A 58-year-old female patient with recurrent left adrenal cortical carcinoma following surgery developed severe nausea, vomiting, anorexia, and hypovolemic shock, accompanied by profound hyponatremia, approximately 2 weeks after receiving pembrolizumab immunotherapy. She was diagnosed with an acute adrenal crisis. The patient had a prior history of mitotane therapy and radiotherapy. It was believed that the adrenal crisis was triggered by pembrolizumab-induced immune-mediated adrenalitis, compounded by cumulative damage to adrenal function from both the treatment and the tumor. After aggressive management, including anti-shock treatment, high-dose glucocorticoid replacement, and symptomatic supportive care, the patient's condition improved. At the 1-month follow-up after discharge, the patient had fully recovered, with normalized hormone levels and no evidence of tumor progression. This case highlights the potential for immune checkpoint inhibitor therapy to induce life-threatening adrenal crises in patients with pre-existing adrenal insufficiency. Clinicians must remain highly vigilant, performing early hormone level screening, promptly initiating hormone replacement therapy, and ensuring multidisciplinary team (MDT) collaboration to improve patient outcomes.

PURPOSE: Adrenocortical insufficiency (AI), one of the most common hormonal deficiencies, is associated with significant mortality due to acute precipitation of adrenal crisis. This study aims to assess trends and disparities in mortality due to AI in the United States of America (US) from 1999 to 2020. METHODS: Death certificate data pertaining to AI-related mortality were retrieved from the CDC WONDER database. Crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) were calculated per 1,000,000 population. Annual percentage change (APC) and average APC were used to assess temporal trends using Joinpoint regression. RESULTS: A total of 26,791 deaths occurred due to AI in the US from 1999 to 2020, with an increasing overall trend (average APC: 1.68). Males (5.89) had a higher AAMR than females (5.52). Non-Hispanic (NH) American Indians (9.62) had the highest AAMR and Hispanics (4.11) had the lowest. CMRs in older adults (19.81) aged 65 + years were ten times higher than those of young adults (2.37) aged 25–64 years. Rural areas (6.72) had higher mortality than urban areas (5.43). The Midwest (6.27) reported the highest mortality among the census regions, and the Northeast (4.91) the least. The states with the highest AAMRs were North Dakota (11.25) and Oklahoma (9.54), while Florida (3.32) and Nevada (2.99) had the lowest. CONCLUSION: Adults in the US have shown increasing mortality burden due to AI, with men, NH American Indians, older adults and rural populations being the most high-risk. Targeted strategies need to be developed to curb the rise in mortality rates.

This case report describes a novel intronic mutation, CYP21A2:c.738+75C>T (rs1463196531), identified in a 4-year-old male with congenital adrenal insufficiency, and expands the known mutation spectrum associated with this condition. The patient, born full-term to unrelated parents, presented with adrenal failure within the first month of life, characterized by acute adrenal crisis symptoms such as vomiting, dehydration, weight loss, hypotension, and electrolyte imbalances. Hormonal evaluations confirmed primary adrenocortical insufficiency, necessitating ongoing hydrocortisone and fludrocortisone therapy. Using family trio-based amplicon sequencing of the CYP21A2 gene, we identified compound heterozygosity consisting of a full gene deletion and a novel pathogenic intronic mutation. Additionally, analysis of WGS data was performed to rule out pathogenic variants in genes that might lead to a similar phenotype, thereby eliminating the possibility of other genes contributing to the proband's disease. This case demonstrates the potential of using amplicon sequencing in molecular genetic diagnostic testing to detect rare intronic variants in the CYP21A2 gene in cases of early-onset adrenal failure. It also contributes to a better understanding of the genetic basis of congenital adrenal hyperplasia (CAH), which remains a significant autosomal recessive disorder affecting cortisol and aldosterone production, with an incidence of 1 in 10,000 to 1 in 15,000 globally.

