absence of classical signs of PHP, to reduce diagnostic delay.

Presentation: Thursday, June 15, 2023
THU148 Changes In Cortisol:Cortisone Ratio In Youth With Obesity One Year Following Sleeve Gastrectomy Compared To Non-surgical Controls.
Authors: López López Ana Paola , Tuli Shubhangi , Becetti Imen , Lauze Meghan , Pedreira Clarissa C , Bredella Miriam , Misra Madhusmita , Singhal Vibha
Published: October 2023

Disclosure: A.P. López López: None. S. Tuli: None. I. Becetti: None. M. Lauze: None. C.C. Pedreira: None. M. Bredella: None. M. Misra: None. V. Singhal: None.

Introduction: Glucocorticoid metabolites are associated with body composition measures and are altered with weight status. Metabolic and bariatric surgery (MBS) results in significant changes in weight and body composition. However, effects of MBS on glucocorticoid metabolites are unknown. Objective: To evaluate (i) changes in the cortisol:cortisone ratio [indicator of 11β-Hydroxysteroid Dehydrogenase (11 β -HSD) global activity] in youth with obesity 12 months after sleeve gastrectomy (SG) compared with non-surgical controls with obesity (NS), and (ii) associations of these changes with body composition changes. Methods: 60 participants 13-25 years old with obesity (44 female) were followed for 12 months. 28 participants underwent SG and 32 were followed with routine care (non-surgical, NS). Fasting blood was assessed for cortisol and cortisone using LC-MS as part of metabolomic analysis, and the cortisol:cortisone ratio calculated. Single slice MRI of the abdomen was performed to assess subcutaneous, visceral and total adipose tissue (SAT, VAT and TAT) and DXA for percent (%) body fat. Results: At baseline, groups did not differ for age or sex. SG vs. NS had higher median BMI [46.4 (41.0, 52.8) vs. 41.9 (37.9, 46.9) kg/m2, p=0.007] and % body fat [51.2 (47.8, 52.3) vs. 47.2 (39.0, 47.2) %, p=0.005)]. Groups did not differ for baseline VAT, SAT, TAT and cortisol:cortisone [10.47 (9.52, 13.86) vs. 11.05 (6.37, 14.79), p=0.58]. Significant reductions were noted over 12 months in BMI, BMIz, % body fat, TAT, VAT, SAT and VAT/SAT within the SG vs. NS groups (p ≤ 0.03). No within group changes in cortisol:cortisone over one year were noted in the NS group, but the ratio trended to decrease in the SG group [-1.40 (-5.08, 0.06), p=0.08]. No associations were found between changes in cortisol:cortisone and changes in body composition. Conclusions: The cortisol:cortisone ratio tended to decrease 12 months following SG. No associations were found between changes in the cortisol:cortisone ratio and body composition changes. Further studies with larger numbers of participants are necessary to confirm these findings.

Presentation: Thursday, June 15, 2023
THU149 A Novel Frameshift Mutation (p.H485fs) Of The Ldl Receptor Gene
Authors: Chang Seong Hwan , Yang Eun Mi , Kim Chan Jong
Published: October 2023

Disclosure: S. Chang: None. E. Yang: None. C. Kim: None.

Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction. It is an autosomal dominant inherited disease due to mutations in either the low-density lipoprotein receptor (LDL-R), the apolipoprotein B or the proprotein convertase subtilisin/kexin type 9 genes. In this study, we report a novel mutation in LDL receptor gene in a Korean family. A 10 year-old boy was referred to our hospital for hypercholesterolemia (530 mg/dl). On family history, His father and uncle have been treated for hypercholesterolemia and his grandfather died of coronary artery disease. Because of persisted hypercholesterolemia despite statin treatment for 18 months and his family history, we performed LDL-R gene study using polymerase chain reaction (PCR) sequencing. Direct sequencing of the 18 exons and exon-intron boundaries of LDL-R gene revealed deletions of C and A of exon 10 (c.1455_1456del). Study showed a novel heterozygous frameshift-deletion mutation (p.His485Glnfs*50) (p.H485fs). We performed PCR sequencing to detect same mutation on his family. Father and two siblings of the patient have same mutation (p.His485Glnfs*50) (p.H485fs) on study. Now we report a novel frameshift mutation (p.H485fs) located in exon 10 of LDL receptor gene that causes familial hypercholesterolemia in a Korean family.

