Cause Of Primary Adrenal Insufficiency Research Articles

Adrenal Histoplasmosis: An Uncommon Cause of Adrenal Crisis in an Immunocompetent Man

Abstract Background Histoplasmosis is a rare cause of primary adrenal insufficiency. Adrenal involvement is commonly encountered with disseminated disease in immunocompromised individuals though some have been reported in immunocompetent patients. Primary adrenal histoplasmosis where adrenals are the only organs with demonstrable disease is uncommon. Case Presentation A 33-year-old immunocompetent man presented with an adrenal crisis. Further evaluation of the underling etiology of primary adrenal insufficiency revealed bilateral adrenal enlargement that was confirmed to be histoplasmosis on adrenal biopsy. Conclusion The case highlights the importance of considering histoplasmosis as an underlying cause of primary adrenal insufficiency in patients from high endemic areas.

Clinical Profile of Addison's Disease in a Tertiary Care Institute, Southern India - The Changing Landscape.

Aims and Objectives:Clinical, biochemical, and radiological profiles of Addison’s disease and to assess the various etiological spectrum of primary adrenal insufficiency (PAI) in adults.Materials and Methods:A retrospective cohort study was carried out in the Department of Endocrinology, Madurai Medical College, Madurai between January 2014 and January 2021 over a 7-year period.Inclusion Criteria:All the patients with clinical symptoms and or signs of suspected PAI, such as hyperpigmentation, weight loss, persistent nausea or vomiting, fatigue, and hypotension, were recruited. All suspected cases underwent measurement of 8-AM plasma ACTH and cortisol levels. In possible cases and equivocal cortisol levels, patients underwent Co-syntropin/ACTH stimulation test. To know the underlying etiology of PAI, 21-hydroxylase autoantibodies (21OHAb), thyroid function test, Anti TPO, calcium, parathyroid hormone (PTH), LH and FSH, CT of chest and abdomen, and sputum AFB based on the clinical pattern of involvement were performed.Exclusion Criteria:Patients with onset of PAI at infancy and childhood, secondary adrenal insufficiency or exogenous Cushing’s syndrome, and central hypocortisolism, including Sheehan’s syndrome, were excluded.Results:Thirty-six patients were diagnosed with PAI in this study; 19 (53%) were females and 17 were males (47%). The median age of diagnosis was 35 years. Patients were divided into acute presentation and subacute presentation. Twenty-six patients presented with acute presentation and ten were presented with progressive evolved symptoms. Non-tuberculous etiology was the predominant finding noted in our cohort study (87%, 31 out of 36 patients). The other causes of Addison disease included isolated auto-immune PAI, polyglandular autoimmune syndrome type 1 and II, APLA Syndrome, and adrenal metastasis.Conclusion:Non-tuberculous causes of PAI are the leading etiology in our retrospective study. Autoimmune PAI and Polyglandular autoimmune syndromes are increasingly being recognized as the cause of Addison’s disease. PAI individuals require lifelong surveillance for possible development of coexisting autoimmune syndromes and need for glucocorticoid/mineralocorticoid therapy.

Bilateral adrenal masses due to tuberculosis: how to diagnose without extra-adrenal tuberculosis.

