Adrenal Insufficiency Research Articles

8252 Central Adrenal Insufficiency Masquerading as Syndrome of Inappropriate Antidiuretic Hormone (SIADH): A Case Report

Abstract Disclosure: J.G. Sazon: None. J.L. Reyes: None. J.V. Chua: None. S.A. Kho: None. Hyponatremia, the most common electrolyte imbalance encountered in clinical practice, has various causes and presentation. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is a frequent hospital-related cause, potentially leading to misdiagnosis with adrenal insufficiency due to shared clinical features which may cause potential deleterious effect. We present a case of a 41-year-old male hyponatremic patient with a two-month history of progressive generalized body weakness and lightheadedness, initially managed as SIADH. Upon admission, the patient persistently showed low serum sodium level (122mmol/L) (NV: 135-145mmol/L), exhibited signs of euvolemic hyponatremia despite fluid restriction, intravenous furosemide, and sodium chloride tablets. Further work-up revealed normocytic normochromic anemia (Hgb 107 g/L) (NV: 120-160g/L), elevated ESR of (31mm/hr) (NV: 0-15mm/hr), low Ft4 (2.97 pmol/L) (NV: 12-22 pmol/L) and normal TSH (2.2 uIU/mL) (NV: 0.27-4.20 uIU/mL). During hospital stay, he experienced an episode of hypotension at 80/50mmHg and hypoglycemia at 65 mg/dL. Investigation revealed adrenal insufficiency secondary to pituitary macroadenoma with apoplexy as showed in magnetic resonance imaging. Patient was started on Prednisone. Pre-operatively, hydrocortisone 100mg IV every 8 hours preoperatively. He underwent transsphenoidal surgery; excising a 2.5cm soft and grayish suprasellar mass. Post-operatively, he was given Prednisone and Levothyroxine resulting in symptom improvement and normal sodium levels.The occurrence of hyponatremia due to adrenal insufficiency is relatively uncommon, emphasizing the need for heightened suspicion when assessing patients with prolonged or recurring hyponatremia. This paper highlight the need to replace glucocorticoid prior supplementation of thyroid hormone in such cases, averting the occurrence of adrenal crisis. This case indicated a mechanism of persistent hyponatremia attributed to secondary adrenal insufficiency, with added therapeutic benefits observed through the use of glucocorticoids and transsphenoidal surgery. Presentation: 6/1/2024

6768 A Rare Presentation of Primary Adrenal Insufficiency with Hypertension & Hypokalemia

Abstract Disclosure: A.M. San Hernandez: None. R. Alshantti: None. G. Espinoza Mercado: None. J.L. San Hernandez: None. Introduction: Adrenal Insufficiency is caused by the failure of the adrenal cortex to produce glucocorticoids +/- mineralocorticoids. This can be due to a defect in the adrenal cortex, or in the hypothalamic pituitary axis. The clinical manifestations are usually non-specific, ranging from mild vague symptoms to life threatening crisis. Therefore, diagnosis requires a high level of suspicion by providers. Unusual presentations of primary adrenal insufficiency (PAI) with hypertension and hypokalemia have been rarely described in the literature. We present a rare case of PAI with hypertension and hypokalemia. Case Presentation: A 68 years old female with a medical history of rheumatoid arthritis, hypothyroidism on Levothyroxine, chronic transaminitis, and bicytopenia presented to the hospital with a 6 weeks history of generalized weakness, loss of appetite, weight loss, and dizziness. Patient denied any diuretic or steroid use within the last 2 years. On arrival, she was afebrile, hypertensive (168/84mmHg), with normal oxygenation and pulse. Physical examination was unremarkable with normal volume status. Initial laboratory results showed low sodium 116 mEq/L, low serum osmolality 247 MEQ/kg, normal potassium 3.6 mEq/L, Creatinine 0.3 mg/dL & BUN 9 mg/dL. She was initially started on IVF normal saline. Further workup revealed normal TSH & FT4 levels. Urine study showed urine osmolality (477 MOSM/KG), & urine sodium (127 mEq/L). Given these findings, SIADH was suspected and fluid restriction was started. Sodium level continued to be low with minimal improvement to 120 mEq/L, potassium levels also dropped (3.3-3.2 mEq/L), requiring daily replacement. BP remained elevated ranging from 150s to 160s systolic and 80s to 90s diastolic. Hypertension was controlled with her home medication Amlodipine. Although atypical presentation with hypertension & hypokalemia, the diagnosis of adrenal insufficiency was considered. Laboratory evaluation showed low morning cortisol 5.2 ug/dL, with album level 3.5 g/dL. Cosyntropin stimulation test showed 1.3 ug/dL (at baseline), 9.9 (30 min post administration), and 14.4 (1 hour post administration); results confirming PAI. ACTH, Renin, Aldosterone, & DHEAS levels were normal. CT adrenal was normal. Patient was started on hydrocortisone; some of her symptoms & Na level improved. Further investigation of the etiology of PAI and possible hyperaldosteronism is pending outpatient follow up. Conclusion: Adrenal insufficiency is a life threatening condition with serious consequences if diagnosis is missed. It manifests by a wide spectrum of symptoms and signs, some can be masked by the presence of other comorbid conditions leading to atypical presentations. Our case highlights the importance of maintaining a high level of suspicion of adrenal insufficiency in patients with atypical presentation, including those with hypertension & hypokalemia. Presentation: 6/3/2024

