bluuebunny/crossref_metadata_2025 huggingface dataset:
5152 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes
Authors: Das Pratyusa , Jabal Dania Abou , Sunny Dale Ann , Ellsworth Buffy Sue
Published: October 2024

Disclosure: P. Das: None. D.A. Jabal: None. D.A. Sunny: None. B.S. Ellsworth: None.

Our research focuses on the role of glucocorticoid (GC) in regulating the maturation of pituitary somatotropes. We previously demonstrated that deletion of the forkhead transcription factor, FOXO1, affects the development of somatotropes both in vivo and in vitro. Our studies reveal that treating pregnant mice with the synthetic glucocorticoid, dexamethasone leads to premature somatotrope maturation. Interestingly, we have observed that the ability of GC to promote Gh1 expression is compromised in the absence of FOXO1 in a somatotrope-like cell line. This finding leads to further investigation into the GC receptor, NR3C1, and its developmental role in the pituitary gland. In mouse embryos, we detect NR3C1-positive cells localized primarily in the nucleus, initially in small numbers at embryonic day (e)12.5 and becoming more abundant by e14.5. At e14.5 there is a subset of cells where NR3C1 co-localizes with POU1F1, a marker of pre-somatotropes, suggesting the importance of NR3C1 in the formation of the somatotrope lineage. In dexamethasone-treated animals, we observe an increase in NR3C1-positive cells. However, no significant change was noted in POU1F1 expression. Significantly, the premature somatotropes identified are NR3C1 and POU1F1-positive, suggesting the pituitary cells expressing both POU1F1 and NR3C1 at e14.5 are likely differentiating into somatotropes when exposed to GC. Normally, by e16.5, GH-positive cells begin to appear in mice. Double immunostaining reveals that some of these cells also express NR3C1. Further supporting this finding, the deletion of Nr3c1 results in a decreased number of GH-positive cells at e16.5. Altogether these findings demonstrate that NR3C1 and FOXO1 are key factors regulating somatotrope maturation.

Presentation: 6/2/2024
9384 Two Siblings With Hypogonadotropic Hypogonadism As First Presentation Of The Severe Neuroendocrine Disorder Caused By RNF216
Authors: Rochtus A M , Vermeer S , Antonio L
Published: October 2024

Disclosure: A.M. Rochtus: None. S. Vermeer: None. L. Antonio: None.

Background: Biallelic mutations in RNF216 cause a syndrome characterized by hypogonadotropic hypogonadism, cerebellar ataxia, chorea and cognitive impairment, a combination first described over a century ago named Gordon Holmes syndrome (MIM 212840). Hypogonadotropic hypogonadism can be the initial manifestation of this severe neuroendocrine disorder. Case reportWe report two siblings born to consanguineous parents who were referred due to absent or delayed puberty progression. The elder sibling, a 17-year old male adolescent, presented with absence of secondary sexual characteristics and a high-pitched voice. He had normal cognitive development and no anosmia. Clinical examination revealed Tanner stage 1 and bilateral gynecomastia. Blood tests showed low levels of gonadotropins (LH < 0.3 IU/L [normal range: 1.7-8.6] and FSH < 0.3 IU/L [normal range: 1.2-7.7]) and low morning testosterone 11.4 ng/dL [normal range: 300-1000]. Examination of other pituitary hormones was normal. His 15-year old sister was referred due to primary amenorrhea. She had spontaneous thelarche and presented with Tanner stage 3. Blood examination revealed LH 1.1 IU/L, FSH 4.6 IU/L, and estradiol 2.5 ng/L [normal range: 15-350 ng/L]. Pituitary MRI was performed in the brother due to suspicion of Kallmann syndrome, revealing a normal anterior pituitary, hypoplastic posterior pituitary, and an extensive supratentorial leuko-encephalopathy. Whole-exome sequencing revealed a homozygous variant in RNF216 (c.1705_1710del, p.(Leu569_Ile570del)) (OMIM #212840) in both affected siblings. Further segregation analysis revealed that both parents were heterozygous carriers. RNF216 mutations cause a disorder characterized by combined neurodegeneration and reproductive dysfunction, with the majority of variants leading to amino-acid changes or truncation of the RBR domain or C-terminal extension, as observed in our family. ConclusionThis case report describes two siblings with absent or delayed puberty progression due to a homozygous novel RNF216 mutation. Further research is essential to elucidate the phenotypic variability present in patients with RNF216 mutations.

Presentation: 6/1/2024
8698 Unique populations of pituitary macrophages regulate gonadotropin secretion
Authors: Del Mundo Z , Ha J , Zhang A , Wiggins K D , De Robles G , Garcia C , Ujagar N , Nicholas D
Published: October 2024

Disclosure: Z. Del Mundo: None. J. Ha: None. A. Zhang: None. K.D. Wiggins: None. G. De Robles: None. C. Garcia: None. N. Ujagar: None. D. Nicholas: None.

Chronic inflammation disrupts hormonal balance in the Hypothalamic-Pituitary-Gonadal (HPG) axis, contributing to reproductive disorders. Despite extensive studies on immune cells in the hypothalamus and ovaries, their impact on the pituitary is largely unexplored. Our research reveals that macrophages are the primary immune population in the pituitary during homeostasis. In response to in vivo chronic lipopolysaccharide exposure in mice, a transient macrophage population emerges, associated with reproductive changes, including elevated serum testosterone, prolonged estrous cycle stage, and reduced ovarian antral follicle count. This study aims to characterize pituitary macrophages and elucidate their impact on the HPG axis. We hypothesize that pituitary macrophages change inflammatory status as a response to stimuli and, as a result, modulate gonadotropin secretion. We pinpointed differentially expressed genes (DEGs) in pituitary macrophages using scRNAseq, distinguishing them from other tissue-resident macrophages, including microglia. These DEGs include markers for macrophage activation, phagocytosis, migration, hormone synthesis, and lipid metabolism. Immunohistochemistry validated the distinctive morphology of pituitary macrophages compared to microglia. In vitro depletion of macrophages from mouse pituitaries resulted in decreased pituitary hormone secretion and decreased secretion of G-CSF, IL-9, and CXCL5. These results highlight the role of pituitary macrophages in hormonal regulation, setting the stage for future immunotherapeutic strategies to restore hormonal balance in reproductive disorders.