SummaryPrimary adrenal insufficiency is a rare disease and can masquerade as other conditions; therefore, it is sometimes incorrectly diagnosed. Herein, we reported the case of a 39-year-old Vietnamese male with primary adrenal insufficiency due to bilateral adrenal tuberculosis. The patient presented to the emergency room with acute adrenal crisis and a 3-day history of nausea, vomiting, epigastric pain, and diarrhoea with a background of 6 months of fatigue, weight loss, and anorexia. Abdominal CT revealed bilateral adrenal masses. Biochemically, unequivocal low morning plasma cortisol (<83 nmol/L) and high plasma adrenocorticotropic hormone levels were consistent with primary adrenal insufficiency. There was no evidence of malignancy or lymphoma. As the patient was from a tuberculosis-endemic area, extra-adrenal tuberculosis was excluded during the work up. A retroperitoneal laparoscopic left adrenalectomy was performed, and tuberculous adrenalitis was confirmed by the histopathological results. The patient was started on antituberculous therapy, in addition to glucocorticoid replacement. In conclusion, even without evidence of extra-adrenal tuberculosis, a diagnosis of bilateral adrenal tuberculosis is required. A histopathological examination has a significant role along with clinical judgement and hormonal workup in establishing a definitive diagnosis of adrenal tuberculosis without evidence of active extra-adrenal involvement.Learning pointsPrimary adrenal insufficiency can be misdiagnosed as other mimicking diseases, such as gastrointestinal illness, leading to diagnostic pitfalls.Adrenal insufficiency can be confirmed with significantly low morning plasma cortisol levels of <83 nmol/L without a dynamic short cosyntropin stimulation test.Tuberculous adrenalitis is an uncommon treatable condition; however, it remains an important cause of primary adrenal insufficiency, especially in developing countries. In the absence of extra-adrenal involvement, adrenal biopsy plays a key role in the diagnostic process. Alternatively, adrenalectomy for histopathological purposes should be considered if CT scan-guided fine needle aspiration is infeasible in cases of small adrenal masses.

Hyponatremia, Metabolic Acidosis, and Abnormal Newborn Screen in a Preterm Neonate.

A 2,250-g male neonate is born at 34 weeks of gestation via spontaneous vaginal delivery to a 30-year-old gravida 1, para 0 woman after presentation to a community hospital with uterine contractions and spontaneous rupture of membranes. The mother receives 1 dose of ampicillin, 1 dose of betamethasone, and magnesium before delivery. At delivery, the neonate is vigorous and crying. His Apgar scores are 8 and 9 at 1 and 5 minutes after birth, respectively, with no abnormalities noted on physical examination. In the first couple of hours after birth, he develops persistent oxygen desaturations and is started on continuous positive airway pressure.He is admitted to the NICU for prematurity and low birthweight. Admission examination demonstrates nondysmorphic features, no respiratory distress with good air exchange, regular heart rate and rhythm without murmur, soft and flat abdomen, patent anus, normal external male genitalia, unremarkable neurologic findings, and pink skin color.Chest radiography shows mild diffuse ground-glass reticular densities. He is placed on a stock solution of parenteral nutrition via a peripheral intravenous catheter. Antibiotics are started because of the mother’s unknown group B Streptococcus status and preterm labor. Initial surveillance of electrolytes demonstrates sodium, potassium, calcium, phosphorus, and glucose levels within normal limits. On day 4 after birth, the neonate continues on nasal canula for tachypnea, receiving parenteral nutrition, and advancing gavage feeds of maternal breast milk or formula. A capillary blood gas measurement shows mild metabolic acidosis, with a pH of 7.28, Pco2 32 mm Hg (4.26 kPa), and bicarbonate 19 mEq/L (19 mmol/L).On day 6 after birth, repeat surveillance of electrolytes shows a sodium concentration of 126 mEq/L (126 mmol/L) and potassium of 6.7 mEq/L (6.7 mmol/L). Glucose concentration is 53 mg/dL (2.94 mmol/L). Blood gas continues to show mild metabolic acidosis with a pH of 7.27, Pco2 31 mm Hg (4.12 kPa), and bicarbonate 19 mEq/L (19 mmol/L). Results of the state newborn screening demonstrate an elevated 17-hydroxyprogesterone (17-OHP) of 221 nmol/L (normal <80 nmol/L) on dried blood spot testing, or 14,586 ng/dL (normal <5,280 ng/dL) as serum equivalent. A confirmatory serum 17-OHP level is sent that same day. The pediatric endocrinology service is consulted for the concerning laboratory results.The neonate is transferred to a tertiary care pediatric hospital for further management. He is started on hydrocortisone and fludrocortisone replacements along with sodium chloride supplementation. Repeat serum 17-OHP before treatment is greater than 50,000 ng/dL, and the actual diagnosis of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is made.The neonate continues to appear well with normal vital signs, including blood pressure. He is breathing room air, receiving full enteral feeds, and working on oral feeds with the occupational therapist. Parenteral nutrition has been discontinued.The differential diagnosis for hyponatremia and hyperkalemia in a neonate includes CAH, pseudohypoaldosteronism, inappropriate parenteral nutrition composition, and exogenous diuretic use.CAH is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway and is the most common cause of primary adrenal insufficiency in children. The classic form of CAH affects 1 in 15,000 neonates and is commonly identified through newborn screening, (1) with screening mandated across the United States since 2008. (2) Most cases of CAH are caused by 21-OHD, which is marked by an elevated serum 17-OHP. In the steroidogenic pathway, 17-OHP is the precursor in the enzymatic reaction that is catalyzed by 21-OHD, and is the primary analyte tested in newborn screening for CAH. If treatment is not initiated early, neonates may present in acute salt-wasting adrenal crisis with vomiting, hypotension, and severe dehydration, electrolyte abnormalities, and hypoglycemia. (1)(3)(4)(5) Female neonates with classic CAH also present with virilization of external genitalia at birth.False-positive newborn screening results for CAH are common in preterm neonates, related to the fact that healthy preterm neonates have higher overall levels of 17-OHP compared with term neonates. (6) Thus, many screening programs have established reference ranges that are based on weight and gestational age.For neonates with classic CAH, therapy should be initiated soon after birth to reduce the potentially life-threatening sequelae of CAH. Classic CAH is treated with steroid hormone replacements including hydrocortisone (to replace cortisol) and fludrocortisone (to replace aldosterone). Supplemental sodium chloride (salt) is also recommended for neonates with classic CAH who could have salt-wasting.

