bluuebunny/crossref_metadata_2025 huggingface dataset:
5132 Unraveling the Enigma: A COVID-19 Triggered Revelation of Adult Idiopathic ACTH Deficiency
Authors: Arao Kevin A , Gadbois Alexander E
Published: October 2024

Disclosure: K.A. Arao: None. A.E. Gadbois: None.

Introduction: Adult idiopathic ACTH deficiency (AIAD) is a rare and potentially life-threatening condition that is frequently misdiagnosed or even missed. We present a case of AIAD in a patient who exhibited altered mental status alongside a COVID-19 infection and was fortunately diagnosed after responding to empiric treatment with oral steroids for another condition. Case Presentation: A 76-year-old man was admitted to the hospital for bilateral leg weakness. His hospital stay was complicated by the development of febrile episodes and delirium. He tested positive for COVID-19, and the rest of infectious work-up yielded negative results. He then received a course of remdesivir. In the evaluation of his delirium, a CT scan of the brain, MRI of the brain, and lumbar puncture with CSF analysis were done, all of which were unremarkable. Initially, the delirium was attributed solely to COVID-19 infection. After consultation with neurology and rheumatology, the patient received empiric treatment with prednisone 5 mg twice daily for possible polymyalgia rheumatica as a cause of his bilateral leg weakness. His mental status significantly improved following steroid administration. With the improvement in symptoms, an AM cortisol test was added on his morning blood tests, revealing a cortisol level of 2.56 mcg/dL with an albumin level of 2.3 g/dL, raising concerns for adrenal insufficiency. An outpatient endocrinology evaluation recommended transitioning from prednisone to physiologic twice-daily dosing of hydrocortisone. An ACTH stimulation test was performed, which peaked at an AM cortisol of 6.1 mcg/dL, with a baseline ACTH level of 4.1 pg/mL. A review of the recent brain MRI showed no pituitary pathology. Other pituitary hormones were normal, and he was eventually diagnosed with AIAD. He was subsequently maintained on physiologic dosing of hydrocortisone, resulting in clinical stability. Discussion: AIAD is characterized by secondary adrenal insufficiency, normal production of other pituitary hormones, and the absence of structural pituitary pathology. The etiology of AIAD remains unknown, with most cases attributed to an autoimmune process. AIAD can have diverse clinical manifestations and may only become more apparent with triggers like infections or illnesses. As in our case, the COVID-19 infection likely unmasked the underlying AIAD, presenting with altered mental status. Identifying AIAD can be challenging, leading to high rates of misdiagnosis and clinical omission. Physicians should consider AIAD when dealing with unexplained altered mental status, as the administration of a simple treatment with steroids can be life-changing.

Presentation: 6/3/2024
5147 Use of hypertonic saline in severe symptomatic hyponatraemia; results from a national survey from United Kingdom
Authors: Arshad M , Iqbal A
Published: October 2024

Disclosure: M. Arshad: None. A. Iqbal: None.

Background: Acute severe symptomatic hyponatraemia is potentially life-threatening. Irrespective of the underlying aetiology, hypertonic saline (HTS) is effective at rapidly correcting serum sodium. Several clinical treatment guidelines have aimed to standardise the administration of HTS. The European Society of Endocrinology (ESE) guidelines (2014) recommend two boluses of 150 mL 3% HTS with an aim to raise serum sodium concentration by 5 mmol/L([1]). It is important to note that the evidence supporting this approach is limited, and concerns have been raised regarding the potential for overcorrection using this protocol(2). Aim: To assess the practices and perceptions surrounding hypertonic saline (HTS) use in severe symptomatic hyponatraemia among United Kingdom (UK) endocrinologists and specialty trainees (fellows). Methods: An anonymous online survey was disseminated to all clinical members of the Society for Endocrinology (UK) between 24/10/2023 and 30/11/2023 using Survey Monkey ®, a web-based multiple-choice questionnaire. Results: Of 133 respondents (60.1% consultants, 33.1% specialty trainees, 6.8% other), 85% employed bolus treatment with HTS only, with 9.8% using both bolus and continuous infusions. Most (50.4%) preferred 150 mL boluses, followed by 100 mL boluses (18.8%). Commonly used HTS strengths were 2.7% (45.1%), followed by 1.8% (31.6%), while the 3% HTS strength recommended by ESE guidance was used by 21.8%. Only 7 (5.3%) respondents used weight-based HTS dosage. Contrary to guidelines, 74.4% did not administer a second bolus without waiting for sodium result from the first bolus. Also, 86% have experience using venous blood gas sodium readings for monitoring, even though this has not been mentioned or recommended in the guidelines. HTS was always administered in high-dependency settings by 16.5% and mostly administered in this setting by 49.6%. Overcorrection targets defined by 10 and 8 mmol/24 hours cut-offs were used by 48.9% and 39.9%, respectively. For definite or expected overcorrection, 75.9% preferred 5% dextrose, while 40.6% had experience with desmopressin (DDAVP). Conclusion: Significant variation exists in HTS use for severe symptomatic hyponatraemia in the UK, deviating from guidelines, especially regarding a second bolus without assessing the first bolus's biochemical impact. European guidelines warrant an evidence-based revision to harmonize clinical practice. References: (1) Spasovski et al. Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. doi: 10.1530/EJE-13-1020(2) Arshad et al. Letter to Editor: Call for review of European Society of Endocrinology guidelines for symptomatic hyponatraemia. Endocrine. 2023 Apr;80(1): 234-235. doi: 10.1007/s12020-023-03322-w

Presentation: 6/1/2024
6376 Wnt/beta-catenin Pathway is Associated with Cell Proliferation in Growth Hormone-producing Pituitary Tumors
Authors: Kuwabara Saki , Kameda Hiraku , Nomoto Hiroshi , Cho Kyu Yong , Nakamura Akinobu , Ishi Yukitomo , Motegi Hiroaki , Fujimura Miki , Atsumi Tatsuya
Published: October 2024

Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. M. Fujimura: None. T. Atsumi: None.