12670 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

9341 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

7438 DAX1/NR0B1 Related Adrenal Hypoplasia Congenita Without Hypogonadotropic Hypogonadism

Abstract Disclosure: R.L. Figueiredo: None. J.B. Drummond: None. A. Meireles: None. J.L. Machado: None. G. Vidigal: None. B.S. Rocha: None. Background: X-linked congenital adrenal hypoplasia (AHC) is a rare disease caused by genetic mutations in DXA1/NRB01 gene, which encodes a nuclear hormone receptor expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary gland, occurring in less than 1:12,500 live births (1,2). AHC is characterized by primary adrenal insufficiency (PAI) associated with hypogonadotropic hypogonadism (HH) and impaired spermatogenesis (oligospermia or azoospermia). Although DAX1/NR0B1 mutations can manifest with different phenotypes, HH is mostly present, which makes this present case a diagnostic challenge. Clinical case: A 23-year-old man presented with typical symptoms of adrenal insufficiency at the age of 7 (abdominal pain, dehydration, nausea, vomiting and cutaneous hyperpigmentation). Initial testing was consistent with primary adrenal failure: elevated ACTH levels (1250pg/mL, RR<46pg/mL) and very low serum cortisol (0.8mcg/dL, RR 3-20mcg/dL). Etiological investigation excluded autoimmune etiology (negative anti-adrenal and anti-21-hydroxylase antibodies) as well as adrenoleukodystrophy (normal very long chain fatty acid levels). Physical exam revealed normal virilization, testicular volume and penile length. The patient reported normal libido and sexual function. Hormonal evaluation showed normal total testosterone (424 and 713ng/dL, RR 165 to 753ng/dL) as well as calculated free testosterone (7.2 and 11.4ng/mL, RR>3.8ng/mL) levels. Abdominal CT showed signs of bilateral adrenal hypoplasia. We then proceeded to genetic testing that revealed a pathological variant c.625C>T:p (Gln 209*) in hemizygosity in exon 1 of the DAX 1/NR0B1 gene. This is a nonsense mutation that introduces a premature stop codon. This variant is not present on the global and Brazilian genetic databases (gnomAD and ABraOM) and has not been previously described in the literature. The patient is currently being treated for adrenal insufficiency with the lowest tolerated dose of prednisone (7.5mg/day) and fludrocortisone 0.1mg/day. Conclusion: Etiological investigation of patients with PAI is essential to understand the evolution of the disease, monitoring extra-adrenal manifestations and the possibility of genetic counseling for the family. An intact hypothalamic-pituitary gonadal axis should not preclude genetic evaluation for a DAX/NR0B1 mutation in patients with PAI and suspected AHC. Further studies will clarify if this specific mutation carries a genotype-phenotype correlation in patients with AHC without HH.

9202 Characterizing The Physiological Side-Effects Of Over-The-Counter Arthritis Supplements

Abstract Disclosure: K.S. Wei: None. M.O. De La Torre: None. A. Flores: None. C.E. Chiu: None. T.E. Angell: None. Introduction: Over the counter (OTC) health supplements are commonly used by patients for a variety of ailments but may contain active ingredients that are not stated, such as glucocorticoids. Here, we present a case series of 12 patients seen by the Endocrinology Consult service at an urban safety net hospital during 2022-2023 and determined to have iatrogenic adrenal insufficiency (AI) from specific OTC supplements that surreptitiously contained glucocorticoids. Clinical Cases:12 patients using OTC arthritis supplements [Artri King (n=8), Ardosons (n=3), and Ajo Rey (n=1)] were identified. Median age was 52 years and 33.3% were female. All started using the supplements because of joint pain. Median length of use prior to cessation was 6 months. The most common presenting symptoms were nausea/vomiting (42%), fatigue (42%), abdominal pain (33%), and dizziness (17%). The most common physical exam findings of steroid excess included moon facies (66%), central adiposity (66%), abdominal striae (50%), dorsocervical fat pad (33%), and bruising (33%). 3/12 patients required ICU admission. Cortisol assessment was performed in 11/12 patients, which showed normal cortisol level in 1 patient (cortisol ≥16 mcg/dL), AI in 3 patients (cortisol ≤3 mcg/dL), and an equivocal level (cortisol 3-16 mcg/dL) in 7 patients. Cosyntropin stimulation testing in 6/7 patients with equivocal cortisol levels suggested AI in 4 (cortisol level <16 mcg/dL at 60 minutes after ACTH stimulation), whereas 2 showed lower but normal response (cortisol levels 18.2 mcg/dL and 18.4 mcg/dL). In total, 10/12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis. The most common regimens were hydrocortisone 20mg qAM/10mg qPM (33%) and hydrocortisone 5mg qAM/5mg qPM (17%). To date, 2/10 patients have successfully discontinued steroid replacement. Conclusion: These cases demonstrate possible Cushing’s syndrome and/or adrenal insufficiency after unintentional exposure to glucocorticoids in these OTC arthritis supplements, which has only previously been reported in a small number of case reports (1). This series collected over a 2-year period offers important clinical insights: Because patients may not identify or recall a supplement, possible use of OTC medications for arthritis or other anti-inflammatory purposes should be specifically assessed in patients presenting with adrenal insufficiency (especially with concomitant findings suggesting Cushing’s syndrome). For patients on such supplements, immediate discontinuation may not be possible without cortisol replacement and should be done with caution. 1)Boncompagni A.C. et al. A case of iatrogenic Cushing syndrome and subsequent adrenal insufficiency from a hidden ingredient in the supplement Artri Ajo King. J Am Coll Emerg Physicians Open. 2023;4(4):e13007. Presentation: 6/1/2024