An Early Association between X-Linked Adrenoleukodystrophy and Type 1 Diabetes Mellitus - A Case Report

X-linked Adrenoleukodystrophy (X-ALD) is a rare genetic disorder of peroxisomal metabolism and is one of the causes of primary adrenal insufficiency. X-ALD is also associated with various neurological manifestations, however the endocrine features may precede neurological symptoms. As it is rare to have two endocrinological conditions with X-ALD, here we present a unique case of a child with confirmed X-ALD and concurrent Type 1 Diabetes Mellitus (T1DM).

Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

ContextAlthough primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood.ObjectiveWe investigated genetic causes of PAI in children and young people over a 25 year period.Design, Setting and ParticipantsUnpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers.Intervention and Outcome MeasurementsGenetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018).ResultsA genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause.ConclusionsPAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.

Adrenal Insufficiency: Hidden Mimicker With Other Autoimmune Disease Potentials

Background: Adrenal insufficiency has various nonspecific symptoms, which are often overlooked until the patient presents with a life-threatening adrenal crisis. Our patient presented during the COVID19 pandemic, which further blurred our diagnostic sense.Clinical Case: A 26-year-old female presented with sudden intractable non-bloody non-bilious vomiting occurring every 30 minutes along with sharp epigastric pain radiating to her back, dizziness, and extreme fatigue for the last 2 days. She had similar but milder episodes in the past 2–3 years as well and endorsed unintentional weight loss for the same duration. She had been extensively investigated previously but was misdiagnosed as gastroparesis or anxiety and was prescribed medications for the same (pantoprazole, sucralfate, and Lexapro).On presentation this time, she was hypotensive and tachycardic but partially responsive to IV fluids. Her BMI was 15.31 and the abdominal exam was benign. Her basic labs showed Na 125, K 4.9, Calcium 10.5, Cr 1, WBCs 9K, lipase 8, normal LFTs, TSH 6.96, Free T4 1.18. Infectious workup was done and the patient was started on empirical antibiotics. Negative infectious workup, hypotension partially responsive to IV fluid, along with hyponatremia and borderline high potassium level prompted us to check Cortisol. We found Cortisol of 1.3(very low for the degree of her illness). ACTH stimulation test with 250mcg IV cosyntropin showed cortisol of 1.3 at 30 minutes and 1.1 at 60 minutes confirming the diagnosis of adrenal insufficiency. Further workup revealed a positive 21 hydroxylase antibody and ACTH level of 322 (high due to lack of negative feedback to the pituitary). She was comprehensively tested for other autoimmune diseases which showed positive Endomysial IgA and Tissue Transglutaminase antibodies indicating asymptomatic celiac disease. She improved drastically after starting hydrocortisone. TSH was repeated in 3 months which was normal.Conclusion: The onset of chronic adrenal insufficiency is very gradual with vague presentation and it may go undetected unless illness or other stress precipitates acute crisis as in our patient. Since autoimmune adrenalitis is the most common cause of primary adrenal insufficiency (Addison’s disease), patients with a confirmed diagnosis should also undergo workup for other autoimmune diseases.