Presentation: Thursday, June 15, 2023
THU150 The Association Between Glycated Albumin And HbA1c In Pediatric Acute Leukemia Patients
Authors: Sim Soo Yeun , Ahn Moon Bae , Suh Byung-Kyu
Published: October 2023

Disclosure: S. Sim: None. M. Ahn: None. B. Suh: None.

Introduction: Traditionally, HbA1c has been used as a preferred glycemic index in diabetes patients. However, as many acute leukemia patients often present with anemia and/or pancytopenia, HbA1c may not accurately represent blood glucose level in this group. Glycated albumin represents the average level of blood glucose in recent 2-3 weeks, independent of red blood cell life. In this study, we aim to evaluate the usefulness of glycated albumin as glycemic monitoring index in pediatric patients diagnosed with acute leukemia. Methods: We performed retrospective analysis of a total of 206 pediatric patients from The Seoul St. Mary’s hospital, Catholic university of Korea. Medical records of 25 patients diagnosed with type 2 DM and 66 patients with acute leukemia were investigated for serum glycated albumin, HbA1c, fasting blood glucose level, and demographic data such as sex, age, height, weight and BMI z-scores. 115 children and adolescents who visited our outpatient center for routine child health examination were enrolled as the control group. Results: The median serum glycated albumin levels were 12.4%, 19.1% for acute leukemia and T2DM patients. HbA1c and fasting blood glucose levels, 5.3% and 7.6%, 92mg/dl and 129mg/dl respectively, also differed in the two groups. All glycated albumin, HbA1c and fasting blood glucose level did not appear different in between the control and acute leukemia group. In type 2 DM patients, glycated albumin and HbA1c showed positive correlations (r=0.926, p<0.01). Fasting blood glucose level was also positively correlated to glycated albumin (r=0.821, p<0.001) and HbA1c (r=0.773, p<0.001). While glycated albumin did not appear related to HbA1c in the normal control group (r=-0.02, p=0.824), patients with acute leukemia also revealed a positive correlation between glycated albumin and HbA1c (r=0.253, p=0.04). Glycated albumin was negatively related to BMI z-scores in the control group (r=0.554, p<0.001); however, the level showed no correlation to BMI z-scores in acute leukemia group and in T2DM patients (r=-0.133, p=0.286 and r=-0.292, p=0.156). HbA1c level was positively related to BMI z-scores in the control group (r=0.241, p=0.01) and showed no relations in the other two groups. Regression analysis found glycated albumin to be positively correlated to HbA1c both in acute leukemia pediatric patients and T2DM patients even when adjusted for age, sex and BMI z-score (p=0.039, p=0.007). Conclusion: In acute leukemia patients, glycated albumin may be a complementary parameter of glycemic status as in diabetic patients.

Presentation: Thursday, June 15, 2023
THU151 Undiagnosed MODY In Case Of Morbid Obesity
Authors: Abdulkader Ahmad , Ten Svetlana B
Published: October 2023

Disclosure: A. Abdulkader: None. S.B. Ten: None.

