bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT266 Transcriptional Changes Associated With Loss Of Function Of Fumarate Hydratase In A Cellular Model Of Pheochromocytoma
Authors: Hall Charlotte Louise , Read Jordan Elise , Salsbury Grace , Lim Eugénie , Akker Scott , Chapple Paul 
Published: October 2023

Abstract
Disclosure: C.L. Hall: None. J.E. Read: None. G. Salsbury: None. E. Lim: None. S. Akker: None. P. Chapple: None.
Mutations in fumarate hydratase (FH) predispose to development of pheochromocytomas and paragangliomas (PPGLs), as well as leiomyomas and renal cell carcinoma. Loss of FH function leads to accumulation of fumarate which acts as an oncometabolite to drive tumorigenesis, although the molecular mechanisms leading to the development of these rare tumours are not fully understood. We have used CRISPR/Cas9 genome editing to generate a series of FH knockouts in the PC-12 cell line, derived from MAX-mutated pheochromocytoma in rat. Our knockout cell lines were used as a model to investigate the molecular consequences of loss of FH function. Comparison of the transcriptome of FH knockout cells with isogenic controls identified 1016 differentially expressed genes (adjusted p&lt;0.05 Log2fold±1). This list of differentially expressed genes was then analysed to identify cellular pathways that were dysregulated in the absence of FH. Canonical pathways that were significantly altered, based on transcript expression relative to controls, included axonal signalling pathway (p=7.29x10-11), wound healing signalling pathway (p=1.74x10-07), pulmonary fibrosis idiopathic signalling pathway (p=4.10x10-07) and IL-15 production (p=1.03x10-05). Our results suggest cell adhesion and immune regulation pathways may be relevant to the development of PPGLs with germline mutations in FH, but will require validation in the context of human tissue. We have also performed metabolic flux analysis to identify differences in metabolite profile associated with loss of FH. Interestingly, changes in gene expression, revealed by our transcriptomic analysis, may explain some alterations in cellular metabolism of FH knockout cells.
Presentation: Saturday, June 17, 2023
SAT274 Multilocus Imprinting Disorder Due To Genome-wide Paternal Uniparental Disomy Associated With Adrenocortical Tumors
Authors: Pinto Emilia Modolo , Lalli Enzo , Wu Gang , Ribeiro Raul , Zambetti Gerard 
Published: October 2023

Abstract
Disclosure: E.M. Pinto: None. E. Lalli: None. G. Wu: None. R. Ribeiro: None. G. Zambetti: None.
Pediatric adrenocortical tumor (ACT) is an uncommon malignancy frequently associated with Li-Fraumeni syndrome, a familial cancer predisposition disorder caused by germline mutations in the tumor suppressor TP53. ACT is also associated with other genetic constitutional disorders, such as Beckwith-Wiedemann syndrome (BWS) which results from the deregulation of a gene cluster on chromosome 11p15. We report here the identification of three pediatric patients with ACT and additional tumors, two of which received a clinical diagnosis of BWS. Family histories of these two probands include multiple unsuccessful pregnancies. All patients have wild-type TP53 sequence and no evidence for germline chromosome 11p15 alterations. Molecular analyses by whole genome sequencing revealed genome-wide copy neutral loss of heterozygosity (cnLOH) in all tumors. Microsatellite STR and MS-MLPA confirmed genome-wide cnLOH with the selective loss of all maternal chromosomes and duplication of paternal chromosomes in each tumor. Analysis of skin fibroblasts showed mosaic paternal uniparental disomy with partial LOH for all chromosomes, while no LOH was detected in blood DNA. The most prominent clinical feature of genome-wide cnLOH is an unbalanced monoallelic and parent-of-origin specific expression of imprinted genes known as multilocus imprinting disorder (MID). MID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (DMRs) in early embryogenesis. In addition, causative trans-acting factors in imprinting disorders, including the subcortical maternal complex (SCMC), have the potential to affect multiple DMRs across the genome, resulting in a multilocus imprinting disorder. Our study identifies three pediatric patients who developed ACT and other tumors that have undergone genome wide cnLOH that specifically selected against all maternal chromosomes. None of three patients presented with germline alterations in TP53 or 11p15, typical of pediatric ACT. WGS data revealed a germline mutation (p.M573T) in the histone methyltransferase NSD1 in the mother of patient #2. NSD1 mutations are reportedly associated with recurrent miscarriages, tissue overgrowth and increased cancer risk. Alterations in other epigenetic regulators, such as SETD1B (p.R226C), a component of a histone methyltransferase complex and TNRC18 (p.P454L), that enables chromatin binding activity were observed in both mother and child in each family. Further analysis of maternal-effect variants associated with abnormal pregnancies and MID will be important for understanding the mechanisms underlying genome-wide cnLOH. Our results support the molecular testing of multiple loci in atypical clinical presentations of patients with pediatric ACT.