Presentation: 6/3/2024
6977 Unraveling Secondary Adrenal Insufficiency and an Invasive Pituitary Macroadenoma in a COVID-19 Positive Patient
Authors: Sayed Farah El , Banka Ajaz Ahamad
Published: October 2024

Disclosure: F. El Sayed: None. A.A. Banka: None.

Invasive pituitary macroadenomas extend into the extrasellar region and invade surrounding dural, periosteal, or mucosal tissues, often exceeding 1 centimeter and potentially compressing adjacent structures. Nonfunctioning pituitary adenomas (NFPAs), as they enlarge, can cause visual field impairment and ophthalmoplegia, with the decision for surgical intervention influenced by the degree of optic chiasm compression. NFPAs are sometimes associated with impaired endocrine function, particularly secondary adrenal insufficiency (sAI), which, warrants specific clinical attention. Management involves a combination of surgical interventions, such as transsphenoidal surgery, and medical approaches, including tailored hormone therapy or radiation therapy based on the tumor's characteristics. Clinical case: A 51-year-old female with a history of Sjogren's disease presented with a one-week duration of nausea, vomiting, diarrhea, and fatigue. Upon admission, she tested positive for COVID-19. Her vital signs indicated hypotension with a blood pressure in the 80s/40s range, a heart rate in the 90s, and she was afebrile on room air. Laboratory findings revealed significant hyponatremia (Na+ 118), K+ 4.3, HCO3- 19, and glucose 80. Workup for hyponatremia included a cortisol stimulation test, revealing secondary adrenal insufficiency with baseline cortisol of 3.5 ug/dl, 10.7ug/dl after 30 minutes, and 12.7ug/dl after 60 minutes. The patient denied exogenous steroid use, hypothyroid symptoms, polyuria, or polydipsia, and reported no headaches or visual symptoms. Endocrine evaluation showed hypogonadism despite post-menopausal status, with low estrone, estradiol, LH, and FSH levels. She was initiated on Cortef (hydrocortisone) with symptomatic improvement. Further investigation through an MRI revealed a large lobulated sellar mass measuring 3.2 x 2.8 x 3.5 cm compressing the optic chiasm and partially encasing the right internal carotid artery, leading to peripheral visual defects confirmed on perimetry. Following endoscopic endonasal pituitary macroadenoma resection, there was no evidence of interval growth on a one-year follow-up MRI scan. Discussion: The presented case highlights the importance of considering invasive pituitary macroadenomas in the differential diagnosis of patients with hyponatremia, particularly when accompanied by suggestive symptoms and an atypical cortisol response. The coexistence of COVID-19 adds a layer of complexity to the clinical scenario, necessitating a comprehensive approach to both infectious and endocrine management. Timely recognition, appropriate endocrine assessment, and targeted interventions, such as hydrocortisone replacement and surgical resection, are crucial for optimizing outcomes in patients with this intricate interplay of pituitary pathology and infectious states

Presentation: 6/1/2024
12391 When Pressure Drops, Consequences Rise: A Case Of Pituitary Apoplexy And Watershed Infarcts
Authors: Watashi Diego Moreno , Alkaissi Hussam R , Sharma Meeta B
Published: October 2024

Disclosure: D. Moreno Watashi: None. H.R. Alkaissi: None. M.B. Sharma: None.

Introduction: Pituitary apoplexy (PA) results from sudden hemorrhaging and infarction of the pituitary gland, typically within a pituitary adenoma. The primary symptom is a sudden, severe headache, often followed by acute endocrine dysfunction, ophthalmoplegia and visual or neurological disturbances. Case Description: A 68-year-old male with a past medical history of hypertension presented to the emergency department with acute chest and upper back pain, beginning one day prior. No history of smoking, alcohol intake or drug use. Blood pressure (BP) on arrival was 180/95 mmHg. Initial labs revealed mild electrolyte abnormalities. Troponins were normal, but ECG showed diffuse T wave inversion and ST depression. CT angiography revealed a type B aortic dissection. He was managed in the critical care unit with continuous esmolol intravenous (IV) infusion and planned for endovascular repair. During his stay, he became disoriented and hypotensive. MRI from the brain incidentally discovered a pituitary macroadenoma measuring 2.9x2.2x3cm and recent infarcts, with a distribution concerning for hypoperfusion. Fundoscopy concerning for optic chiasm compression. Labs indicated secondary hypothyroidism and hypogonadism (TSH 0.3 uUI/ml, free T4 0.88 ng/dL, total testosterone 56.3 ng/dL). Neurosurgical intervention was deferred until after aortic repair. Endovascular aortic repair was performed with episodes of hypotension. Post-procedure, the patient developed fever (39.5°C) and worsening mental status. Head CT revealed an increased suprasellar extension of the pituitary macroadenoma and vasogenic edema, consistent with hemorrhage of the lesion. He was started on stress doses of hydrocortisone, levothyroxine 125mcg and managed conservatively due to a high surgical risk. Discussion: PA's extrinsic risk factors include angiographic procedures, endocrinological dynamic tests, anticoagulation therapy, exogenous estrogen administration, orthopedic and cardiac surgeries (due to BP fluctuations). The intrinsic risk factors are non-functioning adenomas, macroadenomas and suprasellar extension. Treatment is focused on immediate correction of endocrine derangements and relieving local compression. Stress dosage of corticosteroids should be administered IV as soon as the diagnosis is confirmed to prevent life-threatening corticotropic deficiency. Neurosurgical decompression via a transsphenoidal approach is the definitive therapy to relieve local compression with severe visual loss, obtundation or rapidly progressive course. The potential outcomes are based on the extent of hemorrhage, necrosis, and edema. PA should be treated as a medical emergency in the setting of hemodynamic changes from acute corticotropic deficiency and irreversible neurological damage from acute intracranial compression. The risk factors for PA should be known to assist in early diagnosis.

