Normal Adrenal Function Research Articles

Molecular and Genetics Perspectives on Primary Adrenocortical Hyperfunction Disorders.

Adrenocortical disorders encompass a broad spectrum of conditions ranging from benign hyperplasia to malignant tumors, significantly disrupting hormone balance and causing a variety of clinical manifestations. By leveraging next-generation sequencing and in silico analyses, recent studies have uncovered the genetic and molecular pathways implicated in these transitions. In this review, we explored the molecular and genetic alterations in adrenocortical disorders, with a particular focus on the transitions from normal adrenal function to hyperfunction. The insights gained are intended to enhance diagnostic and therapeutic strategies, offering up-to-date knowledge for managing these complex conditions effectively.

Diagnostic and therapeutic approaches to a case of pregnancy complicated by bilateral adrenocortical adenomas with primary aldosteronism and Cushing's syndrome.

Aldosterone/cortisol co-secreting adenomas (A/CPA) are a rare type of primary aldosteronism(PA), and cases of aldosterone/cortisol co-secreting adenomas during pregnancy are extremely rare, with no reported cases to date. The unique physiological state of pregnancy increases cortisol secretion through the hypothalamic-pituitary-adrenal (HPA) axis and leads to elevated levels of all components of the renin-angiotensin-aldosterone system (RAAS). This can cause overlapping symptoms with abnormal cortisol and aldosterone secretion, making diagnosis very challenging. This case involves a 29-year-old woman who developed hypercortisolism at 33 weeks of pregnancy. Despite receiving treatment for her symptoms and having a successful delivery, she continued to experience hypertension and hypokalaemia after giving birth. Eventually, she was diagnosed with ACTH-independent Cushing's syndrome and primary aldosteronism due to independent cortisol and aldosterone secretion from bilateral adrenal adenomas. Following a thorough diagnosis, classification, treatment, and follow-up, the patient achieved a clinical cure while preserving normal adrenal function. Further investigation revealed that both diseases were caused by KCNJ5 and PRKACA mutations found in the bilateral adrenal adenomas.

6712 Intractable Hypoglycemia: A Clue to Tumor Diagnosis

Abstract Disclosure: N. Kharkongor Chengappa: None. E.I. Krug: None. Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) known as Doege-Potter syndrome, is a rare paraneoplastic syndrome of hypo-insulinemic hypoglycemia caused by excessive production of partially processed IGF-II from a solitary fibrous tumor (SFT).We present a case of a patient admitted with intractable hypoglycemia leading to the diagnosis and treatment of a large pelvic SFT. Clinical Case: A 59-year-old male with type 2 Diabetes Mellitus on metformin mono therapy, was admitted after he collapsed at work and was found to have blood glucose (BG) of 22 mg/dl. He was previously in his usual state of health except for an increase in his shoe size over the past year. Physical examination revealed coarse thick skin, large coarse bullous nose, enlarged fingers and a non-tender, firm abdomen with no obvious organomegaly. Laboratory results including CBC, CMP and thyroid function were normal. ACTH stimulation test revealed normal adrenal function. Hypoglycemic drug screen and insulin antibodies were negative. During a hypoglycemic event (BG of 45mg/dl) he had C-peptide level < 0.1ng/ml, beta-hydroxybutyrate levels of <0.05 and insulin level <0.4uIU/ml, indicating non-insulin mediated hypoglycemia. IGF-I and IGF-II levels were ordered. Due to a concern for paraneoplastic etiology of hypoglycemia. CT scan revealed a 20 cm solid mass, filling most of the pelvis and extending into the lower abdomen. Further investigations revealed normal PSA, CEA, CA19-9 and undetectable hCG and AFP levels. MRI confirmed a presence of 23 cm pelvic mass with few areas of central necrosis, extending into the lower abdomen. CT-guided biopsy revealed spindle cell neoplasm consistent with SFT. The patient underwent pelvic mass resection. Postoperatively, hypoglycemia resolved with BG readings of 138mg/dl to 178mg/dl. Surgical pathology results confirmed malignant SFT with positive STAT 6 and CD34 markers. IGF-II level obtained prior to surgery was markedly elevated at 2029 ng/ml (38-267 ng/mL). Conclusion: NICTH was described in 1930 by KW Doege and RP Potter. Less than 5% of patients with SFTs develop NICTH. Diagnosis requires manifestation of Whipple's triad, low insulin, pro-insulin and C-peptide levels, elevated IGF-II levels, or an IGF-I/IGF-II ratio>2, and the identification of the tumor. Positive immunohistochemical stain of the tumor for STAT6 confirms the diagnosis. Management involves resection of the tumor when feasible or debulking. For higher-risk tumors, radiation therapy may be considered. In inoperable cases, glucocorticoids, recombinant hGH and glucagon are recommended for palliation of hypoglycemia. Octreotide and Diazoxide are ineffective in NICTH.