Objective: It has been well recognized that the Wnt/β-catenin pathway regulates cell proliferation, and that translocation of β-catenin from the cytoplasm to the nucleus promotes cell proliferation. There have been, however, limited reports on the Wnt/β-catenin pathway in growth hormone-producing pituitary tumors (GHomas), and we aimed to investigate the impact of the Wnt/β-catenin pathway on cell proliferation in GHomas. Methods: We performed three types of experiments with patient pathological specimens, disease model cell lines, and primary culture of GHoma cells. 1.The intracellular localization of β-catenin was evaluated using immunofluorescence staining of pathological specimens from GHoma patients and subsequently its association with clinical data was analyzed. 2.The Wnt/β-catenin inhibitor iCRT14 was administered to rat GHoma cells GH1, using the WST-1 assay to measure cell viability and real-time PCR to assess GH and cell cycle genes expression. 3. The Wnt/β-catenin inhibitor iCRT14 was added to cultured cells obtained from GHoma patients to evaluate cell viability and gene expression. Results: 1. Samples from 26 cases (42%) exhibited strong dot-like expression of β-catenin in the nucleus (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). Tumors in the DP group had a larger size than non-DP group (diameters 18.3±9.2 vs. 13.4±7.4 mm, p<0.05), and the postoperative remission rate was lower (23 vs. 50%, p<0.05). 2. Viability evaluation using WST-1 assay showed a maximum decrease of 25%. Gene expression showed concentration-dependent reduction in GH gene expression by up to 40% (p<0.05) and cyclin D1 gene up to 50% (p<0.05) following iCRT14 administration. 3. Among 6 cases, 3 showed a tendency toward cell growth inhibition, and 4 showed a tendency toward decreased cyclin D1 gene expression. Conclusion: It is suggested that the Wnt/β-catenin pathway is activated in the DP group because of the nucleus accumulation of β-catenin, and given the larger tumor size and lower postoperative remission rate in DP group, the Wnt/β-catenin pathway may stimulate cell proliferation in GHomas. In addition, cyclin D1-mediated effects were considered. Wnt/β-catenin pathway could play a role in GHomas growth, therefore this pathway would be a potential therapeutic target for treating affected patients.

Presentation: 6/3/2024
6789 Do Obesity-Associated MRAP2 Variants Modulate MC4R and GHSR Signaling?
Authors: Rondon Alejandra Virginia Rodriguez , Volker Femke , Welling Mila Sofie , de Groot Corjan , van Haelst Mieke M , van den Akker Erica L T , van Rossum Elisabeth F C , Delhanty Patric John , Visser Jenny A
Published: October 2024

Disclosure: A.V. Rodriguez Rondon: None. F. Volker: None. M.S. Welling: None. C. de Groot: None. M.M. van Haelst: None. E.L. van den Akker: None. E.F. van Rossum: None. P.J. Delhanty: None. J.A. Visser: None.

Melanocortin 2 receptor accessory protein 2 (MRAP2) is a membrane-bound protein expressed on hypothalamic neurons that modulate the function of appetite-regulating receptors, including melanocortin-4 receptor (MC4R) and growth hormone secretagogue receptor (GHSR). While pathogenic variants in the MRAP2 gene are associated with obesity, the mechanism for this remains unclear. The aim of this study is to investigate the functional impact of wildtype (WT) MRAP2 and MRAP2 variants on MC4R and GHSR signaling. Four MRAP2 variants (S80F, R125C, P167A and Q174X) were identified in patients with obesity by obesity gene panel analysis. The functional effects of these variants were analyzed by co-transfecting HEK293 cells with expression plasmids encoding WT or variant MRAP2 and WT MC4R or WT GHSR. Endpoint analyses included cell surface expression, and ligand-induced second messenger responses (α-MSH-induced cAMP response for MC4R and ghrelin-induced Ca2+ mobilization for GHSR), β-arrestin-2 recruitment, and internalization. WT MRAP2 significantly decreased basal MC4R cell surface expression by 68.1±4.3% (p<0.001). In the absence of MRAP2, α-MSH induced MC4R internalization. However, in the presence of WT MRAP2, MC4R cell surface expression was increased by 89.4±6.9% upon α-MSH stimulation (p<0.001). GHSR cell surface expression and ghrelin-induced internalization were not affected by WT MRAP2. Furthermore, in the cells expressing MC4R with WT MRAP2, the maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased by 29.8±5.2% and 81.3±4.2% respectively (p<0.001), compared with those lacking MRAP2. We also investigated GHSR ghrelin-induced Ca2+ mobilization and found that, in the presence of WT MRAP2, this increased significantly by 95.37±21.9%, (p<0.0003). However, ghrelin-induced β-arrestin-2 recruitment was suppressed by 69.8±7.6%, (p<0.001). Using these endpoints we found no effect of the variants on the ability of MRAP2 to modulate ligand-induced signaling by MC4R and GHSR. Our results indicate that WT MRAP2 enhances the cAMP response by increasing MC4R cell membrane expression upon α-MSH stimulation, and enhances GHSR Ca2+ mobilization by decreasing β-arrestin-2 recruitment upon ghrelin stimulation. The MRAP2 variants assessed in this study behaved as WT MRAP2 in α-MSH-induced MC4R and ghrelin-induced GHSR signaling, suggesting that these may be benign variants. However, since MRAP2 can modulate multiple receptors, we cannot rule out that these MRAP2 variants affect other appetite-regulating receptors and thereby influence body weight regulation via other pathways.