Presentation: 6/1/2024
6825 α-Klotho Levels in Girls with Central Precocious Puberty
Authors: Hwang I , Kim E
Published: October 2024

Disclosure: I. Hwang: None. E. Kim: None.

Background: The exact mechanisms that trigger the onset of puberty are not fully understood. While it is known that elevated estradiol during puberty induces an increase in IGF-1, which subsequently promotes a rise in α-klotho levels, the relevance of these elevated α-klotho levels in children with Central Precocious Puberty (CPP) remains to be established. Given the potential significance of α-klotho in pubertal development, we initiated this study to determine whether increased α-klotho levels in CPP children are meaningfully pronounced and if these levels could serve as a reliable marker for CPP diagnosis and monitoring. Methods: A total of 139 girls were enrolled in the study, comprised of 82 diagnosed with CPP and 57 who were healthy prepubertal controls. From March 2020 to May 2023, we assessed both α-klotho levels and clinical parameters. α-klotho concentrations were measured using an α-klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Result: α-Klotho levels were higher in the CPP group compared with the controls (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001). α-Klotho significantly decreased after 6 months on GnRH agonist treatment.(2147± 789 pg/mL) (P < 0.001). α-Klotho levels were positively correlated with height-SDS, weight-SDS, bone age, ALP, IGF-1 SDS, baseline FSH and LH. α-Klotho relationship with IGF-1 SDS, baseline LH studied by partial correlation with adjustment for age, height and weight SDS (r= 0.275, p= 0.003; r= -0.229, p= 0.014). A ROC curve analysis identified an α-klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing CPP girls from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: Our study indicates a notable association between elevated α-klotho levels and CPP, especially as these levels adjust following GnRH agonist treatment. Based on our findings, considering α-klotho concentrations might offer a way to distinguish CPP from controls. Further studies could elucidate the potential of α-klotho as a biomarker for CPP diagnosis and monitoring.

Presentation: 6/1/2024
12431 14-year-old Presenting With Thrombocytopenia-Associated Multi-Organ Failure In The Setting Of Diabetic Ketoacidosis/Hyperosmolar Hyperglycemic Syndrome
Authors: Gunaratne-Breaux Naiomi C , Deplewski Dianne
Published: October 2024

Disclosure: N.C. Gunaratne-Breaux: None. D. Deplewski: None.

Title: 14-Year-Old Presenting with Thrombocytopenia Associated Multi-Organ Failure in the setting of Diabetic Ketoacidosis/Hyperosmolar Hyperglycemic Syndrome Background: Coagulation complications are rare in hyperglycemia emergencies in children and adolescents. In patients presenting with severe and atypical hyperglycemia emergencies, special considerations need to be made to rule out life-threatening coagulopathy. Clinical Case: A 14-year-old male with history of Type 1 Diabetes presented in severe Diabetic Ketoacidosis/Hyperosmolar Hyperglycemic Syndrome overlap. Initially had severe hypotension and altered mental status concerning for cerebral edema. Initial venous blood gas showed pH of 6.82, pCO2 17.1, and HCO3 2.8, serum glucose was 1375 mg/dL, serum ketones >7.00 mmol/L, and serum osmolality was 384 mOsm/kg. Once insulin drip was started, glucose, ketones, and serum osmolality improved, but patient continued to be encephalopathic and had worsening tachypnea and desaturations. Patient was eventually intubated. After intubation, patient’s acidosis improved, but patient developed kidney failure (prompting initiation of dialysis), liver injury, decreased cardiac function, and high inflammatory state. A comprehensive multi-specialty team including pediatric intensive care, infectious diseases, rheumatology, neurology, and cardiology were involved in the care. On day three of admission, patient had multiple areas of ischemia on fingertips and ear and clotting of multiple IV and dialysis catheters, prompting a coagulopathy evaluation. Labs showed microcytic anemia (hemoglobin 10.0 g/dL; mean corpuscular volume 75fL), thrombocytopenia (platelet count 17 10e3/uL), coagulopathy (prothrombin time 16.8 sec, INR 1.3, prolonged thrombin time 48.8 sec), and elevated ferritin (507 ng/mL). Given labs and multi-organ involvement, determined by hematology to be Thrombocytopenia Associated Multi-Organ Failure (TAMOF). Patient was started on plasmapheresis and had dramatic improvement – was eventually extubated and returned to neurologic baseline without any notable deficits. Multi-specialty team ruled out all other possible causes of TAMOF; determination that the TAMOF developed secondary to DKA/HHS. Conclusion: Hyperglycemia emergencies can lead to a hyperinflammatory state that can lead to disruption of the coagulation cascade, including disseminated intravascular coagulopathy or thrombotic thrombocytopenia purpura. There have been rare reports of thrombocytopenia associated multi-organ failure provoked by DKA, thought secondary to critical illness mediated low ADAMST13 levels. This is a novel case of TAMOF caused by DKA/HHS overlap syndrome. It is important to screen for coagulopathy in cases of patients with DKA or DKA/HHS who do not show clinical improvement with resolution of ketosis and hyperosmolarity.