Presentation: Saturday, June 17, 2023
SAT276 Glucocorticoid Excess Elevates Metabolic Rate Via A 11b-HSD1 Dependent Mechanism In C57BL/6J Mice
Authors: Heaselgrave Samuel , Heising Silke , Morgan Stuart Andrew , Kabli Ali , Sagmeister Michael , Doig Craig , Hardy Rowan Samuel , Morton Nicholas M , Tsintzas Kostas , Lavery Gareth Geoffrey 
Published: October 2023

Abstract
Disclosure: S. Heaselgrave: None. S. Heising: None. S.A. Morgan: None. A. Kabli: None. M. Sagmeister: None. C. Doig: None. R.S. Hardy: None. N.M. Morton: None. K. Tsintzas: None. G.G. Lavery: None.
Introduction: Glucocorticoids are vital metabolic regulators. However, glucocorticoid excess (GE) causes severe metabolic dysfunction, ultimately leading to Cushing’s Syndrome. This dysfunction is often dependent on the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Whether GE also alters metabolic rate, and whether this is also dependent on 11β-HSD1, remains unclear and merits investigation in a mouse model of GE and 11β-HSD1 inhibition. Methods: Male and female wild type (WT) C57BL/6J and 11β-HSD1KO mice were treated with corticosterone or vehicle control ad libitum via drinking water for 3 weeks whilst being fed a standard chow diet (n=12). Mice were housed in a TSE Phenomaster system for the final week of treatment for comprehensive metabolic assessment. Results: Corticosterone treatment in WT mice resulted in a phenotype typical of GE, however female mice experienced greater fat accumulation and bodyweight gain compared to males. 11β-HSD1KO mice did not experience this phenotype. Corticosterone treatment elevated energy expenditure (EE) in female WT mice during the day alone (25±5.9%). Male WT mice did not experience a significant increase. Corticosterone did significantly elevate the respiratory exchange ratio (RER) towards 1 in both male (10.7±5.7%) and female (11.8±7.0%) WT mice during the day. RER remained elevated in female WT mice (7.6±4.8%) and moderately so in male WT mice (3.2±2.6%) at night, indicating a continued suppression of lipid oxidation in favour of carbohydrate oxidation. Activity, assessed in female WT mice only, was continually decreased by corticosterone treatment (-53.1±54.8%). Corticosterone treated WT mice became hyperphagic and polydipsic, continuously eating and drinking more than controls. Male and female 11β-HSD1KO mice treated with corticosterone did not experience these effects. Conclusion: These findings provide further insights into the metabolic consequences of GE as well as the dependency on 11β-HSD1 to facilitate them. Whilst elevations are seen in both male and female WT mice, they are greater in females. Activity is decreased meaning it is not responsible for the elevations. However, hyperphagia and the subsequent chemical energy cost of de novo lipogenesis might be responsible and merits further investigation.