Presentation: 6/3/2024
7540 Recognition of Need for Optimization of Diabetes Education for Children with Type 1 diabetes: Long term Provider Experience
Authors: Begum-Hasan J
Published: October 2024

Disclosure: J. Begum-Hasan: None.

Title: Recognition of need for optimization of diabetes education for children with Type 1 diabetes: long term “On call provider experience “Janhanara Begum – Hasan, MD, PhD. Jacob school medicine. UBMD Pediatrics Context: Pediatric endocrinologist does provide on call service 24/7 to support patient care as needed for the family with children with diabetes. Complication of diabetes including DKA is preventable However, based on interaction with the family with children diabetes, the trend shows sub optimal education in this regard. Aim/Objective: To review case scenario and provide recommendation to optimize diabetes management with a goal of prevention of complications. Case discussion: 3 case scenarios are selected to review. Case 1: The father called at 2 am as his daughter’s (12 year F) Insulin pump is broken and BGs are elevated in upper 300s. Her urine is +ve for moderate ketone and she has nausea. He does not have any short acting pen or syringe to provide correction Insulin. He reports that he is not aware of her Insulin settings in the pump. Parents are separated and mother is more involved in her care. Short /long acting Insulin pen were prescribed with recommendations including correction dose as per weight with a plan for follow up. Case 2: The mother called at 9 pm and reported that by mistake, she did administer “Admelog” at 18 units instead of Basaglar, for her son, 11 year old with Type 1 diabetes. He was on Lantus and Humalog before. She gets confused with short and long acting Insulin particularly with changes. The mother was advised on close monitoring of BGs with recommendation of treatment of Hypoglycemia including Glucagon therapy. He was followed closely with stabilization of BGs with extra carbohydrate overnight. Case 3: The father calls to inform that his son, 14 year, with recent onset Typ1 diabetes, has been vomiting with high BG in 400s with large ketone. His Insulin dose was decreased recently as he was told to be in “Honeymoon phase” and planned for close follow up. However, the family missed endocrine FU >12 months now. His BGs have been high in upper 200s to 300s for last 2-3 months. The parents are in the process of divorce. He was sent to local ED with clinical impression of DKA. He was treated for his severe DKA as found after metabolic labs. He did well after 2 days hospitalization for management of his DKA. Conclusion: -Complications of Type 1 diabetes are preventable. The family needs further education on diabetes management including review of Insulin therapy when Insulin pump does malfunction, with a copy of written instruction of Insulin doses, differences in long and short acting Insulin along with psychosocial support to optimize care of children with Type 1 diabetes.

Presentation: 6/2/2024
12333 46 XX/XY Chimerism - Positive NIPT And Post-natal Karyotype Is It Real?
Authors: Del Rosario Kychelle L , Sheriden Nina , Vijayakanthi Nandini
Published: October 2024

Disclosure: K.L. Del Rosario: None. N. Sheriden: None. N. Vijayakanthi: None.

Introduction: Non-Invasive Prenatal Testing(NIPT) using cell free fetal DNA in plasma of pregnant women has become a routine part of prenatal care in screening for fetal aneuploidies including sex chromosome abnormalities in most regions around the world. False positive results are increasingly imposing challenges in pre-natal as well as post-natal care. Case Discussion: We report a neonate born at 32+2 weeks gestation to a 42-year-old G2 P2 mother. Pregnancy was complicated by insulin dependent maternal type 2 diabetes mellitus, maternal chronic hypertension and a positive NIPT for high-risk monosomy X. Prenatal ultrasound showed male anatomy. Interestingly on physical exam after birth, the neonate had typical male external genitalia with bilateral normal male gonads. Chromosome analysis done immediately after birth revealed the presence of two cell lines: 40 of the 50 cells (80%) had a normal female 46 XX karyotype and 10 of the 50 cells (20%) had a normal male 46 XY karyotype. These findings could be due to reabsorbed twin, Klinefelter syndrome with two trisomy rescue events, maternal cell contamination or true chimerism. In addition, fluorescence in situ hybridization (FISH) analysis for X and Y probes revealed the presence of two cell lines. The first cell line (70% of the cells) had two hybridization signals for chromosome X and the second cell line (∼25% of the cells) had one hybridization signal for chromosome X and one for chromosome Y. Postnatal ultrasound showed normal testicles with no evidence of Mullerian structures. Newborn screening was negative for congenital adrenal hyperplasia (CAH). Genetics was consulted and recommended repeat chromosomal analysis, parental testing to determine sex chromosome segregation, and follow-up with pediatric endocrinology. Repeat cytogenetic testing at 2 weeks of life resulted in a normal male chromosome complement of 46,XY. Previous abnormal cytogenetics were thought to be due to maternal cell contamination. Further endocrine labs showed LH(1.16 uIU/ml) and testosterone levels ( 87 ng/dL), appropriate levels for age indicating normal Hypothalamic Pituitary Gonadal (HPG) axis and testicular Leydig cell function. Since the family was previously counseled regarding the concept of maternal cell contamination, they expressed understanding and were happy with the update of the normal karyotype result. Conclusion: False-positive results concerning for rare chimerism on NIPT can occur and should prompt a thorough history, physical exam, ultrasound studies and repeat testing to confirm its presence. Careful consideration should be taken when counseling family about the implications of these results, especially communication about gender assignment of the infant.