6625 Adrenocortical Oncocytoma: Illuminating The Clinical And Biological Behavior Of An Extremely Rare Tumor Of The Adrenal Gland

Abstract Disclosure: H. Usmani: None. M. Arguello, MD: None. Background: Only 120 cases of adrenocortical oncocytoma have been reported in English literature (1). Standardized diagnostic criteria, or a typical clinical or biological course, have yet to be established. 58 yo woman with PMH HTN, COPD, CREST syndrome on chronic prednisone, previous 38-pk yr smoker, pulmonary nodule, current vaper, was incidentally found to have a left adrenal mass when she went for CT abd pelvis with IV and oral contrast to evaluate for suspected diverticulosis and anemia. CT showed a mass in the left adrenal gland measuring 5.6 x 4.4 cm in size, heterogeneous in density, with possible areas of necrosis. It is unclear how long the adrenal mass was there since the patient never had a CT scan before. Patient was asymptomatic except 50 lb wt loss in the last couple of years with a feeble appetite, self-reported abnormal hair growth (no hirsutism on exam), voice deepening attributed to smoking, and HTN- well controlled with nifedipine. Patient has no FHx of endocrinopathy. Adrenal function tests wnl except for plasma free normetanephrines slightly high at 1.64 nmol/L, which was unlikely from tumor considering tumor size. Normal adrenal function tests included 11-deoxycortisol, DHEA-S, plasma-free metanephrine, aldosterone, renin, aldosterone: renin ratio, androstenedione, ACTH, 1 mg overnight dexamethasone suppression test.She underwent left-sided lap adrenalectomy 4 mos after discovery of adrenal mass, with no complications. 6 days after surgery, a left in JP drain caught on a door at patient’s home, causing splenic subcapsular tear requiring emergent splenectomy. The path report shows an encapsulated neoplasm consisting of sheet-like proliferation of eosinophilia polygonal cells with nuclear atypia, low mitotic activity, and no capsular or vascular invasion. Immunohistochemical markers show neoplastic cells positive for SF1, Mart1, inhibin (focal), and synaptophysin (focal); negative for CK-OSCAR, CK7, CK20, chromogranin, HMB45, and TTF-1, Ki67 and pHH3 show low proliferative index. The pathology slides were sent to U of M, where the diagnosis of adrenal cortical oncocytoma was made. Removal of oncocytoma has not affected patient’s weight, blood pressure, deep voice, or hair growth on 4 month follow up. Lin-Wiess-bisceglia system (2) suggests a benign lesion. But, as mutation rate for this rare tumor is unclear, plan for CT abd pelvis in 1 yr. Conclusion: This case elucidates the clinical and biological course and pathologic diagnosis of an exceedingly rare adrenal tumor.

A retrospective review of the short Synacthen test in Queensland hospitals.

The short Synacthen test (SST) is widely used to investigate adrenal insufficiency, but it can be time-consuming, costly and labour-intensive to perform and is not without risk of adverse events. To review SST requesting patterns and practices across public hospitals in Queensland. The electronic medical records of patients who underwent a SST with Pathology Queensland between January 2020 and December 2020 were reviewed to collect data regarding the indication for the test, the requesting speciality, SST results and any adverse events. Six hundred and fifty-two SSTs were identified, of which 363 individual patients were included in the analysis. The majority of the tests (n = 198, 54.5%) were performed in the inpatient setting. Endocrinology most commonly ordered SSTs (n = 188, 51.8%). The suspected aetiology of adrenal insufficiency was unclear in a large proportion of requests (n = 167, 46.0%). Static testing of morning cortisol prior to SST was performed in only 249 (68.6%) patients. Of 140 inpatients data, 17.9% (n = 25) showed a robust static cortisol of ≥400 nmol/L and were treated as having normal adrenal function, suggesting SST was unnecessary in these patients. Twenty-two (6.1%) patients had a documented adverse event occurring during or after the SST. There was wide variability in requesting patterns and practices for SSTs across Queensland. More than one in six SSTs could have been avoided if a static morning cortisol had been performed prior. Clinician education and the adoption of a structured referral form may improve testing practices.