Presentation: Saturday, June 17, 2023
SAT340 Matters Of The HAART - Ritonavir Induced CYP3A4 Inhibition of Intranasal Fluticasone Leading To Cushing’s Syndrome
Authors: Ramachandran Aishwarya , Ghaith Sarah , Ramachandran Akshaya 
Published: October 2023

Abstract
Disclosure: A. Ramachandran: None. S. Ghaith: None. A. Ramachandran: None.
Background: Ritonavir, a potent inhibitor of the CYP3A4 enzyme, can lead to high systemic concentrations of even intranasal steroids causing Cushing’s syndrome. Case: A fifty-seven-year-old man with history of HIV on HAART presented with a 3-month history of fatigue, weight gain and easy bruising. History was negative for heat/cold intolerance, hair loss, constipation, erectile dysfunction. Medications included emtricitabine-tenofovir-alafenamide and ritonavir at stable doses for several years. He denied taking any oral or topical steroids, but reported using over the counter (OTC) fluticasone propionate (FP) for the past 6 months for seasonal allergies. Physical examination was significant for moon facies and abdominal striae. Labs were remarkable for low serum morning cortisol of 0.6 µg/dl (0.4-22.6 µg/dl), and low serum ACTH of &lt;5 pg/ml (7-69 pg/ml). A diagnosis of exogenous steroid induced Cushing’s syndrome, as a result of ritonavir induced increase in FP levels was made. FP was gradually tapered and stopped. Serum cortisol and ACTH levels normalized at 15 µg/dl and 13 pg/ml respectively and his symptoms resolved completely after three months. Discussion: Ritonavir, a protease inhibitor (PI), is one of the strongest known inhibitors of CYP3A4 and is generally used to boost the plasma levels of other PIs. FP, a potent glucocorticoid, is generally used as monotherapy or as a combination inhaler in the treatment of asthma. It is rapidly metabolized by CYP3A4 and hence produces minimal side effects. However, its concurrent use with ritonavir results in increased serum concentration of FP leading to systemic adverse effects of glucocorticoids. Due to emerging awareness about this drug-drug interaction among physicians, prescription of inhalational steroids in patients on ritonavir is avoided. However, FP is an OTC intranasal glucocorticoid that is easily accessible, and its self-use is often times not reported by patients which makes it difficult for physicians to track on their patient’s medication list. A thorough review of OTC medications/supplements needs to be done when Cushing’s syndrome from exogenous steroids is suspected. It is also imperative that patients on ritonavir be counseled about the risks of taking any form of steroid formulations by any route. Conclusion: Educating patients on ritonavir about steroids being a component of many OTC medications/supplements, and a careful medication history and drug-drug interaction assessment is important in preventing steroid related adverse effects.
Presentation: Saturday, June 17, 2023
THU400 Parameters Of Vitamin D Metabolism, Calcium And Phosphate Homeostasis In Patients Undergoing Bariatric Surgery
Authors: Zhukov Artem , Povaliaeva Alexandra , Abilov Zaur , Usoltseva Liliia , Trukhina Diana , Pigarova Ekaterina , Rozhinskaya Liudmila 
Published: October 2023

Abstract
Disclosure: A. Zhukov: Grant Recipient; Self; Russian Science Foundation (project 19-15-00243-P). A. Povaliaeva: Grant Recipient; Self; Russian Science Foundation (project 19-15-00243-P). Z. Abilov: Grant Recipient; Self; Russian Science Foundation (project 19-15-00243-P). L. Usoltseva: None. D. Trukhina: None. E. Pigarova: Grant Recipient; Self; Russian Science Foundation (project 19-15-00243-P). L. Rozhinskaya: Grant Recipient; Self; Russian Science Foundation (project 19-15-00243-P).