Presentation: 6/3/2024
7204 An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation
Authors: Leopold Kaitlin , Polites Stephanie , Binkovitz Larry , Casas Luis , Lteif Aida Nadim
Published: October 2024

Disclosure: K. Leopold: None. S. Polites: None. L. Binkovitz: None. L. Casas: None. A.N. Lteif: None.

Title: An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation. Introduction: Individuals with Succinate Dehydrogenase (SDHx) gene mutations have an increased risk of paragangliomas and pheochromocytomas beginning in childhood.Clinical Case: A 9 year old male with Cornelia de Lange syndrome and a paternally inherited SDHA pathogenic gene variant (c1534C>T) presented with worsening migraine headaches and skin pallor with activity. 24 hour urine fractionated metanephrines were mildly elevated, with metanephrine 122 mcg/24h (29-92 mcg/24 h), normetanephrine 187 mcg/24 h (34-169 mcg/24 h), and total metanephrine 309 mcg/24 h (47-223 mcg/24 h). Ga-68 DOTATATE PET/CT showed a focus of moderately increased radiotracer activity in the anterior aspect of the distal gastric antrum with a max SUV 8.2 corresponding to a 9x7 mm nodule on CT in the same area, suggestive of underlying somatostatin receptor positive lesion such as a paraganglioma. MRI with contrast completed to further characterize the lesion showed no visible mass corresponding to the focal area of radiotracer uptake on DOTATATE PET/CT. Repeat 24 h urine metanephrines continued to show mild elevation of metanephrine (138 mcg/24h), normetanephrine (200 mcg/24h), and total metanephrines (338 mcg/24h). 24 hour urine catecholamines, 5-Hydroxyindoleacetic acid, and homovanillic acid were normal. An upper endoscopic ultrasound was completed which confirmed the presence of a lesion near the stomach but not arising from the stomach wall and not consistent with a gastrointestinal stromal tumor. CT enterography with IV contrast showed a 6x6 mm enhancing mass within the distal right lateral gastric wall. Due to ongoing symptoms, mild elevations in urine fractionated metanephrines, and a clear mass on US and CT, the patient underwent laparoscopic abdominal exploration where a 14x14x13 mm mass with surrounding gastric and duodenal serosa was excised with primary closure of the bowel. Pathology showed ectopic pancreatic tissue in the wall of the small bowel and stomach. Repeat Ga-68 DOTATATE PET/CT 5 months following surgery showed resolution of the distal gastric somatostatin receptor avidity. Clinical Lesson: This is the first case of ectopic pancreatic tissue mimicking a paraganglioma in a pediatric patient with hereditary paraganglioma-pheochromocytoma syndrome. False positive imaging should be considered in patients with SDHx mutations when the uptake is atypical in location and when the elevation in urine metanephrines is mild.

Presentation: 6/3/2024
7960 Clinical Outcomes of Image-Guided Therapies In Patients With Adrenocortical Carcinoma: A Tertiary Referral Center Retrospective Study
Authors: Chahla Brenda , Pal Koustav , Balderrama Brondani Vânia , Yaylaci Mert Feyza , Campbell Matthew , Sheth Rahul , Amir Habra Mouhammed
Published: October 2024

Disclosure: B. Chahla: None. K. Pal: None. V. Balderrama Brondani: None. F. Yaylaci Mert: None. M. Campbell: None. R. Sheth: None. M.A. Habra: None.

Background: Image-guided therapies (IGTs) such as cryoablation or embolization are commonly used in oncology, but their role in adrenocortical carcinoma (ACC) is not well-defined. Materials and Methods: A retrospective review of ACC patients treated with IGTs. We assessed time to next line of systemic therapy, disease control rate (DCR), local tumor progression-free survival (LTPFS), and complications of IGTs.Treatment efficacy was assessed based on RECIST v1.1. Complications were categorized based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The study cohort included 26 patients (median age 56 years [range 38-76]; n=18 female) who had 51 IGT sessions to treat 86 lesions. The median Ki-67 is 20 (range 2-79), and median Weiss score is 6 (range 3-9). Seventeen patients received systemic therapy including mitotane, chemotherapy, immunotherapy, and other treatments prior to the first IGT and 10 patients received systemic therapy concurrently with first IGT. IGT modalities included cryoablation (n = 49), microwave ablation (n = 21), combined microwave and bland transarterial embolization (n = 8), bland transarterial embolization alone (n = 3), radioembolization (n = 3), and radiofrequency ablation (n = 2). Treated sites included the liver (n=37), intraperitoneal (n=11), adrenalectomy bed (n=10), lung (n=6), lymph nodes (n=6), retroperitoneal soft tissue (n=6) and other soft tissues (n=10). The median largest pre-IGT anteroposterior tumor dimension was 2.3 cm (range 0.5-8.6). DCR was 81.4% (70 out of 86), of which 66.3% of tumors showed complete response, 18.6% showed progressive disease, 8.1% showed partial response, and 7.0% showed stable disease. LTPFS rates were 73% and 63% at 1 and 2 years, respectively. Fourteen lesions needed re-ablation. Ten patients did not require systemic therapy while 16 patients (61.5%) received new systemic therapy following IGT, with a median time from first IGT to systemic therapy of 12.5 months (95% CI: 8.6 months- upper limit not reached). There was 1 reported CTCAE grade 3 adverse event (biloma) following IGT. Conclusion: IGT use in properly selected ACC lesions is safe and associated with prolonged disease control and delay in the need for systemic therapy.