Presentation: 6/2/2024
8721 A Case of Congenital Hyperinsulinism Manifesting as Transient Hypoglycemia During Illness Due to Mosaic Variant of Unknown Significance in ABCC8
Authors: Bell-Sambataro Esther Eunice , Mamilly Leena
Published: October 2024

Disclosure: E.E. Bell-Sambataro: None. L. Mamilly: None.

Background: Congenital hyperinsulinism (CHI) is characterized by inappropriate secretion of insulin during periods of low blood glucose. CHI can lead to significant complications such as seizures, developmental delays and neurologic damage. CHI can be caused by multiple genetic variants. The most common genetic etiologies are loss of function mutations in the genes ABCC8 and KCNJ11 encoding the pancreatic Beta (β)-cell ATP-sensitive potassium channel causing over secretion of insulin from the β-cells. We report a challenging pediatric case with a clinical presentation of CHI in an infant with a de novo mosaic ABCC8 gene variant of unknown significance manifesting only during times of illness. Clinical Case: A male infant born at 36 weeks gestational age was transferred to a tertiary center NICU secondary to seizure activity and hypoglycemia after the 24 hours of life with glucose levels as low as 32 mg/dL. His birth weight was normal and there was not maternal history of diabetes mellitus. The hypoglycemia persisted throughout the first week of life and required a glucose infusion rate of 11 mg/kg/min, without success in obtaining a critical sample. He had multiple seizures and MRI brain showed signs of hypoglycemic encephalopathy. Subsequently, he was weaned off IV dextrose and completed a 6 hour safety fast prior to discharge. Rapid genome testing resulted in a de novo, mosaic variant of unknown significance in ABCC8 (C.3622G>A resulting in amino acid substitution p.Glu1208Lys). His family reported significant but transient hypoglycemia during times of illness. At the age of 11 months, he was hospitalized for significant hypoglycemia during an episode of acute gastroenteritis and was treated with dextrose-containing fluids for 36 hours. A subsequent diagnostic fasting study resulted in hypoglycemia within 5.5 hours with capillary glucose of 49 mg/dL. At the time of hypoglycemia, beta hydroxybutyrate was inappropriately low at 0.78 mm, insulin level was suppressed <2 mcIU/mL. Glucagon (30 mcg/Kg) was administered after the initial sample was drawn with a significant increase in glucose from 49 mg/dL to 103 mg/dL. Based on the positive glucagon response and low serum ketone, the clinical diagnosis of CHI was made and diazoxide was initiated while awaiting other results. After the second dose of diazoxide, all glucose levels remained above 80 mg/dL. He was sent home on a continuous glucose monitor and diazoxide. Conclusion: CHI can occur due to autosomal recessive or autosomal dominant ABCC8 loss-of-function mutations of which more than half are not responsive to diazoxide. In this case report, we describe the diagnosis of hyperinsulinemic hypoglycemia in an infant with an ABCC8 variant classified with unknown significance. We describe a good initial response to diazoxide in normalizing blood glucose levels in this infant.

Presentation: 6/2/2024
5174 A longitudinal retrospective cohort study on the application of the Superimposition by translation and rotation (SITAR) model to estimate body composition growth trajectory in Korean children and adolescents during puberty
Authors: Kim Seo Jung , Kim Sujin , Suh Junghwan
Published: October 2024

Disclosure: S. Kim: None. S. Kim: None. J. Suh: None.

Introduction: In addition to adulthood, pediatricians have noted a growing emphasis on research concerning sarcopenic obesity. Studies in this field have expanded beyond basic BMI-related inquiries, actively delving into investigations based on body fat mass (BFM) and fat-free mass (FFM). However, limited research has systematically analyzed the acquisition of body composition during children and adolescence based on longitudinal data. Objective: This study aims to assess the acquisition of weight, FFM, and BFM during the pubertal growth of Korean children and adolescents. Methods: This study utilized mixed longitudinal body measurement and body composition data, employing bioelectrical impedance analysis, from 4,641 height measurements (2,204 for boys and 2,437 for girls) obtained from 361 individuals (170 boys and 191 girls) among Korean children and adolescents aged 7 to 18. The SITAR (the Superimposition by Translation and Rotation) model, a shape-invariant growth curve model, was used to estimate a reference height velocity curve during pubertal growth. Results: The SITAR methodology allowed us to investigate the timing, magnitude, and intensity of adolescent weight, FFM, and BFM gain. The results revealed significant differences in growth trajectories between boys and girls, with boys exhibiting a persistent elevation in FFM and a pattern of ascent followed by a decline in BFM, while girls show an increase in BFM and a deceleration in FFM growth. In Korean boys, the peak weight velocity (PWV) occurred at a mean age of 12.41 years, with a rate of 8.19 kg/year. Peak fat-free mass velocity (PFV) was observed at a mean age of 9.69 years, with a rate of 7.60 kg/year, and peak body fat mass velocity (PBV) at a mean age of 12.70 years, with a rate of 2.67 kg/year. In Korean girls, the mean age of PWV was 11.28 years, with a velocity of 6.33 kg/year. PFV occurred at a mean age of 12.33 years, with a rate of 4.86 kg/year, and PBV at a mean age of 11.13 years, with a rate of 2.72 kg/year. The ages of peak velocities of height (PHV), PWV, PFV, and PBW positively correlated. Conclusions: This study is the first to apply the SITAR model to examine the acquisition of body composition in Korean children and adolescents. Future research should delve into exploring the connections between various disease groups during childhood and adolescence and the patterns of change in body composition.