Objective: to evaluate the parameters of vitamin D metabolism and calcium and phosphate homeostasis in patients undergoing bariatric surgery. Materials and Methods: The study included 10 patients without chronic kidney disease and mineral metabolism disorders who underwent laparoscopic gastric bypass surgery for obesity. After surgery, all patients were recommended to take cholecalciferol depending on the initial level of 25-OH D in blood in accordance with the Endocrine Society Clinical Practice Guideline. Ninety nine [96; 130] days after the surgery, the levels of vitamin D metabolites: D3, 25-OH D3, 24,25-OH2 D3, 1,25-OH2 D3 were determined by ultra-high performance liquid chromatography in combination with tandem mass spectrometry (certified by DEQAS) as well as the PTH, total calcium, albumin, creatinine, phosphorus, magnesium levels in serum. Results: Median age of the patients was 39 [34; 50] years, 80% women, 90% initially had type 2 diabetes mellitus (BMI before surgery 49.1 [39.7; 51.0] kg/m2, median decrease in BMI by the time of inclusion in the study 8.3 [8.0; 9.2] kg/m2). The median level of 25-OH D3 was 28.5 [24.6; 32.0] ng/ml (1 patient had a level less than 20 ng/ml, 6 patients from 20 to 30 ng/ml), D3 levels were below the laboratory sensitivity threshold (12.5 ng/ml) in all participants. The median 24,25-OH2 D3 level was 1.49 [1.04; 1.95] ng/ml (reference interval (RI) 0.5-5.6 ng/ml), the median 25-OH D3/24,25-OH2 D3 ratio was 21.87 [15.57; 22.55] (RI 7-23). All patients had normal levels of 1,25-OH2 D3 (median 45.95 [35.18; 53.65] pg/ml, RI 25-66). One patient had secondary hyperparathyroidism (albumin-adjusted calcium 2.14 mmol/l, RI 2.15-2.55; PTH 73.8 pg/ml, RI 15-65; 25-OH D3 24.8 ng/ml) while other biochemical parameters were normal. The remaining patients had normal levels of PTH, calcium, phosphorus and magnesium. Conclusions: The revealed changes in the levels of D3 and 25-OH D3 in patients undergoing bariatric surgery may be due to malabsorption, increased deposition in adipose tissue, an insufficient dosage of cholecalciferol or low patient compliance. At the subsequent stages of vitamin D metabolism, no abnormalities were identified. It is likely that this cohort of patients requires higher doses of cholecalciferol.
Presentation: Thursday, June 15, 2023
THU436 Small Intestinal Bacterial Overgrowth Causing Osteoporosis In An Adult Male
Authors: Aziz Shima , Patrick Stephanie Arana , Mupparaju Vamsee , Kode Sudha 
Published: October 2023

Abstract
Disclosure: S. Aziz: None. S.A. Patrick: None. V. Mupparaju: None. S. Kode: None.
Background: Small intestinal bacterial overgrowth (SIBO) is a disease caused by intestinal dysbacteriosis which can lead to nutrients malabsorption and chronic metabolic acidosis which affect bones health and cause osteoporosis. Clinical Case: A 45-year-old man with medical issues of GERD presents to the endocrinology clinic in 02/2022 for evaluation of incidental finding of T5 vertebral fracture noted in the chest x-ray done for evaluation of chest tightness. During the clinic visit the patient reported chronic bloating and gassiness. Denied symptoms suggestive of eating disorders, chronic fatigue, decreased libido, recurrent fractures, elastic skin, hypermobile joints or joint dislocation, and steroid use. Patient is married and has two biological children. He drinks alcohol socially and denied tobacco use. Patient was taking cholecalciferol 1000 IU daily at home. His weight is 64 kg with a BMI of 21 kg/m2. Physical examination did not reveal any abnormality. Bone mineral density showed the worst Z-score of -2.3 in his spine. Workup for osteoporosis included 24-hour urine calcium, CBC, CMP (including serum calcium, phosphorus, electrolytes, ALP, and creatinine), PTH, TSH, free plasma cortisol, ACTH, morning total testosterone, 25-hydroxyvitamin D level, SPEP, UPEP, celiac disease screening tests (tissue transglutaminase IgA and tTG IgG), IGF-1 and HbA1c were all within normal limits. The patient was started on alendronate 70 mg once weekly and was referred to a local gastroenterologist for further evaluation of his GI symptoms; he subsequently was diagnosed with SIBO which is the most likely cause for his osteoporosis. Conclusion: SIBO is a disease caused by intestinal dysbacteriosis, which is caused by replacement of physiologic bacteria by pathogenic bacteria from the large intestine leading to maldigestion and malabsorption of nutrients including fat, carbohydrates and protein leading to vitamins deficiencies and metabolic acidosis. Due to impaired absorption of nutrients it can cause systemic complications including osteoporosis. Fat malabsorption can lead to deficiencies of fat-soluble vitamins A, D, K and E. SIBO can also result in protein-losing enteropathy. The state of chronic metabolic acidosis caused by SIBO increases alkali mobilization from the bone and induces dissolution of the bone thus promotes the development of osteoporosis. Gastrointestinal diseases including SIBO should be considered in cases of osteoporosis of unknown origin.