Presentation: 6/2/2024
7202 CPP with Rapid Pubertal Progression in a 9-Year-Old Boy with Hypothalamic Teratoma
Authors: Robilliard R , Tung G , Svokos K , Lulla R , Quintos J Q
Published: October 2024

Disclosure: R. Robilliard: None. G. Tung: None. K. Svokos: None. R. Lulla: None. J.Q. Quintos: None.

Background: Central Precocious Puberty (CPP) in males is rare, with incidence of 0.01-2/10,000. The most common identifiable cause of CPP in young children is hypothalamic hamartoma. No case hypothalamic teratoma has been reported to cause CPP in males. Clinical Case: At the age of 10-years and 5-months, a boy presented to the pediatric endocrinology with signs of precocious puberty including facial hair development, voice deepening, and increased growth velocity that began at 9 years old. There was no significant past medical history and he denied headache, blurry vision, or diplopia. Physical examination showed height of 140.4 cm (47%), Tanner 4 genitalia, Tanner 3 pubic hair, and testicular volumes of 15 cc (left) and 12-15cc (right). Bone age (BA) determined by radiography was 13.5 years with a predicted adult height (PAH) of 63 inches. The mid-parental target height was 67 +/- 4 inches. Evaluation including TSH, glucose, serum and CSF β-HCG, DHEA, CSF AFP was normal. Serum LH was 2.9 IU/L and testosterone level was 109 ng/dl, consistent with CPP. MRI of the pituitary showed a small, heterogeneous and fat-containing lesion extending inferiorly from the tuber cinereum consistent with teratoma. Treatment included GnRH agonist Lupron (30mg) every 3 months. Laboratory evaluation 8 months after initial presentation showed suppressed LH of 0.9 IU/L and FSH 0.5 mIU/mL, and testosterone of 57 ng/dL. Repeat radiography for BA one year after GnRHa suppression showed BA of 14 years at CA of 11 years 6 months and PAH of 64.4 inches. Growth velocity slowed to 5.3 cm/year. At the most recent follow-up visit at CA of 12 years, height was 151.5 cm (61%), growth velocity 6.3 cm/year (74% for age), Tanner 5 penis and pubic hair, left testicular volume of 15-20cc and right testicular volume of 15 cc. Most recent radiographic BA is14 years, and PAH is 65.9 inches. Given response to GnRH agonist injections every 3 months, the absence of CNS symptoms referable to the teratoma and no change in MR imaging, no surgical intervention is recommended. Conclusion: This is the first case of a hypothalamic teratoma reported in a male associated with CPP. Despite this rare cause, the patient has responded to standard treatment with GnRH agonist therapy alone.

Presentation: 6/1/2024
7959 Combination Therapy Of Multi-Targeted Tyrosine Kinase Inhibitors And Immune Checkpoint Inhibitors In Advanced Adrenocortical Carcinoma
Authors: Yaylaci Mert Feyza , Balderrama Brondani Vânia , Marcal Leonardo P , Campbell Matthew , Jimenez Camilo , Varghese Jeena , Yogesh Shah Amishi , Amir Habra Mouhammed
Published: October 2024

Disclosure: F. Yaylaci Mert: None. V. Balderrama Brondani: None. L.P. Marcal: None. M. Campbell: None. C. Jimenez: None. J. Varghese: None. A. Shah: None. M.A. Habra: None.

Background: Adrenocortical carcinoma (ACC) is a rare cancer with limited response to systemic chemotherapies. Monotherapy with multi-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in ACC patients has limited efficacy. Combining TKIs with ICIs increased response rates in other malignancies but the efficacy of this approach in ACC is still unknown. This retrospective study aims to evaluate the efficacy and safety of the combined use of TKIs and ICIs in patients with advanced ACC. Methods: A single-center, retrospective cohort study in patients with advanced ACC treated with the combination of TKIs and ICIs. Response rates, progression-free survival (PFS), overall survival (OS) calculated from the time of combination, disease control rate (DCR), and safety profile were the main study objectives. Results: Seventeen patients were treated with combination therapy of TKI (lenvatinib or cabozantinib) and ICI (pembrolizumab) between January 2017 and December 2023. Eleven patients were women, the median age was 43.4 years (range 21.9-66.6), and 8 (47.1%) patients presented cortisol-producing tumors. All patients had prior systemic therapy, median of 3 (range 1-9) lines of therapy. The median duration of TKI+ICI therapy was 7.1 months (range 0.7-69.7). The treatment was discontinued in one patient due to a grade 3 adverse event (gastrointestinal fistula) after 1.6 months of treatment. Best overall responses were as follows: partial response 2 (13%), stable disease 8 (53%), and progressive disease 5 (34%). DCR was 58.8%. Median PFS was 7.1 months (range 0.7-66.4). One death occurred during the study due to disease progression. The median OS was 21.3 months (range 3.3-70.3). At the time of this report, 7 patients (41%) were still alive. Conclusion: The combined use of TKIs and ICIs in heavily treated ACC patients is associated with occasional durable responses and has a predictable and manageable side effect profile. This combination is worthy of a prospective clinical trial to validate the findings and establish new lines of therapy for this rare disease.