Tiered healthcare in South Africa exposes deficiencies in management and more patients with infectious etiology of primary adrenal insufficiency.

ObjectiveWe wished to determine the prevalence, etiology, presentation, and available management strategies for primary adrenal insufficiency (PAI) in South Africa (SA), hypothesizing a prevalence greater than the described 3.1 per million. There is great inequity in healthcare allocation, as two parallel healthcare systems exist, potentially modifying PAI patients’ clinical profiles, private being better resourced than public healthcare.MethodsAn online survey of physicians’ experience relating to PAI.ResultsThe physicians were managing 811 patients, equal to a prevalence of 14.2 per million. Likely causes of PAI in public/ academic vs private settings included: AIDS-related [304 (44.8%) vs 5 (3.8%); p<0.001], tuberculosis [288 (42.5%) vs 8 (6.0%); p<0.001], autoimmune disease [50 (7.4%) vs 88 (66.2%); p<0.001], malignancy [27 (4.0%) vs 7 (5.3%); p = 0.500], genetic including adrenoleukodystrophy (ALD) [5 (0.7%) vs 16 (12.0%); p<0.001], respectively. Overall, more patients presented with nausea [101 (74.3%) and vomiting 89 (65.9%), than diarrhoea 76 (58.9%); p = 0.008 and 126 (15.5%) in adrenal crisis. Features suggestive of a crisis were hypoglycaemia [40 (78.4%) vs 42 (48.8%); p = 0.001], shock [36 (67.9%) vs 31(36.9%); p<0.001], and loss of consciousness [25 (52.1%) vs 27 (32.9%); p = 0.031]. Greater unavailability of antibody testing in the public vs. the private sector [32 (66.7%) vs 30 (32.1%); p = 0.001], [serum-ACTH 25 (52.1%) vs 16 (19.5%); p<0.001] and glucocorticoids were [26 (54.2%) vs 33 (40.2%); p = 0.015]. Many patients, 389(66.7%) were not using identification, indicating that they need steroids in an emergency.ConclusionA survey of South African physicians suggests a higher prevalence than previously reported. Patients presented with typical symptoms, and 15.5% presented in adrenal crisis. Significant disparities in the availability of physicians’ expertise, diagnostic resources, and management options were noted in the public versus private settings. Greater awareness among health practitioners to timeously diagnose PAI is required to prevent a life-threatening outcome.

Primary adrenal insufficiency: New genetic causes and their long-term consequences

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1). Reaching a specific diagnosis can have life-long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, Addison's disease.

Reversible primary adrenal insufficiency related to anti-programmed cell-death 1 protein active immunotherapy: Insight into an unforeseen outcome of a rare immune-related adverse event

The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 μg Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory work-up with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.