Predicting postoperative hypocortisolism in patients with non-aldosterone-producing adrenocortical adenoma: a retrospective single-centre study

BackgroundLimited information exists on postoperative hypocortisolism and hypothalamus–pituitary–adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy.MethodsA retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1 mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6 days, 6 weeks, 6 months, and a year after surgery.ResultsSix days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1 mg dexamethasone suppression test (median 1 mg dexamethasone suppression test 76.2 [61.8–111.0] nmol/L vs 260.0 [113.0–288.5] nmol/L, p < 0.001). Univariate analysis showed preoperative 1 mg dexamethasone suppression test negatively related with baseline ACTH levels (r = − 0.376; p = 0.041) and negatively associated with the 6-week baseline (r = − 0.395, p = 0.034) and 30-min cortisol levels during Short Synacthen test (r = − 0.534, p = 0.023). Logistic regression analysis demonstrated preoperative 1 mg dexamethasone suppression test as the only biochemical predictor for 6-week adrenal recovery: ROC curve identified a 1 mg dexamethasone suppression test threshold of 131 nmol/L predicting 6-week recovery with 89.5% sensitivity and 72.7% specificity (AUC 0.87; 95% CI 66.9–98.7, p < 0.001). Other preoperative assessments (tumor size, ACTH levels and anthropometrics) were not associated with postoperative hypothalamus–pituitary–adrenal axis function, but the presence of diabetes was associated with a lower probability of recovery (OR = 24.55, p = 0.036). ACTH levels increased postoperatively in all patients but did not predict hypothalamus–pituitary–adrenal axis recovery.ConclusionsThe preoperative 1 mg dexamethasone suppression test cortisol value and presence of diabetes are the only relevant predictor of hypothalamus–pituitary–adrenal axis recovery in patients with non-aldosterone- producing adrenocortical adenoma undergoing surgery, regardless other clinical and biochemical variables. Notably, pre- and postoperative ACTH levels did not predict hypothalamus–pituitary–adrenal axis recovery. These findings point towards the potential for saving resources by optimizing their allocation during follow-up assessments for patients with non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy.

Ectopic adrenal tissue in a cat that underwent an ovariohysterectomy.

To describe the use of ultrasound and adrenal function testing to confirm that excised periovarian tissue is normal ectopic adrenal tissue (EAT). A 6-month-old female domestic shorthair cat. The cat underwent an ovariohysterectomy procedure, during which abnormal tissue was discovered adjacent to both ovaries. The tissue was removed during the ovariohysterectomy and submitted for histopathology, which was consistent with adrenal gland tissue, initially raising concern for an inadvertent adrenalectomy. Abdominal ultrasound and an adrenal function test were performed that confirmed normal adrenal structure and function; thus, the removed structure was diagnosed as EAT. The patient continued to recover from the procedure uneventfully at home. Parovarian nodules are an uncommon finding but when observed and biopsied, may be mistaken for physiologic adrenal tissue on the basis of histopathologic features alone without awareness of their existence and clinical context. The use of abdominal ultrasound and ACTH stimulation test offers an affirmative method of differentiating adrenal gland tissue from EAT.

Gamma knife radiosurgery is effective in patients with thyrotropin-secreting pituitary adenomas.

Thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) is a rare cause of TSH-dependent hyperthyroidism. The first therapeutic option is surgery. Medical treatment with somatostatin analogs is also effective. To obviate the need for lifelong drug therapy, gamma knife radiosurgery (GKRS) might be considered in selected patients. We report the largest series of patients with TSHoma treated by GKRS at a single center. This study was a retrospective analysis of 18 consecutive patients with TSHoma treated by GKRS between 1994 and 2022. Normalization of hyperthyroidism, when present at the time of surgery, and control of tumor growth were the main outcomes of the study. The median follow-up after GKRS treatment was 114months (IQR, 57-213months; range 17-285months). No patients had growth of the residual tumor after GKRS. Remission of hyperthyroidism occurred in 9 of the 11 (81.8%) patients who were hyperthyroid before GKRS. The probability of hyperthyroidism remission three years after GKRS was 59.1% (95% CI 27.9-90.3%). No major side effects occurred after GKRS. One patient out of the 15 patients (6.7%) with normal baseline adrenal function and follow-up longer than 3years developed new onset hypoadrenalism, while hypogonadism did not occur in the 13 patients with baseline normal function. Our study shows that GKRS is an effective and safe adjuvant treatment for selected patients with residual or recurring TSHoma. The option of GKRS as an alternative treatment to lifelong medical treatment with somatostatin analogs should be thoroughly discussed with the patients.