BACKGROUND: Acute adrenocortical insufficiency (adrenal crisis) as a cause of postoperative hypotension is an uncommon and underreported condition in pediatric patients. Charcot-Marie-Tooth (CMT) disease, a hereditary motor and sensory neuropathy, frequently coexists with scoliosis. Surgical correction of severe scoliosis involves significant stress due to considerable surgical trauma and prolonged operative time. CASE DESCRIPTION: A 13-year-old female diagnosed with CMT and severe scoliosis (thoracic curvature Cobb angle 92°) underwent posterior osteotomy and corrective surgery. On postoperative Day 1, the patient experienced persistent hypotension (systolic blood pressure < 90 mmHg) that did not respond to fluid resuscitation or vasopressor support with dopamine. On postoperative Day 4, Adrenocorticotropic Hormone (ACTH) stimulation testing revealed a cortisol level of 323.1 nmol/L which was low in the context of physiological stress, along with a markedly reduced ACTH concentration of 4.72 pg/ml, confirming a diagnosis of acute adrenocortical insufficiency. Hydrocortisone treatment resulted in a gradual normalization of blood pressure, which returned to preoperative levels by postoperative Day 8. Steroid therapy was discontinued following normalization of adrenal hormone levels. CONCLUSION: In pediatric patients undergoing surgery for severe scoliosis, unexplained postoperative hypotension warrants thorough evaluation for adrenal crisis, especially in the context of underlying chronic illness or malnutrition.

Adrenal crisis, also known as acute adrenal insufficiency, is an endocrine emergency that is associated with high mortality rates. Reversible cardiomyopathy with severe heart failure is a rare complication of adrenal crisis. Isolated adrenocorticotropin deficiency (IAD) is a rare condition of pituitary adrenal insufficiency. In this case report, we describe a 74-year-old male patient who was in good physical health and was admitted to our hospital with a sudden onset of fever and confusion that was complicated by hyponatremia and hypotension. Cardiac ultrasound showed significantly reduced left ventricular ejection fraction (LVEF; 10%). The patients was initially diagnosed with "septic shock" because of elevated inflammatory indicators and treated with mechanical circulatory support, antibiotics, fluid resuscitation, and intravenous administration of 50 mg hydrocortisone every 6 h for 2 days (400 mg in total). The symptoms of the patient improved significantly by this treatment in 6 days. The LVEF improved from 10% to 40%. However, the initial treatment did not alleviate hypotension and confusion. Therefore, the status of adrenal function was analyzed using blood and urine cortisol tests. Blood and urinary cortisol levels were significantly reduced, but concurrent increase in the ACTH levels were not observed. This indicated adrenal crisis. Subsequently, the patient was initially administered intravenous injection of hydrocortisone (50-150 mg/day) for 5 days, and then transitioned to a physiological supplement dose orally. The LVEF value improved further to 52%. Finally, the patient was diagnosed with adult isolated ACTH deficiency. The patient was prescribed regular oral hydrocortisone. The patient has not shown any signs of heart failure during follow up for more than half a year. In summary, we described a rare and severe case of adrenal crisis complicated with reversible cardiomyopathy that was caused by isolated ACTH deficiency. In such a case, conventional guideline directed medical therapy (GDMT) for heart failure was not considered suitable because of the underlying hypotension, hypoglycemia, and hyponatremia. Our study showed that timely supplementation of glucocorticoids achieved better therapeutic effects in patients with adrenal crises complicated by severe cardiomyopathy.

Addison disease is an acquired primary adrenal insufficiency. A primary adrenal insufficiency is termed Addison disease when an autoimmune process causes the condition. It is a rare but potentially life-threatening emergency condition. It results from bilateral adrenal cortex destruction leading to decreased adrenocortical hormones, which may include cortisol, aldosterone, and androgens. Addison disease's insidious course of action usually presents with glucocorticoid deficiency followed by mineralocorticoid. However, it can also present acutely, often triggered by intercurrent illness. The presentation of adrenal insufficiency depends on the rate and extent of adrenal function involvement. The most common cause of primary adrenal insufficiency is autoimmune adrenalitis (Addison disease), associated with increased levels of 21-hydroxylase antibodies.[1][2]

Adrenal insufficiency (AI), first described by Thomas Addison in 1855, is characterised by inadequate hormonal production by the adrenal gland, which could either be primary, due to destruction of the adrenal cortex, or secondary/tertiary, due to lack of adrenocorticotropic hormone or its stimulation by corticotropin-releasing hormone. This was an invariably fatal condition in Addison's days with most patients dying within a few years of diagnosis. However, discovery of cortisone in the 1940s not only improved the life expectancy of these patients but also had a dramatic effect on their overall quality of life. The diagnosis, easily confirmed by demonstrating inappropriately low cortisol secretion, is often delayed by months, and many patients present with acute adrenal crisis. Sudden withdrawal from chronic glucocorticoid therapy is the most common cause of AI. Currently, there remains a wide variation in the management of this condition across Europe. As primary AI is a relatively rare condition, most medical specialists will only manage a handful of these patients in their career. Despite many advances in recent years, there is currently no curative option, and modern cortisol replacement regimens fail to adequately mimic physiological cortisol rhythm. A number of new approaches including allograft of adrenocortical tissue and stem cell therapy are being tried but remain largely experimental.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing's syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