SUN-166 Primary Adrenal Insufficiency Caused by Underlying Tuberculosis

IntroductionPrimary adrenal insufficiency (AI) is a rare endocrine disorder affecting 1 in 100,000 people. Primary AI is a gradual destruction of the adrenal cortex. Etiology includes autoimmune, tuberculosis, histoplasmosis, blastomycosis, adrenal metastases, primary adrenal tumors, and opportunistic infections of HIV. Since aggressive treatment of TB, the incidence of TB adrenalitis has significantly declined, now accounting for 20% of reported cases where as autoimmune causes of AI account for 70%. Most common symptoms are non-specific, and diagnosis is often delayed, with patient initially presenting with a life-threatening adrenal crisis.CasePatient is an incarcerated 65 y/o African American male with PMHx of hypothyroidism who was admitted to the hospital for AMS after being found unresponsive in his prison cell. On admission, patient was febrile, hypotensive and tachycardic. He looked disheveled, confused, and lethargic. Other exam findings were negative.Lab results revealed WBC 11.7/μL, serum sodium 116 mmol/L, serum potassium 5.2 mmol/L, serum glucose 68 mg/dL, serum osmolality 237mOsm/kg, TSH 26.3mIU/L, and random cortisol 1.6ug/dL. ACTH stimulation test revealed pre-challenge cortisol levels 5.1ug/dL, 30-minute 4.9ug/dL and 60-minute 4.5ug/dL. ACTH 1271 pg/mL (normal range 7.2-63.3pg/mL). A normal response is a stimulated cortisol level > 18ug/dl. Chest x-ray revealed left lower lobe pneumonia.Clinical signs/symptoms and labs were consistent with primary AI. Adrenal crisis was most likely precipitated by underlying pneumonia. Workup was negative for 21-Hydrolase Antibodies, HIV, CMV, and histoplasmosis. However, QuantiFERON-TB Gold Test was positive. Abdominal CT revealed bilateral enlarged non-enhancing adrenal nodules with coarse calcifications. Biopsy of right adrenal gland revealed necrotizing caseating granulomatous inflammation. Biopsy was negative for isolated aerobic, anerobic, fungal organisms, AFB, and mycobacterium PCR.Due to current findings and high suspicion of TB adrenalitis, patient is currently being treated as culture-negative tuberculosis along with PO hydrocortisone for underlying AI.DiscussionAdrenal tuberculosis is a rare cause of primary adrenal insufficiency in developed countries. There should be high suspicion for AI when a patient presents with hypotension, hyponatremia, hyperkalemia and/or hypoglycemia. In this case, although patient did not have a positive AFB culture, he did have a positive QuantiFERON-TB Gold Test along with consistent findings on CT and biopsy. Thus, case was concluded to have high suspicion of primary AI secondary to underlying untreated tuberculosis. Prompt treatment with antituberculosis medication, appropriate steroid therapy, along with monitoring of adrenal function, underlying adrenal insufficiency may be reversible if detected in early stages and decrease mortality.

MON-158 Rates of Illnesses in Patients with Congenital Adrenal Hyperplasia

Background: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common cause of primary adrenal insufficiency during childhood and patients are at risk for life-threatening adrenal crisis. In a recent study from our group, we reported gastrointestinal and upper respiratory tract infections as the two most common precipitating events for adrenal crises and hospitalizations across all ages. We also reported 11 incidents of life-threatening hypoglycemic events in children, sometimes accompanied by seizures. Objective: To evaluate the annual rates of illnesses in patients with CAH. Methods: We retrospectively reviewed longitudinally collected data over 23 years from 156 CAH patients enrolled in our CAH natural history study (www.clinicaltrials.gov #NCT00250159). Incidence of illnesses and occurrence of stress-dose days were computed per person-years. Incidence rate ratio (IRR) with 95% confidence intervals (CI) were calculated for comparisons. Results: A total of 2298 visits (1909 for children and 389 for adults) were available for evaluation among the 156 patients (21-OHD: 97.4%). A total of 1870 illness events (1664 in children) were observed in 143 patients (121 children) and 2710 stress-dose days (2460 in children) were observed in 141 patients (120 children) during the study period. The incidence rate of illnesses was higher in children than adults (1.5 vs. 0.5 illnesses/person-years, IRR = 3.1, 95% CI 2.7 - 3.6; P<.0001) with incidence highest in young patients: 2.5 illnesses/person-years in <3 year olds. Similarly, the stress-dose days were higher in children than adults (2.2 vs. 0.6 days/person-years, IRR = 3.8, 95% CI 3.3 - 4.3; P<.0001). Conclusions: Patients with CAH do not appear to have higher rates of infectious illnesses than expected, but remain at risk for life-threatening adrenal crises. As expected, illness rates are higher during childhood than adulthood. Prevention of adrenal crisis is crucial and is best accomplished through repeated age-specific education of patients and caregivers. Acknowledgement: This research was supported by the Intramural Research Program at the National Institutes of Health (NIH), Bethesda, Maryland.