P-25 Unusual cause for spontaneous hypoglycemia: Hirata's Disease in Iraqi patient

Abstract Introduction Hirata's Disease, is a rare condition characterized by episodes of spontaneous hypoglycemia associated with hyperinsulinemia with positive insulin autoantibodies. Hypoglycemia is common in patients with diabetes mellitus especially those who are taking insulin therapy or insulin secretogogues oral medications but spontaneous hypoglycemia is rare and there is no clear figures about those patients in Iraq. We receive a lot of persons claim to have hypoglycemia but most of them fail to fulfill the Whipple triad. Although endogenous hyperinsulinemic hypoglycemia especially insulinoma is very rare condition, it is still concern for endocrinologist in patients presented with presumed hypoglycemia. Clinical Case A 43 year old female presented with frequent fainting attacks over several weeks. She has no past medical history a part of localized areas of vertigo for which she received no systematic treatment. Initial medical evaluation was unremarkable but with documented hypoglycemia below 40 mg/dl. She has normal heart, brain, kidney, liver, thyroid and adrenal function. She has multiple emergency admissions treatment with glucose infusion. She gains more weight as she eats more to avoid hypoglycemia. Her specific lab during the attack shows high serum insulin level (141.10 mIU/ml) with high C-peptide 18.55 ng/ml Work up for insulinoma shows normal MRI abdomen, normal endoscopic ultrasound and negative PET Gallium 68 scan. There are no previous reports of Insulin autoimmune syndrome in Iraq. The insulin autoantibodies in this patient were very high (more than 300.00 U/ml) which highly suggestive of this syndrome after excluding other factors that may cause elevation of these autoantibodies. Patient condition persist for about eight months and was advised for small multiple meals and diazoxide was not used much because it is not available in Iraq widely. Her condition resolved spontaneously after one year with dietary modifications. Conclusion Hirata syndrome is very rare but important cause of spontaneous hypoglycemia that should not be ignored. Up to our knowledge this is the first documented case in Iraq.

Prevalence of Adrenal Insufficiency in Korean Patients undergoing Total Knee Arthroplasty.

This study investigated the prevalence of adrenal insufficiency among patients admitted for total knee arthroplasty (TKA) due to osteoarthritis and identified factors contributing to adrenal insufficiency. We divided the patients into two groups based on the results of preoperative standard-dose short synchronous stimulation tests: group 1 (adrenal insufficiency) and group 2 (normal adrenal function). We also assessed the prevalence of adrenal insufficiency and compared the numbers of patients who received oral steroids, the frequency of previous steroid injection use, and the frequency of systemic symptoms of steroid depletion such as fatigue and loss of appetite between the two groups. Multiple regression analysis was performed to identify factors related to adrenal insufficiency. The prevalence of adrenal insufficiency was 60.0% (120/200). Group 1 had higher numbers of previous steroid injections (12.8±10.2 vs. 6.8±7.9) and patients taking oral steroids (18/120 vs. 3/80) (p&lt;0.001 and p=0.011, respectively). The frequency of systemic symptoms of steroid depletion, such as fatigue and loss of appetite, was also higher in group 1 (94/120 vs. 42/80, p&lt;0.001). Recent steroid injections and loss of appetite were associated with adrenal insufficiency (p=0.002 and p=0.009, respectively). The results of this study revealed a high prevalence of adrenal insufficiency in Korean patients hospitalized for TKA due to end-stage osteoarthritis. Recent steroid injections were causally related to the development of adrenal insufficiency. Therefore, adrenal function should be assessed preoperatively to prevent postoperative complications related to adrenal insufficiency.

Glucocorticoid Withdrawal Symptoms and Quality of Life in Patients with Systemic Lupus Erythematosus.