8205 Within day Symptoms Of Adrenal Insufficiency Predict Reduced Quality Of Life And Adrenal Crises In 712 MyAI Registry Participants

Abstract Disclosure: J.G. Kallet: None. W. Hover: None. A. Krein: None. M. Lowe: None. M.F. Slovick: None. G. Kinney: None. S. Majka: None. K. Warren: None. S. Watts: None. M.T. McDermott: None. E.A. Regan: None. Multiple studies have shown reduced quality of life in people with adrenal insufficiency based on 1- 4 week recall of symptoms. However, “within-day” symptoms are commonly reported to treating physicians, and there is no clear understanding of what these symptoms represent for quality of life or adequate disease management. Lack of adequate cortisol has been postulated as a factor for both persistent symptoms and reduced quality of life but dose adjustment is not typically prescribed. Within-day symptoms are similar to those reported prior to treatment, and include lack of energy, nausea, vomiting, anorexia, headache, dizziness, shakiness, muscle cramps, and cognitive impairments. Addressing the relationship between “within-day” symptoms and replacement dosing could improve disease management. Further, understanding the association of within-day symptoms to outcomes (quality of life and adrenal crises) provides an impetus to change the standard of care. Individuals enrolled in the MyAI registry provided information about “within-day” symptoms. These included energy to accomplish tasks, cognitive symptoms, and overall symptoms. The questions were scored with increased values representing greater and more frequent symptoms and were summed to create a severity score. Patients also reported adrenal crisis within the past year and completed the AddiQoL as quality of life over the past 4 weeks.Responses were obtained from 712 adult registry participants - 84% female, age range 23-89, mean 51.2 (15.2) years - and 47% reported an adrenal crisis within the past year. Within-day symptom score range was 3-15 points with mean 7.9 and SD of 2.96. Higher “within-day” symptom scores were associated with stepwise reductions in the AddiQoL (worse quality of life). Individuals who reported an adrenal crisis within the past year had significantly increased symptom scores [8.8 (2.9) vs 6.7 (2.5), p<0.0001]. Regression model for the AddiQoL total score (R2 = 0.8) found after adjusting for group, age and sex, that BMI (p = 0.0002) and symptom score (p<0.0001) were highly significant predictors of worse AddiQoL score. ConclusionAdrenal crisis is reported frequently by patients who are being treated for adrenal insufficiency. We found a strong association of “within-day” symptoms to both risk of adrenal crisis and reduced quality of life. Addressing persistent disease-related symptoms in adrenal insufficiency would be an appropriate disease management response to improve care. The initial choice of replacement dosing based on body surface area or other metric may be a starting point for care but should be informed by studies that show large variation in absorption and metabolism between individuals. Adjusting doses of replacement hormones and careful management of adrenal insufficiency symptoms could improve outcomes. Presentation: 6/1/2024

7741 Artri King As A Cause Of Adrenal Insufficiency

Abstract Disclosure: Q. Aziz: None. S. Fatima: None. A.L. Champion: None. K.E. Izuora: None. IntroductionDietary supplements are highly unregulated and may have substance that can be harmful. Due to its easy availability, more patients may have access to these supplements which can cause detrimental health outcomes, such as adrenal insufficiency. Clinical Case Patient is a 46 year old female with past medical history of hypertension and obesity presents to the hospital for worsening left hip pain, which started 2 weeks ago. She heard a crack in her left hip and denied any trauma or injury prior. She was found to have subtrochanteric fracture. Nine months ago, she had right hip pain and was unable to bear weight. Physical exam was notable for alopecia in frontal and temporal region, dorsocervical fat pad, multiple bruises, round facies, and multiple purple straie. She also reported a 50 pound weight gain in the last year. She stated that she took an over the counter “pain medication”, but denied any supplements. Due to the non-traumatic fracture and physical features, AM cortisol was ordered for suspicion of Cushing’s Syndrome by primary team and was low at 2.4. Endocrinology team was consulted. Cosyntropin stimulation test showed baseline AM cortisol level 1.4 and 1 hour after cosyntropin, cortisol was 8.3. ACTH 3.4, testosterone undetectable, androstendione undetectable, Aldosterone 42.2, DHEA undetectable. It was found later that patient was taking an over the counter supplement called Artri King, up to 4 tablets a day. Artri King has been advertised as a supplement for joint and muscle pain and contains unknown amount of dexamethasone and diclofenac. She was soon placed on hydrocortisone for adrenal insufficiency and was titrated down. The hypothalamic-pituitary-adrenal (HPA) axis can be suppressed with as low as 5 mg prednisone equivalent a day. This can lead to inadequate adrenal response to stress. If a patient has prolonged exposure to exogenous steroids, insufficient ACTH secretion can lead to atrophy of the zona fasciculata and reticularis, resulting in reduced ability to secrete cortisol. Therefore, it is important to help withdraw patient from glucocorticoids. When initiating glucocorticoid withdrawal, hydrocortisone may be helpful due to short half life, allowing HPA axis more opportunity to recover. Adrenal atrophy may be slowly reversible, but 4 years after diagnosis of glucocorticoid induced adrenal insufficiency, recovery of adrenal function is unlikely to occur. ConclusionsIt is important to obtain a thorough history, especially for supplements. Many supplements are not regulated and can pose harm to our patients. Adrenal insufficiency due to glucocorticoids may not only occur from steroid injections, long course of prescription glucocorticoids, but can include supplements if it is hidden from the ingredient list. Presentation: 6/3/2024