Presentation: 6/1/2024
7772 A Study on Role of Anti-Mullerian Hormone and Inhibin B in 46,XY Disorders Of Sexual Development
Authors: Kudugunti Neelaveni , Bangaru Sai kiran , Sahay Rakesh Kumar
Published: October 2024

Disclosure: N. Kudugunti: None. S. Bangaru: None. R.K. Sahay: None.

Background: In pre-pubertal period, a major part of the testicular tissue is constituted by Sertoli cells for which AMH, Inhibin B are specific biomarkersHigh AMH, Inhibin B levels in the prepubertal period is via FSH stimulation, which is mistakenly considered to be silent due to its reduced activity Aim & Objectives: To assess AMH and Inhibin B measurements in the diagnostic workup of prepubertal children with different subtypes of 46,XY DSD and comparing with normal controls To assess Sertoli cell function with AMH and Inhibin B and to assess correlation between testosterone elevation after hCG stimulation, basal AMH and Inhibin B Patients and methods: Pilot study-Single centered, Cross-sectional Observational study. After ethical committee approval, 40 children with 46,XY DSD & 40 healthy age matched, boys as controls recruited after taking assent. All children with DSD underwent karyotyping, assessment of hCG stimulated testosterone, DHT and androstenedione. Basal AMH and inhibin B were measured in both cases and controls. Data were analysed using IBM SPSS version 25. Results: The mean age at presentation was 4.09 years.The diagnosis was made clinically and biochemically, genetic analysis done in few patients. Out of 40 cases, 26 had normal hCG stimulated testosterone of >100 ng/dl (17 cases were 5 alpha reductase type 2 deficiency [5αR2D], 9 cases were PAIS) & 14 had low hCG stimulated testosterone of <100 ng/dl (8 cases were 17βHSD3 deficiency, 4 cases were Partial gonadal dysgenesis [PGD], 2 cases were Vanishing testis syndrome). In the low testosterone group, mean AMH in 17βHSD3 deficiency-279.95 ng/ml, in PGD-31.16 ng/ml which is statistically significant in differentiating these disorders(p-0.002)& mean Inhibin B in 17βHSD3 deficiency-186.41 pg/ml, in PGD-35.95 pg/ml which is statistically significant in differentiating these disorders (p-0.007). In vanishing testis syndrome, AMH & Inhibin B were helpful in confirming the absent functioning testicular tissue Whereas in normal testosterone group, mean AMH in PAIS-235.65 ng/ml, in 5αR2D-289.08 ng/ml difference is not statistically significant(p-0.36)& mean Inhibin B in PAIS-204.50 pg/ml, in 5αR2D-190.91 pg/ml difference is not statistically significant(p-0.72) There was significant correlation between basal AMH and hCG stimulated testosterone (r=0.434; p-0.002), Inhibin B and hCG stimulated testosterone(r=0.438; p-0.001), AMH and Inhibin B(r=0.770; p<0.001). Conclusion: AMH and Inhibin B are valuable in differentiating PGD, 17βHSD3 deficiency in low hCG stimulated testosterone patients, but not helpful in differentiating PAIS, 5αR2D in normal hCG stimulated testosterone patients. Especially in PGD they may have a role with respect to fertility prospects and malignancy risk assessment.

Presentation: 6/3/2024
7316 A Unique Presentation of Diabetes Mellitus in an 8-Year-Old Male Positive For 3 Different Mutations Related to MODY
Authors: Senguttuvan R , Pamfil A
Published: October 2024

Disclosure: R. Senguttuvan: None. A. Pamfil: None.

Background: Maturity-Onset Diabetes of the Young (MODY) is the most common form of inherited non-autoimmune diabetes mellitus, characterized by autosomal dominant inheritance, young age at onset and beta cell dysfunction. There are at least 14 MODY mutations and we present a pediatric case not meeting criteria for type 1[T1DM] or type 2 diabetes mellitus[T2DM], who tested positive for mutations in 3 different genes known to cause MODY. Case: An 8-year-old male, born full term, 2776 grams and 48.3 cm, without history of neonatal hypoglycemia or hyperglycemia, was referred for new onset diabetes mellitus management. While undergoing evaluation for abdominal pain and constipation, he was found to have a fasting glucose of 126 mg/dL (7 mmol/L) and hemoglobin A1C of 6.5%. He endorsed polyuria, but no polydipsia. He had no clinical signs of insulin resistance (e.g., acanthosis nigricans) and a BMI of 23.65 kg/m2, at the 97th percentile. Family history is positive for diabetes mellitus requiring insulin, in father (diagnosed at 11 years) and paternal grandmother and T2DM in paternal aunt. Laboratory evaluation was negative for all 5 antibodies (GAD, IA-2, Anti-islet cell antibody, Zinc Transporter 8 and Insulin antibodies) and revealed an insulin level of 15.9 uIU/mL (RR: <2.0-13.0) and C peptide: 2.3 ng/mL (RR: 1.1-4.4). Lacking diagnostic criteria for T1DM or T2DM, genetic testing was performed. Patient tested heterozygous for mutations in 3 genes known to cause MODY: GCK [(c.350 G>T p. (G117V)], ABCC8 [(c.2270 C>G p.(T757R)], and HNF1B [(c.68A>G p.(K23R)], all variant of uncertain significance. Over an 8-month period, patient's weight decreased from 98 lbs. (44.9 kg) to 90 lbs. (41.1 kg) after meeting with our dietician and implementing healthy dietary changes, and his beta cell function markers improved from diagnosis: Fasting insulin (4.5 uIU/mL), C peptide (1.3 ng/mL), and glucose 119 mg/dL; Hemoglobin A1C remained relatively stable at 6.1%. A kidney ultrasound was normal. No medical intervention were started yet, and patient is being monitored clinically and biochemically every 3-4 months. Discussion: Clinical monitoring over time, genetic testing in the parents, are critical in this patient’s long-term treatment plan and prognosis. To our knowledge, this may be the first case of diabetes mellitus in a pediatric patient, positive for mutations in 3 different genes known to cause MODY. South Texas has one of the highest incidences of T2DM in the USA. In addition to screening for genetic forms of diabetes, in patients with negative T1DM antibodies and atypical phenotype for T2DM, we should consider genetic screening in mildly obese pediatric and young adult patients without significant acanthosis nigricans, who were already diagnosed as T2DM.