SLE patients whose prednisolone had been previously withdrawn or taken <5 mg/day were enrolled. Serum morning cortisol levels were collected after 72-hour GCS discontinuation, and low-dose ACTH stimulation test (LDST) was performed. Patient report outcomes (PROs) included SLE-specific quality of life questionnaire (SLEQoL), functional assessment of chronic illness therapy (FACIT), patient health questionnaire (PHQ-9), and Pittsburgh's sleep quality index (PSQI). Serum morning cortisol of 100 SLE patients was tested. Most patients were female (88%). Seventy-four patients showed remission. The mean ± SD of prednisolone was 0.73 ± 1.08 mg/day. Total SLEQoL and FACIT (mean ± SD) of all patients were 67.05 ± 26.15 and 13.7 ± 8.87, respectively. Eighteen percent of patients had moderate-severe depressive symptoms, and 49% were poor sleepers. Adrenal function was determined by LDST in only 39 patients; 5 patients (12.8%) were adrenal insufficiency (AI), and 34 patients were normal adrenal function. Compared to normal adrenal function patients, SLE patients with AI had higher proportion of moderate-severe depressive symptom (PHQ - 9 > 9), but not statistically significant (40% vs. 20.6%, p = 0.34). PROs were comparable between groups. Independent factors associated with SLEQoL were FACIT (adjusted β 1.31, 95% CI 0.76, 1.86, p < 0.001), PHQ-9 (adjusted β 5.21, 95% CI 4.32, 6.09, p < 0.001), and PSQI (adjusted β 4.23, 95% CI 3.01, 5.45, p < 0.001), but not with AI (adjusted β -5.2, 95% CI -33.26, 22.93, 0.71, p = 0.71). SLE patients with previous GCS exposure could experience AI and withdrawal symptoms such as sleep disturbance and depression during discontinuation of low-dose GCS. Fatigue, depression, and poor sleeper were significantly associated with poor SLEQoL.

FRI188 Exploratory Genomic Analysis From A Brazilian PMAH-Family With ARMC5 Alteration With Insidious Pattern Progression Of The Disease

Abstract Disclosure: H.L. Charchar: None. A.W. Kuhn: None. B.M. Mariani: None. M.Y. Nishi: None. F.L. Ledesma: None. M.C. Zerbini: None. F.Y. Tanno: None. V. Srougi: None. J.L. Chambo: None. M.Q. Almeida: None. B.B. Mendonca: None. M.C. Fragoso: None. Background: The clinical evolution of primary macronodular adrenal hyperplasia (PMAH) is usually slow over many years and is related to the insidious progression of hypercortisolism. The disease presents an autosomal dominant inheritance pattern with incomplete penetrance. Germline heterozygous mutations in the ARMC5 are present in 10% to 55% of the patients. The long-term follow-up of patients harboring germline ARMC5 pathogenic variants with normal evaluation will provide us with important insights regarding the outcomes. Clinical case: A 53-year-old man (index-case) was referred by the cardiologist to our service in October 2012, due to resistant hypertension (HTA), type 2 diabetes mellitus, dyslipidemia, and BMI of 32.4 kg/m2. Hormonal data: low ACTH (&amp;lt;5 pg/mL) and no suppression of cortisol after the overnight DST-1mg (22.7 µg/dL); late-night salivary cortisol, urinary free cortisol, aldosterone/renin ratio and plasma metanephrines were in the normal range. A CT scan showed bilateral enlargement of the adrenals associated with multiple macronodules. He underwent an adrenal-sparing surgery (total adrenalectomy of the left adrenal and partial adrenalectomy of the right adrenal). The macroscopic and histological appearance was consistent with PMAH. Leucocyte DNA genotyping identified the germline heterozygous ARMC5 pathogenic variant in exon 1 c.280del, p.(Ser94Argfs*43). This variant was identified in 3 of the 10 relatives investigated (son#1, daughter#2 and grandson#3). In 2021, the 37-year-old son#1 presented with a BMI of 32.6 kg/m2. Autonomous cortisol secretion was confirmed (cortisol after DST-1mg = 6.7 µg/dL). CT scan showed bilateral enlargement of the adrenals, similar to his father (index-case), with a larger left adrenal. Unilateral left adrenalectomy was performed, and PMAH was histologically confirmed. In 2018, the 21-year-old daugher#2 had normal adrenal function. More recently, in December 2022, she presented with an important weight gain (44kg in 4 years), without any specific signs and symptoms of hypercortisolism. Hormonal investigation showed a possible autonomous cortisol secretion (cortisol after DST-1mg = 2.2 µg/dL); the CT scan demonstrated an adrenal diffusely thickened with several nodules, especially on the left side, as the other relatives. Up to now, she has been using ketoconazole. All of them did not present meningioma of CNS. The grandson#3 with 11-year-old, is asymptomatic so far. Clinical Lesson: PMAH is a heterogenous and underdiagnosed disorder and is more genetically associated than previously thought. Therefore, a careful hormonal-genetic-clinical-radiological study of the relatives of index cases permits the diagnosis of many unsuspected familial-cases, including asymptomatic patients. Surgical or medical treatment should be considered for these patients to avoid progression to a possible overt Cushing syndrome. Presentation: Friday, June 16, 2023