7247 Adrenal Insufficiency In Advanced Cirrhosis: A ‘Shocky’ Clinical Dilemma

Abstract Disclosure: L. Aboishava: None. A. Pareek: None. A. Mertens: None. A. Erokhin: None. Background: In patients with advanced cirrhosis, profound hypoproteinemia can complicate the laboratory assessment of the hypothalamic-pituitary-adrenal axis, but a clinical phenotype of persistent hypotension and suboptimal cortisol response to ACTH stimulation raises the question of whether adrenal insufficiency could also be a contributing factor. Clinical Case: A 65-year-old man with a history of cirrhosis complicated by esophageal varices, ascites, encephalopathy and hepatorenal syndrome was admitted to the ICU with worsening fatigue, profound hypotension, and respiratory arrest. He was started on pressors, antibiotics and was also intubated for a short time. A broad workup was negative for cardiac or infectious causes of shock and showed decreased total protein and albumin (1.6 g/dl (3.5-5.2), with normal serum sodium and potassium. The patient had no previous history of adrenal disease or corticosteroid use. Workup for adrenal insufficiency was initiated and showed decreased morning blood serum cortisol (10.6 ug/dl (2.5-19.5)) and ACTH (<5.0 pg/ml (7.2-63)), as well as suboptimal cortisol response on ACTH stimulation testing (12.5 ug/dl initially, 16.7 ug/dl after stimulation). Head CT on admission was negative for intracranial pathology, and lab results showed normal TSH and mildly increased prolactin of 36.2 ng/ml (4.0-15.0). Pt was started on IV hydrocortisone 50 mg TID. Glucocorticoid therapy didn’t improve his state significantly but was continued with a gradual tapering down of the dose. After intense treatment in the ICU the patient’s state was stabilized. Unfortunately, an endoscopy performed for worsening anemia and blood in stools showed gastric cancer. The patient was transferred to comfort care after a discussion of goals of treatment and died within the next 24 hours. Conclusion: The nature of decreased cortisol levels in patients with cirrhosis is most likely multifactorial, due to impaired hepatic synthetic function, dysregulation of hormone-binding protein balance, abnormal ACTH secretion, and other factors. Impaired corticosteroid-binding globulin synthesis might affect the ratio of globulin-bound and free hormone fractions and alter the accuracy of cortisol assays. Whether adrenal insufficiency is truly one of the complications of advanced cirrhosis contributing to persistent hypotension, or a mere laboratory finding is difficult to answer. It is also yet to be determined whether patients with advanced cirrhosis might benefit from screening and treatment of adrenal insufficiency in circumstances of persistent hypotension, and studies are needed to decide on optimal diagnostic tests to recognize the disease and develop treatment algorithms. Presentation: 6/3/2024

7658 A Case of Recurrent Cardiac Tamponade as Initial Presentation of Primary Adrenal Insufficiency

Abstract Disclosure: A. Farooq: None. A. Ghumatkar: None. J. Snitzer: None. Introduction:Cardiac tamponade, a life-threatening emergency, can be associated with primary adrenal insufficiency (Addison Disease), and accurate diagnosis requires a high degree of clinical suspicion in patients with uncertain etiology and nonspecific signs and symptoms. Case Presentation:A 58-year-old female with a history of Hashimoto thyroiditis was evaluated in the hospital for two episodes of cardiac tamponade requiring emergent pericardiocentesis within one month. The patient had been experiencing symptoms of fatigue, nausea, lightheadedness, dizziness, hiccups, and tanned skin for the past year. She also had a recent flu-like illness with nausea and vomiting four months before her current presentation. Her vitals were notable for hypotension during these episodes. Her lab work showed hyponatremia (128 mEq/L, reference range: 136-145 mEq/L) with normal potassium and glucose levels. Her thyroid function tests were within normal limits on her home levothyroxine dosage (TSH 4.588 IU/ml, reference range: 0.5-8.9 IU/ml). An ACTH stimulation test was performed based on the patient's clinical presentation, consistent with adrenal insufficiency. Her baseline cortisol level was 5.9 mcg/dL (reference range: 6.7-22 mcg/dL), a post-ACTH stimulation level of 6.7 mcg/dL after 30 minutes, and 6.0 mcg/dL after 60 minutes. Her 21 alpha-hydroxylase antibody titer was also positive for Addison Disease (231U/mL, reference range <1 IU/mL). A CT scan of the abdomen with intravenous contrast was done, which revealed no abnormality of the adrenal glands. She was treated with stress doses of hydrocortisone during hospitalization and discharged with maintenance dosage and follow-up with endocrinology. She had another episode of acute adrenal crisis about a month later but had no pericardial effusion this time and responded well to the treatment with stress doses of steroids. She has remained healthy at 14 years of follow-up. Conclusion: This case emphasizes the need to consider adrenal insufficiency in the evaluation of cardiac tamponade or pericardial effusions, especially in patients with existing autoimmune glandular disorders. This patient may have autoimmune polyglandular syndrome type 2 (APS-2), which is a cluster of two or more endocrine glandular disorders primarily diagnosed in adulthood and predominant in females. The risk of adrenal crisis is more than twofold in Addison disease due to APS-2. Lastly, this case highlights that hiccups can be related to adrenal insufficiency, with pathophysiology possibly involving diaphragmatic irritation due to adrenal inflammation that resolves with treatment. Presentation: 6/3/2024