A novel CYP11A1: c.1236 + 5G > A was identified, expanding the mutation spectrum of the congenital adrenal insufficiency with 46,XY sex reversal. In a now 17-year-old girl delivered full-term (G2P2, parents unrelated), adrenal failure was diagnosed in the first year of life based on clinical picture of acute adrenal crisis with vomiting, dehydration, weight loss, hypotension, and electrolyte disturbances. At the time, hormonal tests revealed primary adrenocortical insufficiency and steroid profiles showed lack of products of steroidogenesis, and since then the patient has been treated with substitution doses of hydrocortisone and fludrocortisone. At the age of 14, considering the absence of puberty symptoms, extended diagnostic tests revealed elevated LH levels (26.5 mIU/mL) with pre-puberty FSH levels (4.9 mIU/mL), low estradiol (28 pmol/L), testosterone (<2.5 ng/mL), and extremely high levels of ACTH (4961 pg/mL). A cytogenetic study revealed a 46 XY karyotype. A molecular examination confirmed the missense mutation and a novel splice-site mutation of CYP11A1 gene. Compound heterozygosity for the CYP11A1 gene with a known pathogenic variant in one allele and a novel splice site mutation in the second allele is most probably responsible for congenital adrenal insufficiency with 46,XY sex reversal. We discuss the necessity of cytogenetic test in the case of early onset of adrenal failure in the absence of steroidogenesis metabolites in the steroid profile.

Congenital adrenal hypoplasia is a rare cause of primary adrenocortical failure, which was first described in 1948. During the last two decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these disorders involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, oxidative stress defense-mechanisms, and regulation of cell cycle. Adrenal hypoplasia can occur: 1) secondary to defects in transcription factors involved in pituitary development or 2) defects in ACTH synthesis and secretion; 3) as a primary defect in the development of the adrenal gland; 4) as part of rare syndromes associated with adrenal hypoplasia/aplasia, which are inherited in an autosomal recessive or autosomal dominant manner; and 5) in the context of chromosomal abnormalities. Early diagnosis and management are crucial because of the life-threatening nature of the condition. Depending on the etiology, adrenal crisis may occur in early infancy or could insidiously develop over the course of childhood or adolescence. Moreover, some of these conditions previously thought to occur only in childhood, may also be diagnosed later in adulthood and present with variable phenotypes, including isolated infertility or disorders of sex differentiation. The clinical manifestations of primary adrenal insufficiency (PAI) result from deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). The acute presentation can be precipitated by physiologic stress, such as surgery, trauma, or an intercurrent infection. Patients may present with signs and symptoms of complete adrenal insufficiency, usually early in life, including hypoglycemic convulsions, hyponatremia, hyperkalemia, metabolic acidosis or later with hyperpigmentation, vomiting and poor weight gain. It should be remembered, that the most common cause of PAI in children is congenital adrenal hyperplasia due to 21-hydroxylase deficiency and can be excluded by measuring baseline or ACTH-stimulated 17-hydroxyprogesterone levels in serum. Screening for autoimmune Addison disease includes detection of 21-hydroxylase antibodies. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy measuring very–long-chain fatty acids concentrations in plasma. The presence of alacrima in patients with PAI should raise suspicion for Triple A syndrome, whereas the combination of PAI and hypogonadotropic hypogonadism in a male patient point towards X-linked adrenal hypoplasia congenita. To date, molecular genetic testing is commercially available for the identification of several genes involved in adrenal hypoplasia syndromes. The early identification of these diseases can have important prognostic and therapeutic implications for patients with respect to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk. Adrenal insufficiency is potentially life threatening, thus treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis. Therapy consists of life-long replacement therapy with glucocorticoids and mineralocorticoids. Hypogonadism or other associated disorders should be treated appropriately. Screening of family members for the disease or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.