FRI697 Severe Hypocalcemia Due To Idiopathic Hypoparathyroidism In An Elderly Female

Abstract Disclosure: K.A. Chopra: None. Most cases of acquired hypoparathyroidism in adulthood occur after neck surgery or radiation. However, idiopathic cases, although rare, do occur in elderly patients and should be a diagnosis of exclusion after thorough investigation. 76-year-old female with a history of chronic kidney disease, anemia of chronic disease, and hypertension presented with fatigue. Labs showed calcium (Ca) 5.7(RR 8.4-10.2 mg/dL), albumin 3.5(RR 3.5-5 g/dL), magnesium 2(RR 1.6-2.5 mg/dL), phosphorus 7.8(RR 2.5-4.4 mg/dL), parathyroid hormone 9(RR 15-75 pg/mL), 25-hydroxyvitamin D 32(RR 12-99 ng/mL). Patient denied history of neck surgery or radiation. Patient denied nephrolithiasis, perioral numbness, paresthesias, family history of hypoparathyroidism. Physical exam notable for positive Chvostek sign. Neck ultrasound unremarkable, no evidence of infiltrative disease. Urine Ca was low at 6 mg/24 hour(RR 100-300 mg/24hr). ACE level 10 nmol/ml/min(RR&amp;lt;40 nmol/ml/min) and 1,25 dihydroxyvitamin D level 12(RR 18-78 pg/mL) making sarcoidosis or granulomatous disease unlikely. HIV screen negative and interferon gamma response to mycobacterium tuberculosis antigens was not detected. Ferritin elevated at 300(RR 12-150 ng/mL) but transferrin saturation was 15%(RR 15-55%), not consistent with hemochromatosis. Antiparathyroid antibodies were negative. Patient denied mucocutaneous candidiasis, however testing for underlying autoimmune polyglandular syndrome type 1 (APS type 1) and adrenal insufficiency was completed with cosyntropin stimulation test. Patient had normal response to cosyntropin with baseline cortisol 20.1 (RR 6-18.4 ug/dL) and ACTH 37.7(RR&amp;lt;52 pg/mL), 30 minute cortisol 27(RR 6-18.4 ug/dL) and 60 minute cortisol 37(RR 6-18.4 ug/dL). Patient was treated with Ca gluconate infusion (100 ml of 10% Ca gluconate in 1000 mL of normal saline) at 30 ml/hr and Ca level gradually improved. Once Ca level was greater than 8.0(RR 8.4-10.2 mg/dL), Ca drip was discontinued. Due to patient’s lack of prior neck surgery history, lack of evidence of infiltrative conditions, negative antiparathyroid antibodies, normal adrenal function (unlikely APS type 1), lack of family history, and low urine Ca (unlikely activating mutation of Ca sensing receptor), patient’s hypoparathyroidism was considered idiopathic. Patient was discharged on oral Ca carbonate, Ca acetate, and calcitriol tablets. On follow up, patient had Ca 8.5(RR 8.4-10.2 mg/dL) with symptom improvement. Although hypocalcemia is commonly encountered, it is rare to see severe hypocalcemia in an elderly patient due to hypoparathyroidism without a history of neck surgery or radiation. Therefore, it is vitally important to conduct a thorough investigation to rule out underlying causes before diagnosing idiopathic hypoparathyroidism as highlighted in our case to guide future treatment and optimize patient health. Presentation: Friday, June 16, 2023

FRI562 Not JUST Severe Hypothyroidism: Recognizing Autoimmune Polyglandular Syndrome