8191 Navigating The Maze Of Adrenal Insufficiency, A Complex Case Of Late Presentation

Abstract Disclosure: K.N. Pereira: None. V. Sundaram: None. V. Mehta: None. K. Desai: None. B. Agrawal: None. Adrenal insufficiency, a rare but potentially life-threatening endocrine disorder, arises from the inadequate production or ineffective response to adrenal hormones, particularly cortisol and aldosterone. It poses diagnostic challenges, especially in individuals with intricate medical histories and manifests as either primary (Addison's disease) or secondary. The subtlety of initial symptoms often leads to a delayed diagnosis, emphasizing the importance of a high index of suspicion among healthcare providers. Timely recognition and intervention are crucial to prevent adrenal crises, which includes severe hypotension, electrolyte imbalances and life-threatening complications. This case report delves into the presentation, diagnosis, and management of primary adrenal insufficiency in a 51-year-old female with a myriad of co-morbidities who presented with persistent low blood pressure, syncope episodes and dizziness both at rest and with exertion, despite being on midodrine with systolic blood pressure readings ranging from 60s to 80s mmHg. She was also noted to be bradycardic and laboratory results showed hyponatremia, hyperkalemia, hypoglycemia and anemia. She was given prompt fluid resuscitation, stress dose steroids and fludrocortisone, leading to a remarkable improvement in blood pressure and overall clinical status. Subsequent testing showed low serum cortisol level and elevated ACTH level, confirming the diagnosis of primary adrenal insufficiency. Continued steroids resulted in significant symptomatic improvement and with no further episodes of hypotension or syncope on ensuing follow ups. This case serves as a poignant illustration for the need for a heightened clinical suspicion, as the symptoms of adrenal insufficiency can often masquerade within the intricate tapestry of comorbidities. When the utilization of midodrine, aimed at managing orthostatic hypotension, did not abate symptoms, it prompted a thorough investigation into the possibility of underlying adrenal dysfunction. This case also highlights the collaborative, multidisciplinary approach in the management of adrenal insufficiency, with endocrinology playing a pivotal role. Presentation: 6/1/2024

9330 Atumelnant (crn04894) Induces Rapid And Sustained Reductions In Serum And Urine Cortisol In Patients With Acth-Dependent Cushing Syndrome During A Phase 1b/2a, Single Center, 10-day, Inpatient, Open-Label Study

Abstract Disclosure: H. Elenius: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. R. McGlotten: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. C. Moore: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. Y.B. Omotosho: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. L.K. Nieman: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc.. Atumelnant is a potent, once-daily oral, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R) antagonist that blocks ACTH-mediated G-protein activation and subsequent signaling. It is being developed for the treatment of ACTH-dependent Cushing Syndrome (ADCS) and classic congenital adrenal hyperplasia. We report preliminary data from the first-in-disease, dose-finding study of atumelnant in patients with ADCS (NCT05804669). Inpatient participants with active ADCS (24h urine free cortisol (UFC) >1.3xULN, ACTH >10 pg/mL) received atumelnant 80 mg once daily at 08.00 for 10 days (D1-10) followed by a 4-day washout. Endpoints included changes in UFC (upper limit of normal (ULN) 45 ug/d), early morning cortisol (EMC), and early morning ACTH (EMA, ULN 46 pg/mL). Daily questionnaires assessed adverse events (AEs) and signs and symptoms of adrenal insufficiency (AI) and ADCS. Data are shown as median (range). We report 5 participants (4 men; 4 Cushing disease, 1 ectopic ACTH; age 47 years (34-55)); each completed the study. All participants developed biochemical evidence of AI (EMC <5 mcg/dL) after 2 days (1-10) of atumelnant administration and then commenced physiologic hydrocortisone (HC) add-back. Compared to D1, biochemical disease control (normal UFC plus EMC <5 mcg/dL) was shown on D11 in all participants, while receiving HC replacement: UFC 252 mcg (99-293) vs 24 mcg (3.9-51); EMC 14 mcg/dL (10.7-18.1) vs 1.4 (1.0-4.7). This was associated with an increase in EMA: 52.1 pg/mL (33-1088) vs 78 pg/mL (48.8-4045). HC was discontinued when EMC was ≥7 mcg/dL, on D13 (D12-18). Many pre-existing features of ADCS improved during atumelnant administration, including poor concentration, insomnia (n=3 each); brain fog, anxiety, irritability (n=2 each); fatigue, poor memory, low libido, depression, edema and bloating (n=1 each). Low testosterone, neutrophilia (n=3 each) and leukocytosis (n=2) observed at baseline resolved during atumelnant administration. Anti-hypertensive therapy was paused or reduced in 3 subjects. New fatigue, headache, nausea, anorexia, edema (n=2 for each) all coincided with development of biochemical AI; most symptoms improved with HC add-back. Serious adverse events included AI and one non-treatment related transient GI bleed 19 days after the last dose. All other AEs were mild or moderate: transient increases of creatinine (n=2), and ALT (<3xULN, n=2). In conclusion, the first 5 patients with ADCS to receive once daily, oral atumelnant experienced rapid lowering of serum and urine cortisol and improvement or resolution of some signs and symptoms of ADCS. Atumelnant was generally well-tolerated. The observed compensatory increase in ACTH was not associated with loss of efficacy or clinical sequelae. This ongoing study will further explore the relationship between atumelnant dose, including lower doses, and therapeutic response. Presentation: 6/3/2024