MODY is suspected in nonobese subjects with hyperglycemia, negative islet cell antibodies, and a family history of diabetes. Children with morbid obesity and diabetes can still have MODY and require different treatment. Case report The patient was born after a pregnancy complicated with gestational diabetes, treated with insulin, BW 9 1/2 lbs. He had early onset obesity from 3 yrs. of age. At 8 yrs., he developed impaired glucose tolerance, elevated triglycerides, low HDL, and fatty liver. He developed diabetes at 11 yrs. and was treated with Insulin, but treatment was not effective, Hb A1c was 11.4%, and BMI was 51.8 kg/m2. At 12 yrs., he was diagnosed with MODY on the base of normal C-peptide, negative islet cell AB, strong family history of diabetes: mother, uncle and MGM had diabetes. Insulin was discontinued. Glyburide and Metformin were started that improved his glucose level significantly. Hb A1c improved to 6.2%. Diet was changed, physical exercises were added, and he lost 25 lbs., BMI improved to 44.8 kg/m2. His mother, 46 yrs. old, was diagnosed with diabetes type 1 at 18 yrs. and treated with Insulin. She also had morbid obesity with BMI 48 kg/m2. She developed diabetic neuropathy, nephropathy, and had amputation of the left leg below the knee, eGFR 44 mL/min/1.73m2, Hb A1c 10.5%. She was diagnosed with MODY on the base of normal C-peptide 3.21 ng/mL, negative islet cell AB, family history of diabetes: her mother, brother, son have diabetes. Glyburide and pioglitazone were started, Insulin total daily dose was decreased from 90 units to 15 units a day. Her Hb A1c improved to 6 %, insulin was discontinued. She underwent Roux-en-Y Gastric Bypass surgery, lost 30 lbs. BMI improved to 42 kg/m2, Hb A1c became 5.3%. Her current glucose level is normal on Glyburide 2.5 mg and pioglitazone 7.5 mg daily. Results: Patient and his mother had heterozygous gene polymorphism in GLIS3, c.951G>T (p.Glu317Asp). This sequence replaces glutamic acid with aspartic acid at codon 317 of the GLIS3 protein (p.Glu317Asp). GLIS3 is a variant of MODY and is a transcriptional factor in beta cell differentiation and insulin production. Patient and mother had pathogenic heterozygous variant of KSR2 gene, c.1622del, resulting in a frameshift and premature protein termination (p.Lys541Serfs*27). Pathogenic variants in KSR2 are associated with obesity and insulin resistance. Patient was also heterozygous in the NTRK2 gene for a sequence variant c.500C>A, which is predicted to result in the amino acid substitution p.Ser167Tyr, also associated with obesity. Conclusion Genetic analysis of MODY is necessary even in cases of diabetes with morbid obesity, negative islet cell AB, positive family history of diabetes. Diagnosis of MODY helps provide individualized treatment and avoid complications secondary to unnecessary treatment with insulin.

Presentation: Thursday, June 15, 2023
THU183 The Genotype-phenotype Correlation In Human 5α-reductase Type 2 Deficiency: Classified And Analysed From A SRD5A2 Structural Perspective
Authors: Kwon Ahreum , Kim Sujin , Choi Youngha , Choi Hansaem , Kim Ho-Seong
Published: October 2023

Disclosure: A. Kwon: None. S. Kim: None. Y. Choi: None. H. Choi: None. H. Kim: None.

The phenotype of 5α-Reductase type 2 deficiency (5αRD2) by SRD5A2 gene mutation varies, and even though there have been many attempts, the genotype-phenotype correlation has not yet still been evaluated. Recently, the crystal structure of 5α-reductase type 2 isozyme (SRD5A2) was discovered. Therefore, the present study retrospectively evaluated the genotype-phenotype correlation from a structural perspective in 19 Korean patients with 5αRD2. Additionally, variants were classified according to structural categories relative to phenotypic severity based on previously published data. The p.R227Q variant, which belongs to the NADPH binding residue mutation category, exhibited a more masculine phenotype (higher external masculinisation score) than other variants. Furthermore, compound heterozygous mutations with p.R227Q, mitigated phenotypic severity. Similarly, other mutations in this category showed mild to moderate phenotypes. Conversely, those variants categorised as structure destabilising and small to bulky residue mutations showed moderate to severe phenotypes, and the variants categorised as catalytic site and helix breaking mutations exhibited severe phenotypes. Therefore, the SRD5A2 structural approach suggested that a genotype-phenotype correlation does exist in 5αRD2. We can also conclude that the categorisation of SRD5A2 gene variants facilitates prediction of the severity of 5αRD2, its prognosis, and the management and genetic counselling of patients affected by it.

Presentation: Thursday, June 15, 2023
THU196 Insulin-like Growth Factor-1 As A Screening Tool For Central Precocious Puberty
Authors: Chung Lindsey Yoojin , Im Minji
Published: October 2023

Disclosure: L. Chung: None. M. Im: None.

Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard test for diagnosing central precocious puberty (CPP), which needs time and effort to perform. Recently, many studies confirmed that Insulin-like growth factor-1 (IGF-1) is involved in the initiation and progression of puberty. With this inspection, we assumed that the IGF-1 level might be correlated with the pubertal stage in central precocious puberty. This study aimed to investigate the value of IGF-1 levels in screening central precocious puberty. The medical records of 359 patients with a chief complaint of premature breast development and visited the pediatric endocrinology clinic in Myongji Hospital from January 2017 to October 2022 were reviewed. Two hundred thirty-three girls with central precocious puberty (CPP) and 126 girls with premature thelarche (PT) diagnosed were enrolled. Each subject had IGF-1 and GnRH stimulation test results. The anthropometric data between CPP and PT showed no statistical differences except for weight and the existence of lipomastia. The hormonal indicators including peak luteinizing hormone (peak LH), peak follicular stimulating hormone (peak FSH), and estradiol were statistically different between the two groups (P < 0.001). IGF-1 levels were significantly higher in CPP group than in PT group. The IGF-1 levels were positively correlated with peak LH, the diagnostic indicator of CPP. The area under the curve (AUC) of IGF-1 was 0.709. IGF-1 levels were correlated with the diagnostic indicator of CPP. IGF-1 would be a useful tool for screening CPP. Keywords: girls; IGF-1; GnRH stimulation test; precocious puberty.

Presentation: Thursday, June 15, 2023
THU201 Atypical Presentation Of Kallmann Syndrome With A Rare Genetic Mutation
Authors: Montgomery Emily L , Thrasher Bradly , Watson Sara
Published: October 2023

Disclosure: E.L. Montgomery: None. B. Thrasher: None. S. Watson: None.

Kallmann Syndrome presents as idiopathic hypogonadotropic hypogonadism with additional findings of hyposmia or anosmia and midline facial defects, including cleft lip/palate. We present a case of Kallmann Syndrome due to a rare genetic mutation with absent Mullerian structures. A 15 year, 6 month old female with history of cleft lip and palate and short stature was referred for primary amenorrhea. Clinical history was notable for limited sense of smell and no signs of puberty, including thelarche or adrenarche. Family History unknown (adopted). Significant physical exam findings include tanner 1 breast, no pubic or axillary hair, normal external female genitalia without clitoromegaly, unestrogenized vaginal introitus. Height 147cm (0.88%ile for age). Lab evaluation consisted of: LH 0.66 mIU/ml (2.4-12.6 mIU/ml), FSH 1.63 mIU/ml (3.5-12.5 mIU/ml), prolactin 11.30 ng/ml (4.79-23.30 ng/ml), BhCG negative, testosterone 8 ng/dl (2-17 ng/dl), free testosterone 1.1 pg/ml (<2.2 pg/ml), estradiol 3.0 pg/ml (9.0-249.0 pg/ml), AMH 2.46 ng/ml (1.05-12.86 ng/ml), thyroid function testing and growth factors normal. Imaging included pelvic ultrasound that showed no uterus or gonads. An MRI was obtained that confirmed these findings and also a blind-ending vaginal canal. While the presentation is suggestive of Kallmann Syndrome, the lack of Mullerian structures on imaging has not previously been described. Further evaluation included karyotype (46, XX) and hypogonadotropic hypogonadism genetic panel that identified a mutation in the FGFR1 gene with c.2172C>G (p.Asn724Lys), heterozygous, variant of uncertain significance. Estrogen replacement therapy was initiated with subsequent expected pubertal progression. Repeat imaging after seven months of treatment demonstrated presence of normal developing uterus and bilateral ovaries. Clinical Lesson/Conclusion: 1.Rare mutation with now 3 reports suggesting it is a true pathologic variant2.Unique presentation with hypoplastic Mullerian structures not detected on imaging.This patient’s particular variant has previously been described in in 2 individuals (mother/son) with features of Kallmann Syndrome (PMID: 16606836) with normal and partial puberty respectively, increasing the suspicion that this variant is pathogenic. Newly described FGFR1 variant associated with Kallmann Syndrome / hypogonadotropic hypogonadism. Kallmann Syndrome is not associated with lack of Mullerian structures, however this patient presented with features of Kallmann Syndrome and imaging that did not demonstrate presence of Mullerian structures. Since initiating estrogen therapy, she has had appropriate development of uterus and ovaries. This case demonstrates that prior to estrogen therapy, patients with Kallmann Syndrome may have underdeveloped Mullerian structures that not recognized on imaging prior to estrogen replacement therapy.