Abstract Disclosure: S.R. Jafarian-Kerman: None. A. Razzeto: None. G. Saini: None. M. Siddiqui: None. M. Islam: None. D. Behman: None. M. Carson: None. Background: Recognizing Autoimmune Polyglandular Syndrome (AIPS) in a patient who has chronic hypothyroidism, specifically with a non-classic presentation, is challenging. Clinical Case: A woman in her 50’s with hypothyroidism presented with one week of progressive dizziness and weakness. Medications include levothyroxine 125 μg weekly (per the patient, her PCP started this dose 8 months ago based on lab results). On physical examination: BP 101/74 mmHg; HR 56 bpm; T: 98.1 F (36.7 C); RR: 23/min; O2 Sat: 98%. Skin: vitiligo. Lab results demonstrated TSH: 839.6 μIU/mL (0.5-4.5) from 0.28 one year ago, free T4: 0.15 ng/dL (0.4-4.5), phosphorus: 2.3 mg/dL (2.7-4.5), vitamin D: 17.4 ng/dL (&amp;gt;30). She was started on daily levothyroxine 125 μg and intravenous fluids. On day 3 of admission, Rapid Response was called for blood pressure 54/39 mmHg. Myxedema coma was unlikely as she lacked altered mental status, hypothermia, hypoventilation, hyponatremia, or hypoglycemia; CT head was normal. On the same day, hydrocortisone 100 mcg q8h started due to high suspicion of adrenal insufficiency given low normal cortisol [7.1 ug/dL (6-20)] and hypotension. Due to the history of hypothyroidism, vitiligo, and the new diagnosis of adrenal insufficiency, we suspected AIPS. two days later, primary adrenal insufficiency was established by a positive Cosyntropin stimulation test (1 hour cortisol of 14.8 ug/dL; not reaching &amp;gt;18 μg/dL), elevated ACTH 72 pg/mL (6-50), Aldosterone &amp;lt;1 ng/dL (3-16), and low DHEA of 52 ng/dL (345-2030). Other labs were as follow: normal FSH 85.7 mIU/mL (23-116), elevated PTH 153 pg/mL (16-77) which decreased to 62 pg/mL with vitamin D supplementation, normal Vitamin B12, and negative renin and intrinsic factor antibodies. A diagnosis of AIPS was established and she was discharged on levothyroxine, fludrocortisone, and hydrocortisone. Conclusion: AIPS is typically idiopathic and may affect endocrine organ systems either simultaneously or sequentially. The 3 classic patterns are: Type 1 (most common): younger women, presents with candidiasis, hypoparathyroidism, and Addison’s disease. Type 2: middle-aged women, Addison’s disease, autoimmune thyroid disease and/or Type 1 diabetes. Type 3: Type 1 diabetes, pernicious anemia, vitiligo or alopecia, and normal adrenal cortical function. This patient is unique in that she has characteristics of both type 1 and 3 AIPS, but not diabetes. In this case, the combination of hypotension even in the setting of profoundly undertreated hypothyroidism, prompted the expanded evaluation. While isolated hypothyroidism is common among our internal medicine patients, those with additional symptoms, or in this case unexplained hypotension, should be evaluated for AIPS. Presentation: Friday, June 16, 2023

The importance of under-treating adrenal failure in order to allow normal adrenal function following unilateral adrenalectomy for Cushing's syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Cerebral salt wasting syndrome: A case report

Introduction: The development of extracellular volume reduction due to decreased renal sodium transport in individuals with the intracranial illness and normal adrenal and thyroid function is known as a cerebral salt wasting syndrome (CSWS). Complications of cerebral salt-wasting syndrome include symptomatic hyponatremia and dehydration. We reported and discussed the diagnostic approach and the management of a 66-year-old woman who experienced severe hyponatremia with a history of head trauma and was treated at Udayana University Hospital. Case Description: A 66-year-old female patient complained of decreased consciousness. According to family information, the patient complained of having decreased consciousness one hour before admission and was accompanied by vomiting one time. Two weeks before admission, the patient had fallen, and the back of the patient's head had hit the table. The patient also had time to experience stiffness in the right and left hands and stomping. Urine collected 24 hours as much as 3880 ml on the first day of treatment. Conclusion: In cerebral salt wasting syndrome (CSWS) the management mainly focuses on the correction of intravascular volume depletion using 0.9% sodium chloride and hyponatremia, as well as on the replacement of ongoing urinary sodium loss, usually with iv hypertonic saline solutions, Fludrocortisone/mineralocorticoid that directly acts on the renal tubules to increase sodium reabsorption showed a favorable response in CSWS.

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father.

Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G>C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family. The importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance. In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation. With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.

A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD.

Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction-Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.

A Boy with Reset Osmostat Who Developed Chronic Hyponatremia due to Hypothalamic Injury Caused by a Giant Arachnoid Cyst.