Significant barriers to diagnosis and management of adrenal insufficiency in Africa.

BackgroundThe burden and management of primary adrenal insufficiency (PAI) in Africa have not been well documented. We aimed to identify specific disease characteristics, patient demographics, and patterns of clinical management in established PAI in Africa.MethodsAn online survey of physicians’ experience relating to PAI.ResultsThere were 1334 responses received, 589 were complete, and 332 respondents reported managing patients with hypoadrenalism. The described responses were related to a calculated pool of 5787 patients with hypoadrenalism (2746 females, 3041 males), of whom 2302 had PAI. The likely causes of PAI in Sub-Saharan Africa (SSA) vs the Middle East and North Africa (MENA) regions included autoimmune disease (20% vs 60.3%; P < 0.001), tuberculosis (34% vs 4.1%; P < 0.001), AIDS (29.8% vs 1%; P < 0.001), malignancy, and genetic conditions. Sixteen percent of AD patients (376/2302) presented in an adrenal crisis. Medical emergency identification was not used by 1233 (83.6%) SSA vs 330 (40.4%) MENA patients (P < 0.001), respectively. Relative non-availability of diagnostic tests across both regions included adrenal antibodies 63% vs 69.6% (P = 0.328), s-cortisol 49.4 % vs 26.7% (P = 0.004), s-ACTH 55.7% vs 53.3% (P = 0.217), and adrenal CT scans 52.4% vs 31.8% (P = 0.017) in the SSA and MENA region, respectively. Across the entire cohort, the overall hydrocortisone use and extrapolated proportion of synacthen use were 59.4% and 50.7%, respectively.ConclusionsThrough the perception and practice of healthcare professionals, we identified significant challenges in the diagnosis and management of PAI which may herald high mortality. Differences between regions may reflect the allocation of healthcare resources.

Etiology and clinical features of primary adrenal insufficiency

Objective: To summarize the etiology of primary adrenal insufficiency (PAI) and analyze its clinical features. Methods: A retrospective analysis was performed in the Department of Endocrinology, Peking Union Medical College Hospital from October 1981 to June 2019. Patients with PAI as the first symptom were enrolled. The etiology of PAI was analyzed and the clinical characteristics was also summarized. Results: A total of 131 patients with PAI were enrolled, including 87 males and 44 females (57 adolescents, and 74 adults). The age ranged from 0 to 73 years. The primary cause of PAI in adolescents was genetic defects (52.6%, 30/57), in which congenital adrenal dysplasia caused by DAX1 gene deficiency accounted for 50.0% (15/30), followed by autoimmunity (22.8%, 13/57). The primary cause of adult PAI was infection (58.1%, 43/74), of which tuberculosis accounted for the majority (93.0%, 40/43), and autoimmune adrenalitis accounted for 19.0% (14/74). Compared with the tuberculosis group, female patients were more common, and the onset age was younger, the plasma cortisol, serum sodium, fasting blood glucose, creatinine and aldosterone were lower (all P<0.05), and serum potassium and renin levels were higher in the autoimmune adrenalitis group (both P<0.05). Conclusions: In the current study, the proportion of PAI caused by infection in the adult group was higher than that in the adolescent group. The most common cause of adult PAI was tuberculosis infection. The most common cause of childhood PAI was genetic defects. Autoimmune damage to the adrenal glands may be more severe than tuberculosis infection.