12564 A Rare Case Of Pembrolizumab Induced Secondary Adrenal Insufficiency

Abstract Disclosure: L. Escano Volquez: None. P. Desai: None. Pembrolizumab is an immune check-point inhibitor that blocks the PD1 receptor and is currently used in the treatment of a vast variety of malignancies. Despite adrenal insufficiency (AI) already being documented as a rare but potential side effect, its diagnosis is usually delayed due to vague presentation, increasing the risk of deleterious outcomes. We present a case of secondary AI while on pembrolizumab in which diagnosis was delayed due to unspecific clinical picture.This is a 66-year-old male who presented to the hospital with decreased appetite, nausea and generalized weakness. Patient was seen a month prior with similar symptoms which were thought to be secondary to poor oral intake in the setting of underlying malignancy. Medical history remarkable for squamous cell carcinoma of the skin with recent lung metastasis for which he was started on pembrolizumab a year ago. On arrival to the emergency department, patient was hypertensive with BP 144/68 mmHg, HR 88, and RR 15. Orthostatic vitals were positive. Physical examination otherwise unremarkable. Laboratory tests revealed mild hypernatremia of 147, potassium of 4.7, chloride 108, HCO3 18, anion gap 21, BUN 33, elevated creatinine 1.62 and elevated beta-hydroxybutyrate 5.4. EKG revealed sinus rhythm. Patient was admitted for further evaluation of orthostasis and starvation ketosis. Initial management included IV fluids and Midodrine. However, patient continued to have episodes of orthostatic hypotension. Lack of improvement of symptoms led to further workup which revealed low AM cortisol of 1.0 and a low ACTH level <3.0 pg/ml, concerning for secondary adrenal insufficiency. Patient was administered Solu-Medrol 40 mg IV before being transitioned to a daily hydrocortisone regimen with subsequent improvement of symptoms. Pembrolizumab induced AI is a very rare event. It is estimated that the incidence approaches 1% and symptoms can develop at any time throughout treatment. Despite its low incidence, it can be life-threatening if not diagnosed and treated promptly. However, given its very heterogeneous and vague clinical presentation, a prompt diagnosis can be difficult. The clinical course of our patient and subsequent resolution of symptoms after appropriate treatment was started, supports the diagnosis of pembrolizumab induced adrenal insufficiency after a year of initiating treatment. This patient had prior hospitalizations and office visits with symptoms that are usually already present in individuals with underlying malignancy, which resulted in underestimation of his symptoms. This case highlights the importance of always considering AI as a potential adverse effect of immune check-point inhibitors. This will ensure a prompt diagnosis and treatment of an endocrine disorder that could otherwise lead to deleterious outcomes if left untreated. Presentation: 6/1/2024

12337 Nivolumab Induced Secondary Adrenal Insufficiency And Hypothyroidism In A Patient With Graves’ Disease: A Case Report

Abstract Disclosure: F. Sajid: None. J. Kaur: None. A. Zatsepina: None. M. Khan: None. C.A. Resta: None. Introduction: We present a case of a patient with Graves’ disease who developed concurrent secondary adrenal insufficiency (SAI) and primary hypothyroidism while undergoing treatment with nivolumab for non-small cell lung cancer (NSCLC). This case sheds light on the immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy. Case Presentation: A 63-year-old woman with a history of Graves’ disease and NSCLC undergoing neoadjuvant chemoimmunotherapy was admitted with hyponatremia. She was diagnosed with Graves’ disease a year before and was treated with methimazole (MMI). When she was diagnosed with Graves’ disease, her TSI was 1.64 IU/L (<0.55). Before starting nivolumab, TSH had normalized at 0.5 MCIU/mL on MMI therapy. She started nivolumab 3 months before admission. One month after starting nivolumab, her TSH was <0.01. By the time she was admitted, she had severe hypothyroidism and SAI with sodium 116 mmol/L (135-149), TSH 40.34 mIU/mL (0.39-4.08), free T4 <0.25 ng/dL (0.8-1.8), TSI 21.2 IU/L (0.00-0.55) Total Cortisol 0.4 ug/dL (6.7-27.6), AM Cortisol 0.6 ug/dL, ACTH <1.5 pg/mL (7.2-63.3), LH 75.5 IU/L (7.7-58.5), and FSH 179 IU/L (25.8-134.8). MMI was discontinued due to hypothyroidism. She was started on replacement therapy with levothyroxine and hydrocortisone. Subsequent sodium levels normalized. Discussion: Nivolumab has emerged as a promising immunotherapy for NSCLC. Our patient developed irAEs following nivolumab treatment. Notably, this case represents only the third documented case to our knowledge of both primary hypothyroidism and secondary adrenal insufficiency occurring post-nivolumab treatment. Workup for our patient revealed two irAE’s. She developed primary hypothyroidism and isolated ACTH deficiency with other pituitary function remaining normal. The pattern of thyroid profile over time was consistent with thyroiditis due to ICI therapy. TSI increased, ruling out remission from Graves’ disease. Even after discontinuing methimazole, she remained hypothyroid. Hence, in this case, ICI effectively acted as definitive therapy for her Graves’ disease. Conclusion: This case sheds light on the intricate interplay between nivolumab therapy, pre-existing autoimmune conditions such as Graves’ Disease, and the emergence of irAEs. This case underscores the importance of vigilant monitoring of serum sodium levels, and thyroid and pituitary function tests in patients undergoing immunotherapy. Presentation: 6/1/2024