Presentation: 6/1/2024
6471 Adult Height in Male Survivors of Childhood Cancer Treated with Aromatase Inhibitors and Growth Hormone
Authors: Pollock Netanya I , Song Minkeun , Wolf Alexander , Li Yimei , Hawkes Colin , Motamedi Niloofaralsadat , Denburg Michelle R , Mostoufi-Moab Sogol
Published: October 2024

Disclosure: N.I. Pollock: None. M. Song: None. A. Wolf: None. Y. Li: None. C. Hawkes: None. N. Motamedi: None. M.R. Denburg: None. S. Mostoufi-Moab: None.

Title: Adult Height in Male Survivors of Childhood Cancer Treated with Aromatase Inhibitors and Growth Hormone Objectives: Aromatase inhibitor (AI) therapy in combination with growth hormone (GH), or as monotherapy, may have a role in improving height outcomes in male pediatric patients with GH deficiency (GHD). The effectiveness of AI therapy in the childhood cancer survivors is not known. In this retrospective study, we assess adult height (AH) in childhood cancer survivors treated with AI combined with GH therapy compared to those treated with GH alone. Methods: This was a single center retrospective cohort study of male survivors of childhood cancer treated with GH for diagnosis of GHD between 2007 and 2023. We compared AH outcomes in males treated with GH alone or in combination with off-label use of AI. Demographic and clinical characteristics, including anthropometric measurements, endocrinopathies, and cancer history, were obtained from the medical record. AH was noted as height documented at fusion of growth plates or following 18 years of age. Differences in demographic, clinical, and treatment characteristics were assessed using univariate tests of association. Multivariable regression with stepwise selection was used to examine risk factors associated with AH. All statistical analyses were performed using Stata 18.0. Results: Ninety-two patients were included; 70 were treated with GH monotherapy and 22 with combination AI/GH. Median age at AI initiation was 13.6 years (IQR 12.3-14.3) versus 11.2 years (IQR 8.6-12.9) for GH (unpaired t-test p-value <0.01; 95% CI -4.01, -1.91). A greater proportion of patients in the AI/GH group had been treated with stem cell transplantation, abdominal radiation, total body irradiation, and cis-retinoic acid (Fisher’s exact p-value <0.01). There was no statistically significant difference in AH or AH Z-score between treatment groups, with the median AH Z-score in the AI/GH group -1.95 (IQR -3.11, -0.75) versus -1.39 (IQR -2.65, 0.11) in the GH group. In multivariable linear regression, history of radiation to the spine (β= -5.9, 95% CI -11.2, -0.6), height Z-score (β= 0.3, 95% CI 0.11, 0.46), BMI Z-score (β= 3.2, 95% CI 0.95, 5.5), and advanced bone age at GH or AI treatment initiation (β= -10.1, 95% CI -17.3, -2.9) were significantly associated with AH. Conclusions: Adjunctive treatment with AI and GH was not associated with increased AH outcomes in male survivors of childhood cancer compared to GH monotherapy. Future work is needed to determine optimal adjunctive medical therapy to maximize FAH impacted by cancer therapy for this patient population.

Presentation: 6/3/2024
8076 Advancing Career Development of Physician-Scientists Engaged in Diabetes Research: Insights into the National K12 DiabDocs Program
Authors: Dasani Komal D , Bishop Franziska K , Golden Sherita H , Laffel Lori M , Mirmira Raghavendra G , Steck Andrea K , Willi Steven M , Maahs David M , DiMeglio Linda A
Published: October 2024

Disclosure: K.D. Dasani: None. F.K. Bishop: None. S.H. Golden: None. L.M. Laffel: None. R.G. Mirmira: None. A.K. Steck: None. S.M. Willi: None. D.M. Maahs: None. L.A. DiMeglio: None.