Presentation: Thursday, June 15, 2023
THU215 Treatment Of Childhood-onset Craniopharyngioma Patients Using Proton Beam Therapy Versus Photon-based Radiation Therapy In The Prospective Kraniopharyngeom 2007 Trial
Authors: Friedrich Carsten , Boekhoff Svenja , Sowithayasakul Panjarat , Eveslage Maria , Beckhaus Julia , Bison Brigitte , Timmermann Beate , Muller Hermann Lothar
Published: October 2023

Disclosure: C. Friedrich: None. S. Boekhoff: None. P. Sowithayasakul: None. M. Eveslage: None. J. Beckhaus: None. B. Bison: None. B. Timmermann: None. H.L. Muller: None.

Proton beam therapy (PBT) compared to photon-based radiotherapy (XRT) offers the benefit to administer lower radiation doses to critical organs thereby possibly minimizing the risk of sequelae in patients with residual craniopharyngiomas (CP) after hypothalamus-sparing surgery. The validation in large CP patient cohorts is still pending. Of 290 childhood-onset CP patients included 2007-2019 in the prospective multicenter trial KRANIOPHARYNGEOM 2007, 99 (34%) received external RT (65% PBT, 35% XRT). Outcome was compared between the different groups in terms of overall (OS) and event-free survival (EFS), quality of life (QoL using PEDQOL), functional capacity (FMH), and auxological data (BMI and height SDS) one, three and five years after irradiation/CP diagnosis. PBT became the predominant irradiation technique during the study period (used in 23% and 77% of all irradiated patients registered within the first and second half of the enrollment period, respectively). PBT as well as XRT were associated with high (p<0.001) EFS (PBT: 0.917 ± 0.040; XRT: 0.940 ± 0.041) compared to non-RT (EFS: 0.669 ± 0.044). OS was similar in all groups. No differences between PBT, XRT and non-RT CP patients concerning functional capacity and anthropometric parameters (height SDS, BMI SDS) have been obtained. Only in the PEDQOL domain “physical function”, proxy-assessed QoL was lower one year after PBT when compared to XRT treated and non-irradiated CP patients. PBT is similar efficient in preventing relapses in childhood-onset CP patients. During follow-up, clinically relevant differences between PBT and XRT in terms of QoL, functional capacity and degree of obesity as a marker of hypothalamic syndrome were not detectable. While PBT is increasingly applied, studies on larger CP cohorts with longer follow-up after RT are warranted to analyze, whether it can prevent sequelae such as hypothalamic syndrome and severe obesity compared to XRT.

Presentation: Thursday, June 15, 2023
THU218 Congenital Craniopharyngioma - Cases Recruited In The German Kraniopharyngeom Trials And Review Of The Literature
Authors: Boekhoff Svenja , Beckhaus Julia , Bison Brigitte , Friedrich Carsten , Muller Hermann Lothar
Published: October 2023

Disclosure: S. Boekhoff: None. J. Beckhaus: None. B. Bison: None. C. Friedrich: None. H.L. Muller: None.

Background: Craniopharyngiomas (CP) are rare malformational tumors. Clinical presentation and outcome of patients with congenital CP (cCP) are not clear and refer mainly to few case reports in the literature. The aim of this study was to analyze clinical presentation and outcome in patients with cCP. Clinical cases: Seven hundred and nine patients diagnosed with adamantinomatous CP were recruited 1999-2021 in HIT-ENDO, KRANIOPHARYNGEOM 2000 / 2007 / Registry 2019 and prospectively observed. In 3 cases, cCP was diagnosed prenatally and in one case at the 2nd day of life. Pre- and perinatal diagnostic findings, postnatal evaluation, therapeutic interventions and outcome in these 4 cases of cCP were analyzed. When compared to cases of cCP reported in the literature, more recent cases like our reported cCP have an overall better prognosis with regard to survival and sequelae. Two of our 4 cCP suffered from hemiparesis and one patient presented with mild motor retardation. In contrast to historical reports (lethal rate of >50%), all patients in our report recruited after 2000 survived. Prenatal routine ultrasound examination was the usual diagnostic procedure leading to diagnosis of cCP. Tumor resection was performed during early postnatal period (range: 11 - 51 days of age). Complete resection of the mostly large sized tumors could be achieved in two of four patients with cCP. Conclusion: Based on improvements of diagnostic and therapeutical methods and techniques, earlier prenatal diagnosis of cCP should lead to intrauterine transfer of cCP patients to a specialized center for postnatal treatment of newborns with sellar masses by a multidisciplinary team to secure an improved prognosis of these patients.

Presentation: Thursday, June 15, 2023