6977 Unraveling Secondary Adrenal Insufficiency and an Invasive Pituitary Macroadenoma in a COVID-19 Positive Patient

Abstract 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

8045 A Case Report of Primary Adrenal Insufficiency Due to a Novel Pathogenic Variant in NR0B1 (Dax 1) Gene

Abstract Disclosure: M.N. Lemos: None. G.D. Martins: None. J.R. Cicogna: None. N.M. Scalissi: None. J.V. Lima-Jr: None. Background: X-linked adrenal hypoplasia congenita caused by a pathogenic variant in NR0B1/DAX-1 is a rare inherited disorder. Patients with adrenal hypoplasia congenita are usually diagnosed with primary adrenal insufficiency in infancy or early childhood and usually present hypogonadotropic hypogonadism during adolescence. Clinical Case: Our male patient first presented with adrenal crisis at the age of 11 years, managed with glucocorticoids (prednisolone) and mineralocorticoids (fludrocortisone) in a local hospital at Bahia state, Brazil. He was referred to our reference service in Sao Paulo at the age of 14, in regular use of those medications. In this time, he brought some laboratorial analysis from the time of diagnosis, and it showed hyponatremia (sodium 99 mEq/L; NR 135 - 150) and hyperkalemia (potassium 6,7 mEq/L; NR 3,5 - 5), ACTH 23,2 pg/mL (NR < 45) and basal cortisol 6,6 mcg/dL (NR 5 - 18). In addition, we had from this time some additional laboratorial data from our admissional analysis, that found S-DHEA 10,1 mcg/dL (NR: 23,8 - 267,7), total testosterone 472 ng/dL (NR: 240 - 816), FSH 3,05 mUI/L (NR: < 10), LH 2,63 mUI/L (NR: <10), aldosterone 1,9 ng/dL (NR: 5 - 23) and renin > 500µIU/mL (NR: 2,8 - 39,9). Over the years, he started to present hyperpigmented skin lesions, due to primary adrenal insufficiency, resulting in great psychological suffering. We have screened hypogonadism many times during follow-up, but it was never found. The Genetics analysis by next generation sequence (NGS) identified in homozygosity, in gene NR0B1 (DAX1) on X chromosome, a variant of normality (chrX:30.309.248 C>T) were amino acid tryptophan was replaced by a stop codon. The patient does not have any brother, no other similar cases in the family and their parents deny consanguinity. Our case differs from others previously described because of the absence of associated hypogonadism, which is very common in NR0B1 variants. Clinical lesson/Conclusion: This case report shows that the absence of hypogonadism does not exclude the possibility of primary adrenal insufficiency caused by NR0B1(DAX 1) gene variants, and encourages genetic testing to patients living with this disease. Presentation: 6/2/2024

7203 A case of undifferentiated shock found to be due to voriconazole-related primary adrenal insufficiency

Abstract Disclosure: K.X. Zhang: None. C. Bergwitz: None. Primary adrenal insufficiency can be a rare effect observed with azole antifungal therapy, classically ketoconazole, via inhibition of cortisol and aldosterone synthesis. Whether primary AI can be observed with newer triazole drugs used for neutropenic prophylaxis and treating invasive fungal infections is far less understood. We describe a case of a 65-year-old man with medical history notable for COPD and gout, who was on voriconazole for Aspergillus pneumonia, and admitted to the medical ICU with confusion and undifferentiated shock. His potassium was 6.5 mmol/L, sodium 133 mmol/L, bicarbonate 18 mmol/L, and blood pressure 72/63 requiring pressor support. Voriconazole was withdrawn. He also had a fever to 101.7F that was attributed to a gout flare, and he received a course of high dose prednisone. His shock and electrolyte abnormalities quickly resolved, and he was discharged on isavuconazole. At the 1 week mark, he was found to have a morning cortisol 2.3 ug/dL, potassium 5.4 mmol/L, and sodium 134 mmol/L, along with fatigue, nausea, and hypotension, which prompted resumption of steroid and mineralocorticoid replacement. One month after completing his course of isavuconazole, morning cortisol normalized to 11.0 ug/dL and ACTH 22.3 pg/mL. We present a convincing clinical story supporting the etiology of this patient’s initial shock as primary adrenal insufficiency related to a voriconazole effect. This case illustrates how iatrogenic AI can be a missed diagnosis in the emergency room setting. Primary AI has classically been reported following ketoconazole therapy, but there are only 4 reports of primary AI involving the newer triazole posaconazole, and none for voriconazole or isavuconazole. Due to the rarity of this effect, AI due to voriconazole was not on the initial shock differential and timely endocrine labs to seal the diagnosis (morning cortisol, ACTH, and renin/aldosterone levels) were not obtained. If our patient had not received steroids serendipitously for gout, he may have been at risk for adrenal crisis. Whereas central AI is more common and induced by chronic use of systemic steroids, it is important to also think about AI caused by antifungal therapy with newer azoles. Presentation: 6/3/2024

8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency

Abstract Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

6569 An Increase, Rather Than Absolute Amount, Of Corticotropin-Releasing Hormone (Crh) Drives Mouse Anxiety-Like Behavior