Presentation: Thursday, June 15, 2023
THU439 Baby's Coming, Break A Leg! A Case Of Transient Osteoporosis Of The Hip
Authors: Khan Aysha , Syeda Asma , Aftab Hassaan B 
Published: October 2023

Abstract
Disclosure: A. Khan: None. A. Syeda: None. H.B. Aftab: None.
Introduction: Pregnancy-associated osteoporosis (PAO) is a rare condition presenting as fragility fractures usually in the latter part of pregnancy or immediate postpartum period. Vertebral fractures are more commonly reported but femoral fractures have also been described in the literature as a distinct entity: transient osteoporosis of the hip (TOH). We present a case of bilateral (B/L) femoral fractures in a woman during pregnancy and in the postpartum period. Case: A 31-year-old, gravida 1 female developed left leg pain at 26 weeks of gestation. The pain radiated from her left lower back to her left knee. It was severe in intensity resulting in her walking with crutches. Subsequent MRI of the left hip showed subchondral insufficiency fracture of the femoral head with prominent bone marrow edema extending from the head into the femoral neck. She was managed conservatively with non-weight bearing status and oral analgesics. She had an uncomplicated vaginal delivery at 39 weeks of gestation. During the first postpartum week she developed right hip pain. MRI of right hip revealed nondisplaced right femoral head subchondral insufficiency fracture with associated effusion and synovitis. She recovered within the next 3 months with resolution of her pain with conservative management. Other than limited calcium intake in childhood, there were no other identifiable risk factors for osteoporosis. Bone density scan revealed normal Z-scores at the lumbar spine and non-dominant wrist. The hips were not evaluated. Workup for secondary causes of osteoporosis was unremarkable including normal serum calcium, PTH, phosphorus, magnesium, SPEP, tissue transglutaminase antibodies, estradiol, LH, FSH, prolactin levels. However, 24-hour urine calcium level was low at 11 (35-250) mg/24hr. Elevated levels of bone specific alkaline phosphatase and urine N-telopeptide (NTX) were noted at 19.9 (5.3-19.5) mcg/L and 110 (4-64) nM BCE/mM creatinine, respectively. Patient was continued on vitamin D and calcium supplements. She breastfed for the initial 2 months but was advised to stop. At her most recent follow up visit 4 months postpartum patient was doing well. Discussion: TOH is a rare entity, and presentation as B/L femoral fractures is exceedingly rare. During pregnancy and lactation, the skeletal system undergoes bone loss to compensate for the calcium demand of the fetal skeletal system. In TOH, venous stasis from the gravid uterus resulting in bone marrow edema is the proposed mechanism in addition to pregnancy associated bone loss. In our patient, a low 24-hr urine calcium could suggest low calcium intake which could have contributed to the fracture as well. While recurrence of PAO has been described, no recurrence of TOH has been reported in subsequent pregnancies. Our case highlights the importance of keeping this rare entity on the differential in pregnant women presenting with back or hip pain.