Reset osmostat (RO) is classified as type C among the four subtypes of the syndrome of inappropriate secretion of antidiuretic hormone based on antidiuretic hormone (ADH) secretion. It is characterized by a lower plasma osmolality threshold for ADH excretion when plasma sodium concentration is reduced. We report the case of a boy with RO and a giant arachnoid cyst (AC). The patient had been suspected of having AC since the fetal period, and a giant AC in the prepontine cistern was confirmed by brain magnetic resonance imaging 7 days after birth. During the neonatal period, there were no abnormalities in the general condition or blood tests, and he was discharged from the NICU at the 27 after birth. He was born with a -2 standard deviation short stature and mild mental retardation. When he was 6 years old, he was diagnosed with infectious impetigo and had hyponatremia of 121 mmol/L. Investigations revealed normal adrenal and thyroid functions, plasma hyposmolality, high urinary sodium, and high urinary osmolality. The 5% hypertonic saline and water load tests confirmed that ADH was secreted under low sodium and osmolality conditions, and the ability to concentrate urine and excrete a standard water load; therefore, RO was diagnosed. In addition, an anterior pituitary hormone secretion stimulation test was performed, which confirmed growth hormone secretion deficiency and gonadotropin hyperreactivity. Hyponatremia was untreated, but fluid restriction and salt loading were started at age 12 because of the risk of growth obstacles. The diagnosis of RO is important from the viewpoint of clinical hyponatremia treatment options.

PMON312 A De Novo Heterozygous Nonsense Variant In The SEC31A Gene Associated With Pituitary Hormone Deficiency And Disorders Of Sex Development.

Abstract Introduction XYdisorders of sex development (DSD) result from variants in many different human genes but frequently have no detectable molecular cause. In approximately 25% of cases of XY DSD, the index case may have associated malformations. Genetic disorders of endoplasmic reticulum (ER) function are increasingly being recognised but have not been associated with DSD or pituitary disorders. Clinical case Three siblings (with unaffected non-consanguineous parents) were reviewed at the tertiary endocrine clinic. Child I was noted at birth to have cliteromegaly. Imaging and examination under anaesthetic revealed a normal vagina and uterus but gonads of indeterminate origin. She was 46,XY and basal endocrine investigations at the age of 4 years showed a low AMH for male but otherwise normal gonadal and thyroid function and normal IGF-1. She had a laparoscopic bilateral gonadectomy aged 5 years. Pathology demonstrated bilateral testicular tissue, with substantial fibrotic atrophic change and occasional placental alkaline phosphatase (PLAP) positive cells, suggestive of germ cell tumours. Aged 8 years she developed obesity and later hypertension. Child II was reviewed due to short stature and diagnosed with GH deficiency aged 2 years. She has normal adrenal and thyroid function and gonadotrophins. MRI demonstrated an ectopic posterior pituitary. Child III presented with perineal hypospadias, a small phallus, bilateral undescended testes and craniofacial abnormalities. Endocrine investigations revealed hypogonadotrophic hypogonadism, with no testosterone response to hCG stimulation, a low normal AMH and no response of LH or FSH on LHRH stimulation. He has panhypopituitarism with an ectopic posterior pituitary gland on MRI and is currently on treatment with GH, hydrocortisone and levothyroxine. His BP is on the 98th centile for age and height. Child I and Child III have mild developmental delay but are in mainstream school with additional educational support. High-throughput DNA sequencing revealed, in all three siblings, a heterozygous truncating variant in the SEC31A gene that encodes a component of the COPII-complex that coats the vesicles mediating ER to Golgi transport. CRISPR-Cas9 targeted knockout of the corresponding Sec31a region resulted in embryonic lethality in homozygous mice. mRNA phenotyping of ER-related genes demonstrated increased mRNA expression of ATF4 and CHOP in the affected children, genes encoding key ER stress-related proteins, associated with defective protein transport. Conclusions Dysregulation ofanterograde and retrograde COPII-coated-vesicle ER-Golgi transport is increasingly recognised to underlie human developmental disorders, including Craniolenticulosutural dysplasia (OMIM 607812) and Saul-Wilson syndrome (OMIM 618150). The de novo SEC31A nonsense variant in all three affected siblings, the ER stress response, plus reported developmental syndromes with dysfunction of this transport mechanism and evidence from the preclinical mouse model suggest that SEC31A might underlie a previously unrecognised clinical syndrome comprising DSD, endocrine abnormalities, dysmorphic features and developmental delay. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.