Abstract Disclosure: H.R. Friedman: None. L. Gaston: None. L. Chan: None. J.A. Majzoub: None. Approximately 300 million people have an anxiety disorder. We previously found that anxiety-like behavior (AB) is decreased in mice which lack hypothalamic (HT) Crh (1), so we hypothesized that increased HT Crh, due to primary adrenal insufficiency (PAI), would induce increased AB. To evaluate this, we compared AB in wildtype (WT) mice to those with global deletion of either the Crh gene (CrhKO) or the Mrap gene (MrapKO, causing PAI (2)), measuring: 1) HT Crh mRNA by in situ RNAscope, 2) stress-induced (after 15 min of restraint) plasma corticosterone (CORT) and adrenocorticotropin hormone (ACTH) by ELISA, and 3) AB with elevated plus maze (EPM), and open field (OF) automatically-recorded behaviors. Comparisons were evaluated by ANOVA with post hoc Bonferroni corrections vs. WT. As expected, Crh mRNA was highest in MrapKO (n=16) compared to WT (n=11), and undetectable in CrhKO (n=10), and post-restraint CORT was highest in WT (11±2 mcg/dL), and undetectable in CrhKO and MrapKO. CrhKO mice displayed decreased AB (increased EPM open arm duration) vs. WT animals (140±11 vs. 68±8 s, respectively, P<0.0001). However, AB was comparable between MrapKO (97±10 s) vs. WT (68±8 s; P=0.0807) despite higher HT Crh mRNA in the former. To determine if chronically high vs. a dynamic rise in Crh mRNA is associated with increased AB, we treated MrapKO mice with dexamethasone (DEX) for 5-8 weeks to suppress HT Crh mRNA and assayed hypothalamic-pituitary-adrenal axis function and behavior both on DEX (MrapKO-D; N=4) and 1-week post-withdrawal (MrapKO-DW; N=5). As expected, ACTH was highest in the MrapKO-DW vs. WT (1689±535 vs. 378±35 pg/mL, respectively; P<0.0001) and undetectable in MrapKO-D. Notably, MrapKO-DW mice displayed increased AB (decreased OF center duration) vs. WT animals (56±3 s vs. 114±10 s; P=0.0439). In summary, AB was not present in MrapKO mice with chronically elevated HT Crh mRNA but only developed after they were DEX-treated followed by withdrawal from treatment. These data suggest that in mice, a dynamic rise in HT Crh, but not a chronically elevated level, drives AB, and suggest that Crh is a possible target for anxiety treatment.

6369 Weiss-Kruszka Syndrome and Growth Hormone Deficiency, Adrenal Insufficiency, and Morbid Obesity

Abstract Disclosure: T. Falcon-Rodriguez: None. N. Solano: None. A. Diaz: None. Background: Weiss-Kruszka syndrome (WKSA) is a rare autosomal dominant genetic disorder caused by heterozygous loss-of-function variants in the ZNF462 gene. Individuals affected by this condition exhibit distinctive craniofacial features, ptosis, dysgenesis of the corpus callosum, hearing loss, intellectual disability, and hypotonia. There is one other case report that described a boy with empty sella syndrome with growth hormone deficiency and delayed puberty. Case Presentation: We present the case of a 15-year-old boy who initially came under the care of endocrinology at age 9 due to severe obesity and short stature. Past medical history included ADHD (for which he was on stimulants since age 5), microcephaly, VUR, asthma, and developmental delay. He grew along the 2nd percentile for height from the ages of 6 and 13, after which his growth velocity notably decelerated. His initial bone age at 9 years old was advanced by 3 years. His BMI had exceeded the 99th percentile since age 3. His family history was relevant for maternal type 1 diabetes mellitus, paternal height of 165 cm, and maternal height of 160 cm. Upon physical examination, notable findings included short stature, severe obesity, a low anterior hairline, arched eyebrows, upslanted palpebral fissures, low-set ears, a tubular and short nasal bridge, and an exaggerated cupid's bow. At age 9, the patient was diagnosed with growth hormone (GH) deficiency following a clonidine and glucagon stimulation test, with a GH peak of 1.9 ng/mL (normal >7 ng/mL). Additionally, he was diagnosed with adrenal insufficiency (cortisol peak of 5 ug/dL, after 250 mcg of cosyntropin). A brain/sella MRI revealed a hypoplastic pituitary gland. Subsequently, hydrocortisone replacement was initiated at a dose of 6 mg/m2/day, and GH treatment at a weekly dose of 0.3 mg/kg. Despite treatment with growth hormone and IGF-1 levels on the upper side of the normal range, his growth velocity did not improve significantly. He reached his peak adult height of 150 cm at age 15. His BMI had consistently been at the 99th percentile. According to his mother, he did not have issues with satiety, and his portion sizes were considered normal. He did not consume fast foods or sugary drinks, and his level of physical activity was suboptimal. Whole Exome Sequencing identified a heterozygous de novo pathogenic variant in the ZNF462 gene, specificallyc.2664 C>A, p.(C888*) (NM_021224.4), consistent with the diagnosis of Weiss-Kruszka syndrome (OMIM # 618619). Conclusion: We present, to our knowledge, the first report of morbid obesity and central adrenal insufficiency in a child with WSKA. GH deficiency had been previously reported in 1 patient with WSKA. The finding of a hypoplastic pituitary gland supports the diagnosis of GH deficiency and central adrenal insufficiency. Presentation: 6/3/2024