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Addisonian hyperpigmentation in a case of late onset familial glucocorticoid deficiency and dramatic improvement with glucocorticoid supplementation

Addison's disease is a chronic endocrine disorder in which the adrenal glands do not produce enough steroid hormones mostly both glucocorticoid and mineralocorticoid. Most common causes of primary adrenal insufficiency are due to autoimmune adrenalitis in developed world, and tuberculosis in developing world. Here we present a rare case of primary adrenal insufficiency with addisonian pigmentation secondary to familial glucocorticoid deficiency.

Rare causes of primary adrenal insufficiency (PAI) in children from Sudan

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

Primary adrenal insufficiency: New genetic causes and their long-term consequences.

Primary adrenal insufficiency (PAI) is a potentially life‐threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX‐1 (NR0B1) and steroidogenic factor‐1 (SF‐1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain‐of‐function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed‐onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine‐1‐phosphate lyase‐1 (SGPL1). Reaching a specific diagnosis can have life‐long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, “Addison's disease.”

Isolated hypoaldosteronism as first sign of X-linked adrenal hypoplasia congenita caused by a novel mutation in NR0B1/DAX-1 gene: a case report

BackgroundX-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease.Case presentationA 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC.ConclusionsAHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.

MON-LB064 A Zebra of Adrenal Insufficiency: What Was Once Common Is Now Rare

Background: TB was once a common cause of primary adrenal insufficiency, it is now most often autoimmune in the developed world, but there are rarely observed infectious causes, including TB, Fungal, and CMV. The extra-adrenal manifestations typically stem from pulmonary TB. When TB invades the adrenals, imaging of the adrenal glands initially shows hypertrophy, which progresses to fibrosis and calcification in almost half the cases. This adrenal hypertrophy is often a key marker for differentiating tuberculous adrenal insufficiency from autoimmune adrenalitis, in which case adrenals are usually atrophied. Case: A 62 year old woman with a history of CKD, hyperlipidemia, and possible heart failure presented to the hospital with a 3 week history of worsening right knee pain. She was initially hypotensive at 68/48. Her hospital course was complicated by renal failure, persistent hypotension, and hyponatremia. She received approximately 5 liters of fluid with no significant hemodynamic response. Initial labs showed sodium of 125 with normal range 135-145 and a creatinine of 3.63 with sodium levels hovering in the low 130’s throughout the next 8 days while systolic pressure remained less than 110. Endocrinology was consulted to evaluate the ongoing hypotension and hyponatremia 5 days into admission. Infectious disease was also consulted after it was later revealed that the patient had a history of TB with a positive ppd in 2014, treated with Isoniazid but she was unable to confidently state whether she completed treatment. Other lab work was remarkable for a positive ppd test, negative HIV, and random cortisol levels of 1.3 and 1.1. Cosyntropin stimulation test was very abnormal with cortisol results of 1.3 and 1.1 at 30 and 60 minute intervals (normal >18). ACTH on day 6 of admission was greater than 2000, consistent with primary adrenal insufficiency. Abdominal CT without contrast on day 11 showed adrenal fullness with nodal calcifications consistent with post-infectious TB. Blood pressure and sodium improved on hydrocortisone 50 mg three times daily. She was discharged on hydrocortisone 20mg in the AM and 10mg in the PM, fludrocortisone 0.1mg daily and the 4 drug combo for TB; Rifampin, Isoniazid, Pyrazinamide, and Ethambutol. Conclusion: This case of primary adrenal insufficiency highlights an atypical cause that is now rare in the developed world. TB causes adrenal destruction in a gradual manner, targeting the medulla and cortex secondarily as illustrated here by this HIV-negative latent TB patient. Tuberculous adrenal insufficiency typically presents in an insidious manner. This case demonstrates the importance of a thorough history and evaluation coupled with the realization that not all primary adrenal insufficiency is autoimmune. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.