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BackgroundSphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects.ResultsOverall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes.ConclusionOur results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

Introduction: One of the less common and more life-threatening etiologies of adrenal insufficiency is immune checkpoint inhibitor (ICI)-induced primary adrenal insufficiency (PAI). Patients typically present with fatigue, malaise, and nausea and are treated empirically with hydrocortisone.  Case Report: We present the case of a 59-year-old female who presented with hypotension, which initially was thought to be due to hypovolemia or medication-related, but was ultimately found to have PAI. Conclusion: This case highlights the importance of early detection of ICI-induced primary adrenal insufficiency, given its associated morbidity and mortality and its incidence in patients with a history of immunotherapy.

Immune checkpoint inhibitors (ICIs) can trigger immune-related adverse events (irAEs). The appearance pattern of irAEs, who is prone to them, and their mechanisms are still uncertain. In this study, we aimed to monitor patients initiated on ICIs for endocrinological aspects and to investigate the potential predictive markers in the development of endocrine-irAEs. The study prospectively included 43 patients with metastatic disease scheduled for anti-PD-1/ L1 therapy. Endocrinological follow-up was conducted at specified intervals as well as in response to any additional reported complaints. Serum concentrations of CXCL10, IL-1beta, and IL-17A were measured prior to ICI and during the endocrine-irAEs. A total of 39.5% of the patients experienced endocrine-irAEs, with a median onset time of 3 months. Among patients, 34.9% developed thyroid-related adverse events, and 4.6% experienced hypophysitis. Thyroid autoantibodies were associated with a higher incidence of thyroid-related irAEs (P = 0.004). In the irAE group, median pre-ICI CXCL10 and baseline thyroid stimulating hormone (TSH) levels were significantly higher, baseline total testosterone level in men was lower than in the non-irAE group (P < 0.05), whereas IL-1beta and IL-17A levels did not differ (P > 0.05). Serum CXCL10, IL-1beta, and IL-17A concentrations did not differ significantly pre-ICI and during adverse events (P > 0.05). Pre-ICI CXCL10 concentration was correlated positively with anti-TPO levels in patients with at least one thyroid autoantibody positivity (r = 0.706, P = 0.01) and negatively with baseline total testosterone level of men (r = 0.509, P = 0.002). Our results suggest that higher pre-ICI serum CXCL10 and TSH levels might have a predictive role in the development of endocrinopathies. Besides, baseline thyroid antibody measurements could be beneficial in predicting thyroid dysfunction. [ABSTRACT FROM AUTHOR]

Context Glucocorticoids suppress the hypothalamic–pituitary–adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone. Objective To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion. Methods This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured. Results In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P =.008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P =.464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P =.648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P =.693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P =.905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P =.012). Conclusion Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone. [ABSTRACT FROM AUTHOR]

Background: Bilateral adrenal hemorrhage is a rare but often a fatal cause of primary adrenal insufficiency that can result in adrenal crisis if not identified and managed appropriately. Case presentation: We present a case of a 27-year-old Caucasian female who was admitted to the hospital 17 days postpartum with pleuritic chest and flank pain, shortness of breath and nausea. Computed tomography imaging confirmed multiple thromboemboli including pulmonary emboli and noted bilateral bulky adrenal glands. She was managed for infection and pulmonary emboli; however, she complained of persistent headaches, nausea, and vomiting despite appropriate management. Radiology re-review found the computed tomography imaging was consistent with bilateral adrenal hemorrhage in hindsight. Subsequent endocrine evaluation with hypothalamic–pituitary–adrenal axis interrogation and adrenocorticotropic hormone (Synacthen) stimulation testing confirmed resultant primary adrenal insufficiency. She required urgent intravenous hydrocortisone and was subsequently discharged on oral adrenal replacement therapy and anticoagulation. Conclusions: Delay in identification and treatment of adrenal insufficiency can lead to catastrophic outcomes. This case highlights the challenge of diagnosing bilateral adrenal hemorrhage and resultant adrenal insufficiency as patients may not present with the classic risk factors, signs, symptoms, and electrolyte derangements. [ABSTRACT FROM AUTHOR]