Presentation: 6/2/2024
7548 Final adult height in children with idiopathic growth hormone deficiency after growth hormone treatment
Authors: Lee Hae Sang , An Se Jin , Cho Min Hyung , Nam Hyo-Kyung
Published: October 2024

Disclosure: H. Lee: None. S. An: None. M. Cho: None. H. Nam: None.

Objective: The aim of this study was to assess the final adult height (FAH) achieved through recombinant human growth hormone (GH) treatment and the factors influencing FAH. Methods: We retrospectively reviewed the charts of all patients diagnosed with IGHD who were prepubertal when they began GH treatment since August 2007. FAH was determined in 41 patients (28 males and 13 females) by July 2023. Results: 41 patients started treatment at an average age of 9.1 years and continued for 6.5 years. The mean initial height was -2.6 standard deviation scores (SDS) and the mean FAH was -0.6 SDS. GH treatment was initiated at a significantly younger age in females than in males (7.2±1.9 vs 10.0±3.2; p=0.01). The mean FAH was 169.9±4.5cm for males and 156.1±3.2cm for females. Differences between initial height and final height SDS were not significant between males and females. The mean of FAH SDS was higher compared to their mid-parental height -1.0 SDS (p=0.017). In multiple regression analysis, FAH showed a positive correlation with initial height, duration of treatment, and growth rate in the first year of treatment, and a negative correlation with BMI SDS at the start of GH (r2=0.59; p=0.000). FAH SDS was positively related to initial height SDS and growth rate in the first year of treatment. (r2=0.3; p=0.001) Conclusions: The mean FAH SDS after GH treatment was significantly higher than the mean MPH SDS in IGHD patients. Moreover, the good response of GH treatment was associated with longer treatment duration, greater height at the start of treatment, better treatment response at 1 year, and lower initial BMI SDS.

Presentation: 6/3/2024
7673 Genetic Analysis and Clinical Characterization of Patients with Congenital Hypopituitarism Due to Gene Defects
Authors: Sasson T M , Arnhold I J , Mendonca B B , Carvalho L R
Published: October 2024

Disclosure: T.M. Sasson: None. I.J. Arnhold: None. B.B. Mendonca: None. L.R. Carvalho: None.

Introduction: Congenital hypopituitarism is characterized by the deficiency of one or more hormones secreted by the anterior pituitary gland. The genetics of this pathology is complex, and the molecular diagnosis is established in approximately 13% of cases. Objectives: The aim of the present study is to characterize the phenotype harboring pathogenic variants causing congenital hypopituitarism. Methods: Among 393 subjects with congenital hypopituitarism followed up at a tertiary health center, 57 subjects (14,5%) were selected due to a confirmed molecular diagnosis by exome in 9 subjects or by gene panel or Sanger sequencing in 48 subjects. This was a retrospective study where data from medical records, clinical, laboratory and radiological characteristics were analyzed. Results: The most frequent variants identified by sequencing analyzes were in the following genes: PROP1 (29.8%), GH1 (22.8%), GHRHR (15.7%), followed by GLI2, OTX2, HESX1, POU1F1, TGIF1, GHRS, CDH2, SATB1, SOX3 e LZTR1. Consanguinity was reported in 50% of cases, and there was the presence of familial cases of short stature in 60%. The average age at the start of follow-up was 11.1 years (11 SD), 40% of them were male and 52.3% had physical stigmata typical of GH deficiency. Regarding hormonal deficiencies, 27 (47%) had isolated Growth Hormone Deficiency (DGHI) and the others, multiple deficiencies. MRI study of the pituitary gland showed some alteration in 66%, 54% of whom had adenohypophysis hypoplasia and 31% had an ectopic or non-visualized neurohypophysis. From 29 patients with IGF-1 levels available, 28 were below the reference range for sex and age. The serum GH peak after the stimulus test was on average 1.28 ng/mL (1.4SD), of these, only 4 cases had GH peak between 3.3 and 5.0 ng/mL and 1 patient with low IGF-1 and an ectopic neurohypophysis had GH peak of 6.0 ng/mL in a glucagon test. Regarding growth, the initial height in z-score was -4.8 and the average growth at the end of the first year of treatment was 10.7cm, with the average height after this period of Z-3.35. The average of final delta target height (final height Z-score minus the target height Z-score) of patients who underwent hormonal treatment was -0,53 (good response = delta <-1.5). Conclusion: In subjects with congenital hypopituitarism and an established molecular diagnosis, the most frequently affected genes were PROP1 and GH1, the great majority presented a stimulated GH peak < 3.3 ng/mL (only one patient had GH > 5), low basal serum IGF-1 and good increase in growth speed at the end of the first year of treatment with recovery of final height at the end of GH therapy.

Presentation: 6/3/2024
8244 Genetic Evaluation Using Next-Generation Sequencing of Children with Short Stature < A Single Tertiary Center Experience
Authors: Park J , Kim S , Joo E , Lee J E
Published: October 2024

Disclosure: J. Park: None. S. Kim: None. E. Joo: None. J. Lee: None.