Presentation: Thursday, June 15, 2023
THU451 Low Bone Mineral Density In A Patient With Thalassemia Minor
Authors: Woron Felicia , Madhavan Parvathy 
Published: October 2023

Abstract
Disclosure: F. Woron: None. P. Madhavan: None.
Osteoporosis is a known complication of thalassemia major and thalassemia intermedia, but is not typically considered in patients with thalassemia minor. Here, we present a 74-year-old Caucasian male patient with thalassemia minor who presented to us for follow-up of osteoporosis. The patient reports a history of osteoporosis that was diagnosed prior to 2004. Additionally, he has a history of radiation exposure to his head and neck, goiter, prostate cancer status post resection in 2019, and atrial fibrillation, for which he has been on apixaban since 2021. He was treated with risedronate for his osteoporosis from approximately 2004 to about 2011 by other providers, with improvement in bone density to osteopenia. Free testosterone, parathyroid hormone, calcium, and serum protein electrophoresis levels evaluated prior to his diagnosis of osteoporosis were all noted to be normal. He has not had a fracture as an adult. He is being monitored with conservative management and currently aims for a daily calcium intake of 1000-1200 mg, including diet and supplements, and a daily Vitamin D intake of 2000 IU. He engages in frequent weight-bearing exercise. As of September 2021, his bone mineral density was osteopenic in the lumbar spine (T score of −2) and left hip (total T score of the left hip −1.6, and −1.8 in the femoral neck). The patient had no other known risk factors for decreased bone mineral density preceding the onset of his osteoporosis, and a previous workup for secondary causes of his osteoporosis etiology proved negative. Adding to one existing case report in the literature, we propose that thalassemia minor may potentially be a risk factor for osteopenia and osteoporosis, and that we should consider screening thalassemia minor patients with DXA for evaluation of bone health.
Presentation: Thursday, June 15, 2023
THU454 Paget’s Disease Of Bone As An Atypical Cause Of Headaches
Authors: Delgado Nieves Andrea Nicole , Hernandez Christian Gomez , Nassar Rawann , Goulden Peter Anthony 
Published: October 2023

Abstract
Disclosure: A.N. Delgado Nieves: None. C. Gomez Hernandez: None. R. Nassar: None. P.A. Goulden: None.
Background: Worsening Paget’s disease of bone (PDB) typically manifests as pelvic or spine bone pain. Headache as a primary presenting symptom of PDB is uncommon. Case Presentation: A 54-year-old female with Paget’s disease on alendronate presented at our institution with progressively worsening headaches, frontal bossing, alkaline phosphatase (ALP) of 1,668 U/L, and serum C-telopeptide of 986 pg/mL, indicating active disease. Subsequently, a bone scan confirmed active PDB, and zoledronic acid injection was administered in clinic. When re-evaluated, repeat laboratory values showed an ALP of 191 U/L, serum C-telopeptide of 511 pg/mL, PTH of 103 pg/mL, and vitamin D of 25.6 ng/mL, consistent with improved yet persistently active disease. Likewise, the patient complained of ongoing headaches, dizziness, hearing loss, and jaw pain. An X-ray of the skull showed diffuse expansile mixed Paget's disease, predominantly sclerotic, involving the calvarium with some basilar invagination noted. Subsequent whole-body bone scan showed intensely increased uptake in the skull. Audiology evaluation revealed slight to mild sensorineural hearing loss in bilateral ears. A second dose of zoledronic acid infusion was administered, and the patient’s ALP and C-telopeptide decreased to normal levels. Conclusion: We describe a case of advanced Paget’s disease presenting with persistent headaches. Clinicians should identify Paget’s disease as an atypical cause of headaches to provide appropriate treatment and prevent complications of skull involvement such as hearing loss.
Presentation: Thursday, June 15, 2023