Autoimmune adrenal insufficiency (AAI) is a rare disease. This research evaluates three patients with AAI, including autoimmune polyglandular syndrome (APS) type 2. Two patients had APS or AAI during childhood, and one had a history of endocrine autoimmune disease, indicating a possible hereditary basis of the condition. Trio-based exome sequencing and high-resolution HLA typing were employed to analyze patients and their parents. Benign or likely benign variants of the AIRE gene were identified in all participants of the study. These variants, coupled with clinical data and the results of antibody studies to type I interferons, helped to exclude APS-1. Patients with APS-2, in contrast to patient with AAI, inherited distinct variants of unknown significance in the CLEC16A gene, which is associated with autoimmune diseases, including AAI. Various risk alleles in other genes associated with autoimmunity were identified in all patients. HLA typing of class II loci revealed alleles related to APS. Nevertheless, the frequencies of the haplotypes identified are substantial in the healthy Russian population. Immunological tests can detect antibody carriers and assess the risk of autoimmune disease development. In the future, to identify genetic predictors of autoimmune endocrinopathies, it is recommended to analyze the whole genome of patients and their relatives, examining clinically relevant variants in non-coding regions. [ABSTRACT FROM AUTHOR]

Triple A syndrome (TAS), also known as Allgrove syndrome (OMIM#231550), is a rare, autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenal insufficiency. Additional neurological features may be present in two-thirds of patients, involving central, peripheral, and autonomic nervous system manifestations. TAS is caused by genetic alterations in the AAAS gene on chromosome 12q13, which encodes the nuclear pore complex protein termed ALADIN (ALacrima, Achalasia, aDrenal Insufficiency, and Neurologic disorder). ALADIN plays a crucial role in nucleocytoplasmic transport of specific proteins, including the transport of DNA repair proteins. TAS exhibits significant phenotypic variability in terms of symptom onset, frequency, and severity, often presenting with a progressive clinical course indicative of an underlying degenerative process. In this study, we report the case of an infant with exceptionally early and severe manifestations of triple A syndrome, with a review of the literature. Our patient exhibited the complete classical triad of TAS at six months of age, being among the youngest reported cases of the syndrome. The clinical course was complicated by severe involvement of the autonomic nervous system, neurogenic bladder, and recurrent urinary tract infections. Subsequently, the patient developed acute pancreatitis, leading to multiorgan dysfunction and a fatal outcome at 25 months of age. This case underscores the potential for atypical disease presentations and the need for clinical awareness in diagnosing and managing patients with TAS. [ABSTRACT FROM AUTHOR]

Background: We report a rare case of new onset autoimmune adrenal insufficiency in childhood, presenting with severe shock requiring mechanical circulatory support. In the current era of readily available imaging, laboratory and other diagnostic investigations, medical history and careful physical exam can often provide valuable diagnostic information for timely therapy. Case presentation: A 7-year-old boy with a history of mild intermittent asthma, presented with severe cardiogenic shock requiring extracorporeal membrane oxygenation (ECMO). Bronzing of his entire body was noted on physical exam. Stress dose hydrocortisone was given for suspected adrenal insufficiency. After weaning from ECMO and extensive rehabilitation, the patient recovered and was discharged home. Conclusion: Primary adrenal insufficiency (PAI) should be considered in the context of physical exam and laboratory findings, even in the presence of circulatory shock. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case report highlights dilated cardiomyopathy as a cardiovascular complication in autoimmune polyendocrine syndrome type 1 (APS‐1), emphasizing the need for early recognition and a multidisciplinary approach. Comprehensive care and regular follow‐up are crucial in managing these atypical presentations to optimize patient outcomes. APS‐1, also known as Whitaker syndrome, is characterized by a triad of mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. This rare autosomal recessive disorder results from mutations in the autoimmune regulator (AIRE) gene. Cardiovascular and pulmonary manifestations in APS‐1 are infrequently reported in the literature. We present a case of a 28‐year‐old male who presented with shortness of breath and pedal edema. Physical examination revealed alopecia, absence of eyebrows, hyperpigmentation on joints, oral candidiasis, and nail dystrophy. Echocardiography demonstrated dilated cardiomyopathy (DCM) and pericardial effusion. Chest x‐ray showed left‐sided pleural effusion. Laboratory investigations revealed hypocalcemia, hyperphosphatemia, low parathyroid hormone (PTH), low cortisol, and high adrenocorticotropic hormone (ACTH) levels. The combination of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency confirmed the diagnosis of APS‐1. To the best of our knowledge, this is the first Pakistani and second worldwide reported case of APS‐1 presenting with such a combination of manifestations. Early recognition and multidisciplinary management are crucial for improving outcomes in these patients. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndrome 1 (APS1) is an autosomal recessive disorder due to biallelic pathogenic variants in the autoimmune regulator (AIRE) gene that manifests with chronic mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. We report a 39-year-old woman with APS1 who developed partial lipodystrophy during adulthood. She presented with diaper rashes, oral thrush, and tetany during infancy due to candidiasis and hypoparathyroidism. During childhood, she developed hypothyroidism, primary adrenal insufficiency, and ovarian insufficiency. At age 14, she received a sibling-matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At age 35, her serum triglycerides were 914 mg/dL (10.32 mmol/L) and she had loss of subcutaneous fat from the upper and lower extremities and hips. A whole-body dual-energy x-ray absorptiometry revealed lower-extremity fat at less than the first percentile. Whole-exome sequencing on DNA extracted from saliva revealed pathogenic variants, p.Leu28Pro and p.Arg257* in AIRE but none in the known lipodystrophy genes. Phage-immunoprecipitation-sequencing revealed the presence of autoantibodies to MAGEB1, MAGEB4, and RFX6, which have been previously reported in APS1. Our case suggests that patients with APS1 may develop partial lipodystrophy due to autoantibodies against novel adipocyte-expressed proteins. A causal relationship of high levels of autoantibodies in our patient to adipose tissue–expressed ODC1, NUCKS1, or FNBP1L and lipodystrophy remains uncertain. [ABSTRACT FROM AUTHOR]