Background: In July 2022 the NIH established a multi-center National K12 “Diabetes-Docs: Physician-Scientist Career Development Program” (DiabDocs) to support mentored research experiences and tailored career development training for cohorts of physician scientists focused on diabetes research. DiabDocs scholars are board-certified or board-eligible physicians with training in pediatric or adult endocrinology or in another area tied to diabetes research and care. The program addresses the shortage of physicians engaged in diabetes research and is open to scholars at any eligible institution in the United States. Methods: The DiabDocs program was implemented by two multi-center Program Directors (MPD), in collaboration with an Executive Leadership Committee (ELC) comprised of experienced basic science and clinical/translational physician-scientists. Additional faculty from 19 different institutions have engaged in advisory and reviewer roles. The program solicits Letters of Intent (LOIs) annually from interested candidates followed by invitations for full applications; a program retreat features educational workshops and diversity training; and a Study Section selects Scholars. Currently, the program is in its third recruitment cycle for additional scholars to start Summer 2024. Additional career development programming is available through a series of interactive webinars. The program also has a strong commitment to diversity, equity, and inclusion, including a “DiabDiversity” program to support in-person engagement in DiabDocs experiences by under-represented in medicine trainees. Results: After two successful recruitment cycles in 2022-2023 that reviewed 24 LOIs, 11 scholars were selected. The funded scholars (6 Adult and 5 Pediatric Endocrinologists) include 3 individuals self-identifying as underrepresented in medicine and 7 females. For the 2023 application cycle, 24 LOIs were received (11 from Adult and 9 from Pediatric Endocrinology, 2 in combined Pediatric/Adult Endocrinology, and 2 from other specialties). Conclusions: The DiabDocs program aims to identify, recruit, and support outstanding early career physician scientists. The program provides a national network with resources for protected research time, career development programs, and national mentorship to develop cohorts of skilled professionals contributing to the advancement of diabetes research.

Presentation: 6/2/2024
6379 Clonidin does not stimulate copeptin release
Authors: Binder G , Weber K , Peter A , Schweizer R
Published: October 2024

Disclosure: G. Binder: None. K. Weber: None. A. Peter: None. R. Schweizer: None.

Background: Copeptin is secreted in isomolar amounts along with arginine vasopressin peptide from the posterior pituitary. Its stability makes it a perfect candidate for a biomarker of AVP deficiency. In children, the infusion of arginine and bolus of insulin stimulate copeptin; the respective stimulation test could be an alternative to the water deprivation test. Here, we retrospectively studied the effect of clonidine on copeptin release. Design and patients: This is a monocentric retrospective analysis of donated residual serum samples from 42 children with suspected of GH deficiency who underwent clonidine stimulation between 2020 and 2023. Measurements: Copeptin was measured in baseline, 30-, 60-, 90- and 120-min samples by BRAHMS Copeptin proAVP Kryptor immunofluorescence assay. GH was measured using an in-house RIA calibrated against the WHO International Reference Preparation 98/574. Results: According to the test results (clonidine and arginine test), there were 20 patients with GHD and 16 without GHD. No patient had polyuria-polydipsia syndrome. Median age was 6.7 years (quartiles; 5.6-7.8), the median height was -2.92 SDS (-3.42- -2.34), and the median BMI was-0.29 SDS (-1,32 - +0,16). The median baseline level of copeptin was 5,6 pmol/l (3.4-9.6). Median copeptin mildly decreased to 4.5 pmol/l (3.0-10.0) after 30 min; this change was not significant (P=0.45). Thereafter, median values remained low at 4.6, 4.6 and 4.6 pmol/l (60, 90 and 120 min). There was no correlation between baseline copeptin levels and the diagnosis of GHD. Conclusion: The clonidine stimulation test does not stimulate copeptin release and is therefore not suitable for the assessment of AVP deficiency in children.

Presentation: 6/2/2024
8644 Dynamic Insights into Glucocorticoid Receptor Dysfunction: Novel patient-derived T437I Mutation and Its Impact on Glucocorticoid Receptor Function
Authors: Tettey Theophilus , Kim Sohyoung , Wagh Kaustubh , Lao Qizong , Schiltz Louis R , Lafuente Agustina , Stavreva Diana A , Presman Diego Martin , Merke Deborah P , Hager Gordon L
Published: October 2024

Disclosure: T. Tettey: None. S. Kim: None. K. Wagh: None. Q. Lao: None. L.R. Schiltz: None. D.A. Stavreva: None. D.M. Presman: None. D.P. Merke: None. G.L. Hager: None.

The glucocorticoid receptor (GR) is a hormone regulated transcription factor which binds chromatin to regulate many genes, including stress-response and inflammatory genes. Dexamethasone, a GR agonist, is widely used in the treatment of severe inflammation, including COVID-19. GR is vital for life and several GR mutations have been linked to severe pathophysiological conditions. Here we report a novel mutation in the DNA binding domain (DBD) of GR (T437I) in a patient with partial glucocorticoid resistance, a rare genetic disorder characterized by generalized insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic pituitary adrenal axis. While the clinical manifestations of this hT437I GR mutation are apparent, its molecular mechanisms remain unexplored. Employing a comprehensive approach that integrates biophysical methods, molecular biology, and genomics, we investigate the molecular underpinnings of this genetic anomaly. Using CRISPR/Cas9 gene editing, we introduce GFP or Halo-tagged hT437I GR mutant into GR null mouse cells. Our findings indicate that the T437I GR variant exhibits normal hormone binding and nuclear translocation. Live-cell imaging using number and brightness analysis reveals that the mutant receptor maintains a wildtype-like oligomeric state but adopts a heterodimeric conformation in the presence of endogenous GR. Global transcriptomics analyses of the mouse hT437I mutant show that most dexamethasone-regulated genes are unresponsive following hormone treatment. We hypothesize that this mutation within the DBD compromises the binding of GR to regulatory sites of target genes. Leveraging fluorescence high-resolution microscopy, we employ single molecule tracking to study the dynamic behavior of Halo-tagged hT437I GR in mouse cells. Our results indicate that the GR mutant has a higher dwell-time on chromatin compared to the wild-type receptor. This suggests that the hT437I mutation impairs the receptor's binding to genomic sites, potentially leading to a failure in regulating GR target genes. This ongoing exploration of the molecular intricacies aims to deepen our understanding of the clinical phenotype observed in the patient.

Presentation: 6/2/2024
12599 Early Remission Of Chromosome 6 Q 24-related Neonatal Diabetes Mellitus
Authors: Pratibha Rana , Dummula Krishna
Published: October 2024

Disclosure: R. Pratibha: None. K. Dummula: None.