Purpose: We aimed to investigate the genetic causes of suspected genetic short stature in 37 patients using next-generation sequencing (NGS) and describe their phenotypes and various genetic spectra. Methods: We reviewed the medical records of 50 patients who underwent genetic testing using NGS for suspected genetic short stature from June 2019 to December 2022. Patients with short stature caused by non-genetic factors or common chromosomal abnormalities were excluded. Thirty-seven patients from 35 families were enrolled in this study. We administered one of three genetic tests (targeted panel sequencing using two different panels or whole exome sequencing) to patients according to their phenotypes. Results: Clinical and molecular diagnoses were confirmed in 15 of the 37 patients, and the overall diagnostic yield was 40.5 %. Fifteen pathogenic/likely pathogenic variants were identified in 13 genes (ACAN, ANKRD11, ARID1B, CEP152, COL10A1, COL1A2, EXT1, FGFR3, NIPBL, NRAS, PTPN11, SHOX, SLC16A2). The diagnostic rate was high in the patients with small for gestational age (7/11, 63.6 %). Conclusions: Genetic evaluation using NGS can be helpful in patients with suspected genetic short stature who have clinical and genetic heterogeneity. Further studies are needed to develop patient selection algorithms and panels containing growth-related genes. Keywords: Dwarfism, Growth Hormone, Next-Generation Sequencing

Presentation: 6/2/2024
8576 Genomic and Transcriptomic Characterization of Pediatric Thyroid Cancers
Authors: Ricarte-Filho J C , Reichenberger E R , Hinkle K , Isaza A R , Bauer A J , Franco A T
Published: October 2024

Disclosure: J.C. Ricarte-Filho: None. E.R. Reichenberger: None. K. Hinkle: None. A.R. Isaza: None. A.J. Bauer: None. A.T. Franco: None.

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both pediatric and adult populations. Recent genomic profiling of papillary thyroid cancers, including that of the Cancer Genome Atlas, has uncovered the genetic alterations and molecular mechanisms driving thyroid cancer. However, these studies were primarily focused on adult patients. Despite their favorable prognosis, pediatric PTCs have higher rates of metastasis and recurrence than adult PTCs, but the molecular characterization of these tumors have been comparatively lacking. Methods: Here we explore the genomic and transcriptomic landscape of pediatric PTCs from 126 patients, including 107 primary tumors and 19 lymph node metastases (non-paired) using whole-exome sequencing and RNA sequencing. Thirteen primary tumors also had a paired lymph node metastasis analyzed. Results: We found driver alterations in 113 of 126 (90%) of the PTCs investigated, including the identification of a novel receptor tyrosine kinase (RTK) fusion not previously reported in thyroid cancer. Genetic drivers were predominantly kinase fusions (48%), most commonly fusions of RET (22%), NTRK3 (10%), ALK (5%) and NTRK1 (5%). The most common point mutations were BRAF p.V600E (21%), NRAS p.Q61R/K (9%) and hotspot mutations in DICER1 (4%). We found genetic alterations in 12 of the 13 paired lymph node metastasis. In all 12 cases the metastatic tissue harbored the same alterations found in the primary tumor. Eight out of 12 cases had fusions (3 RET, 3 NTRK3 and 2 NTRK1), and the additional 4 cases had point mutations (3 BRAFV600E and 1 TSHRM543T). Fourteen patients (11%) had widely invasive disease with lateral lymph node and distant metastases (N1bM1). Most of these N1bM1 tumors (13/14; 93%) were driven by RTK fusions (5 NTRK3, 3 RET, 3 NTRK1 and 2 ALK). The one case lacking a kinase fusion had a CHEK2 mutation. Conclusion: Our genomic and transcriptomic analysis allowed the detection of driver alterations in ∼90% of the cases, reducing the so-called “dark matter” in our cohort. Our data support that kinase fusions are associated with metastatic disease in pediatric PTC. Patients with RET/NTRK/ALK fusions have worse outcomes than those with BRAF p.V600E mutation and RAS-like alterations (NRAS, DICER1, non-V600 BRAF, PTEN). By using the transcriptional profiling generated in this study, we are currently investigating the molecular mechanisms underlying the metastatic behavior of pediatric PTCs harboring oncogenic fusions, including changes in MAPK transcriptional output, differentiation score and recruitment of signaling pathways potentially associated with the metastatic behavior of these tumors.

Presentation: 6/3/2024
7819 Hypoglycemia with Hereditary Hemorrhagic Telangiextsia in a Boy After Liver Transplantation
Authors: Miyagi Hajime , Igarashi Mizuho , Tanimoto Eri , Horikawa Reiko
Published: October 2024

Disclosure: H. Miyagi: None. M. Igarashi: None. E. Tanimoto: None. R. Horikawa: None.

Introduction: Hereditary hemorrhagic telangiectasia (HHT) causes arteriovenous malformation (AVM) in liver, lung, and brain. It is not clear whether it also causes hypoglycemia. We show a case of HHT combined with hypoglycemia after liver transplantation, improved by nutrition management and growth hormone treatment. Case: 11 months old boy born from a mother with HHT was diagnosed as having with AVM prenatally. He was once operated for the liver AVM but developed a new collateral circulation which caused severe heart failure and lead to liver transplantation. He showed severe growth retardation and malnutrition. His body weight was 4.6 kg and height were 60 cm (-5.8 SD) when he was 1 year old, and blood test showed low albumin for 3 g/dL (3.4 - 4.7 g/dL), and total protein for 4 g/dL (5.7 - 7.5 g/dL). Hypoglycemia was found while switching his nutrition from parenteral to enteral nutrition after operation. His insulin was under 0.3 µU/mL when his blood glucose was 49 mg/dL IGF1 was 17 ng/mL (ref.11 - 149 ng/mL), suggested growth hormone (GH) deficiency. GH stimulation test showed blunted response. GH treatment was started. Other pituitary hormones were within normal range. Nutritional support was added using high-calory milk. After GH treatment, IGF1 level increased to 87 ng/mL. GH and nutritional management improved not only his weight and height gain but also his glycemic control. Discussion: Hypoglycemia may be caused by both GHD and malnutrition. GHD and low IGF1 might be caused by malnutrition. Retesting GH secretion after improvement of nutrition is planned to clarify his pituitary function.