Introduction: Chromosome 6q24 imprinting abnormalities represent the predominant cause of transient neonatal diabetes mellitus (TNDM), accounting for over two-thirds of cases with an estimated prevalence of 1 in 400,000. While remission typically manifests by 3 months of age, herein we detail a case of Chromosome 6q24-related TNDM exhibiting remission by 1.5 months of age. We share our clinical experience in managing this case without hypoglycemia and using C-Peptide levels as a monitoring tool to track the resolution. Case: A female infant, born at 36 weeks via elective C-section due to fetal growth restriction and oligohydramnios, was closely monitored in the nursery for potential hypoglycemia. Contrary to the expectation, she displayed escalating hyperglycemia, necessitating insulin infusion within 25 hours of birth. Apgar scores were 7 and 9, and the birth weight was 2095 g (6th percentile). Maternal history included impaired glucose tolerance in a previous pregnancy with borderline glucose tolerance during this gestation. The newborn physical exam was unremarkable except for mild macroglossia. Despite initial blood glucose (BG) of 52 mg/dl, it rose to 257 mg/dL by 16 hours. Insulin drip was started at 24 hours due to BG of 304 mg/dL. The monogenic diabetes panel obtained on day of life (DOL) #2 was negative; no acidosis was observed. The C- Peptide was low at 0.2 ng/ml. Insulin infusion was continued until DOL # 20. A trial of glyburide commenced on DOL #9 while on Insulin drip, yielded minimal response, prompting a transition to short-acting insulin for correction of hyperglycemia (>250 mg/dL). C-peptide level during sulfonylurea (SU) trial remained low (0.5 ng/mL). The infant required 2 to 3 corrections per day with 0.05 units of Lispro Insulin, with the last dose administered at 44 days. She did not receive any long-acting Insulin. As of her last follow-up at the endocrine clinic at 57 days of age, the infant is thriving well and has normal blood glucose levels. The 6q24 Methylation-MLPA study showed duplication of 6q24 on the paternally inherited chromosome 6. Significantly, she never encountered hypoglycemia during her hospital stay. The C-peptide increased to 0.8 ng/ml at DOL#37 and had normalized to 1.3 ng/mL by DOL#57 indicating remission of TNDM. Conclusion: 6q24-related TNDM may often be characterized by features such as small for gestational age (SGA), macroglossia, umbilical hernia, cardiac and renal abnormalities. Early presentation of hyperglycemia with this phenotype must prompt its diagnostic evaluation. Early resolution by 1.5 months as seen in our case is uncommon. Uniquely, we used C-peptide as a tracking tool to guide resolution and manage insulin therapy.

Presentation: 6/3/2024
7866 Efficacy of Zinc and Myoinositol Supplementation on Metabolic Parameters In A Pediatric Population With Obesity: a Randomized Controlled Trial
Authors: Antoniotti Valentina , Mancioppi Valentina , Solito Arianna , Partenope Cristina , Petri Antonella , Rabbone Ivana , Scotti Lorenza , Prodam Flavia , Bellone Simonetta
Published: October 2024

Disclosure: V. Antoniotti: None. V. Mancioppi: None. A. Solito: None. C. Partenope: None. A. Petri: None. I. Rabbone: None. L. Scotti: None. F. Prodam: None.

Background: In the last decades, pediatric obesity and cardiovascular-associated risks have been relevant challenges. The first treatment against obesity is a lifestyle change, nevertheless, no intervention seems to be effective in the evolution of the condition, especially in the long term. Thus, the interest in non-pharmaceutical as well as pharmaceutical compounds is growing. Inositol compounds have recently been studied in adults with obesity and insulin resistance but have never been investigated in the pediatric age where insulin resistance is a specific trait of puberty. Furthermore, zinc is critical for insulin secretion and growth. Methods. This is a double-blind, randomized, placebo-controlled study aiming to explore the efficacy of 3 months of combined administration of Zinc (5 mg/die) and Myo-inositol (2000 mg/die) in children and adolescents with obesity. 56 patients aged 10- 17.9 years (starting from Tanner 3) with obesity and insulin resistance have been enrolled. The treatment group received 5 mg of Zinc, 2000 mg of Myo-inositol, and 1000 mg of galactooligosaccharides from Pisum sativum, while the placebo group only received 1000 mg of galactooligosaccharides from Pisum sativum. All patients were subjected to an isocaloric diet following the Mediterranean diet style consisting of 55% carbohydrates, 30-35% fat, and 15% protein. Clinical and biochemical evaluations were carried out for the determination of weight, lipid profile, liver function, and glucose-insulin metabolism. Results. At the end of the study, BMI, fasting insulin, and insulin resistance (HOMA-IR) were significantly improved in both groups, while the treatment group also had an increase in HDL cholesterol (p=0.0426). On the other hand, the placebo group significantly improved its eating habits showing greater adherence to the Mediterranean diet than the treatment group. Moreover, subjects were divided according to the degree of obesity. Fasting insulin (p= 0.0137), HOMA-IR (p= 0.0273), and systolic blood pressure (p= 0.0349) showed a significant improvement in treated patients with severe obesity compared to treated patients with low-grade obesity. Thus, subjects with a higher level of obesity respond better to both treatment and lifestyle change than those with a lower grade of obesity. Also, the improvement of the lifestyle and the presence of fiber allow an increase in the metabolic framework in placebo subjects. Conclusions. Supplementation with Zinc and Myo-inositol could be used as a non-pharmacological compound for the control of complications related to obesity also in the pediatric age.

Presentation: 6/1/2024