Presentation: 6/2/2024
8706 Hypoparathyroidism and Hypercalcemia in Premature Secondary to Excessive Vitamin D: Everything in Excess is Opposed
Authors: Bastos Dyrlanne Marcia Lopes , Bastos Ana Clara Freire da Cunha
Published: October 2024

Disclosure: D.M. Bastos: None. A. Bastos: None.

Introduction: Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Coma, ventricular fibrillation, and acute renal insufficiency are possible life-threatening presentations of vitamin D-induced hypercalcemia. Nephrocalcinosis, renal lithiasis, vascular calcifications, and arterial hypertension are known late complications of severe or longstanding hypercalcemia. The most common causes of vitamin D intoxication in children are manufacturing errors, parental dosing errors, and erroneous medical prescriptions. Case Presentation: A premature girl admitted to the neonatal ICU 3 months ago due to poor weight gain and was taking vitamin D and infant formulas and developed tachycardic heart rhythm with irregular rhythm and kidney changes. The investigation of the condition was re-evaluated, and the patient was seen with hypercalcemia, an increase of more than 100x in the dosage of 25(OH)vitamin D, an increase in the dosage of 1.25(OH)vitamin D, suppressed PTH, an increase in creatinine and urea. In addition, an ultrasound was performed showing the presence of small kidney stones, none of which were obstructive. After discontinuing vitamin D supplementation, the patient progressed satisfactorily with a reduction in cardiac and renal changes. Discussion: Currently, vitamin D supplementation has been carried out more frequently, as, in addition to increasing the absorption of calcium in the body, it reduces the risk of diseases, such as rickets and osteopenia of prematurity. The body is only able to produce vitamin D after exposure to sunlight. In the absence of regular exposure, dietary sources alone are not sufficient to maintain adequate levels. Cases of hypervitamin D generally occur in situations of excessive supplementation. In the present report, the dose used was 40 times higher than recommended. Initial tests revealed elevated calcium and undetectable PTH levels. The diagnosis of vitamin D intoxication is not common in cases of hypercalcemia, as it is infrequent, especially before the advent of vitamin D supplementation. Vitamin D toxicity is usually iatrogenic, or due to accidental overdose. These factors, along with a lack of public education about safe dosing, have likely contributed to the increase in reported cases of vitamin D toxicity. Conclusion: Vitamin D supplementation, especially when using compounded medications, must be adequately monitored due to the potential risk of poisoning. Vitamin D toxicity remains a pressing issue and its incidence will likely continue to grow, primarily because of the widespread availability of over-the-counter formulations and public interest.

Presentation: 6/3/2024
6513 Identification of pathogenic ACAN variants in healthy children with normal height and advanced bone age
Authors: Hernandez M , Unanue N , Gallardo V , Van duyvenvoorde H , Mericq M V
Published: October 2024

Disclosure: M. Hernandez: None. N. Unanue: None. V. Gallardo: None. H. Van duyvenvoorde: None. M.V. Mericq: None.

Background/rationale: Linear growth is determined by proliferation and differentiation of growth plate (GP) chondrocytes. The main proteoglycan component of the extracellular matrix of GP is ​​aggrecan, encoded by the ACAN gene. Homozygous pathogenic variants have been reported in patients with spondylo-metaphysial dysplasia. Heterozygous pathogenic variants are associated with non-syndromic short stature of pre or postnatal onset, in most cases with advanced bone age, early-onset dissecting osteoarthritis, and some other dysmorphic features. Hypothesis Children with normal height and significant advanced bone age can present pathogenic variants in the ACAN gene. Patients and methods: Healthy prepubertal children referred for height evaluation because of advanced bone age (≥ 2 SDS using Bayley Pineau, validated using Bonexpert) in combination with normal height (± 2 SDS) and BMI (15th-85th centile ) were included, after signing informed consent. We excluded puberty by clinical Tanner staging, CAH or premature adrenarche (DHEAS > 40 micr/dl RIA), GH excess or thyroid disorders and medications that could advance bone age. Genomic DNA was isolated from peripheral blood using QIAamp DNA Mini kit (Qiagen, Germany). Sequencing was performed on an Illumina platform using the Agilent enrichment kit SureSelectXT Clearseq Inherited Disease Panel (IDP). SNV (single nucleotide variant and CNV (copy number variant) data analysis of all coding exons of the ACAN gene including +/- 20 nucleotides of flanking intron sequences was performed, with exception of the complex Variable Number of Tandem Repeats (VNTR) structure in exon 12. Results : 17 prepubertal Caucasian children (2 females) were genotyped at a mean age 7.7 ±1.8 years, a height of -0.47±0.89 SDS, a BMI of -0.05 ±1.19 SDS, a mid-parental height of -0.34 ±0.59 SDS and mean difference between height and MPH 0.28±0.77 SDS . None of these children had a pathogenic ACAN variant. Conclusion: this study suggests that pathogenic ACAN varians appear not to be a prevalent cause of advanced bone age in healthy prepubertal children. Follow-up of this group of patients will provide us with more information on the impact of the advanced bone age on final height. Dependent on the final height outcome, additional genetic investigations can be considered.

Presentation: 6/3/2024