Background Alopecia areata (AA) has a poor clinical course in children. There are no reliable therapeutic options for children with severe AA, including alopecia totalis (AT) and alopecia universalis (AU). Objectives We evaluated the efficacy and adverse effects of a potent topical corticosteroid (TCS) under occlusion in paediatric patients with severe AA. Methods We reviewed records of 23 patients under the age of 10 years with AT or AU treated with a potent TCS (0.05% clobetasol propionate or 0.3% diflucortolone valerate) for 8 h under occlusion with a plastic film. We used the Severity of Alopecia Tool (SALT) to measure clinical improvement. The primary endpoint was a SALT score of ≤ 20 at 6 months. We analysed the change in cortisol levels to identify the long-term safety of TCS therapy on the hypothalamus–pituitary–adrenal axis. Results Nineteen of the 23 patients (83%) reached SALT ≤ 20 at 6 months. Six patients relapsed over the 6-month follow-up period. Four patients were suspected of having adrenal insufficiency. However, the cortisol levels of the patients recovered to normal within 1 month of lowering the TCS potency or changing to nonsteroidal treatments. Limitations include the retrospective design and small sample size. Conclusions This study shows that a potent TCS occlusion may be a safe treatment option in paediatric patients with severe AA. Further long-term studies are required to evaluate the safety and recurrence of TCS occlusion therapy for paediatric AA. [ABSTRACT FROM AUTHOR]

The sun imposes a 24‐h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically‐based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified‐release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Patients with salt‐wasting congenital adrenal hyperplasia (SW‐CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW‐CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW‐CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW‐CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy. [ABSTRACT FROM AUTHOR]

Corticosteroids play a crucial role as anti-inflammatory and immunomodulatory agents in dermatology and other medical specialties; however, their therapeutic benefits are accompanied by significant risks, especially in older adults. This review examines the broad spectrum of adverse effects (AEs) associated with oral corticosteroid therapy and offers strategies to prevent, monitor, and manage these issues effectively in older adults. AEs associated with systemic corticosteroids include immune suppression, gastrointestinal problems, hyperglycemia, insulin resistance, weight gain, cardiovascular complications, ocular issues, osteoporosis, osteonecrosis, muscle weakness, collagen impairment, psychiatric symptoms, and adrenal suppression. To minimize these AEs, tailored dosing and duration, frequent monitoring, and additional preventative measures can be employed to optimize corticosteroid treatment. By customizing management plans to the specific needs and risk factors associated with each patient, clinicians can promote the safe and effective use of oral corticosteroids, ultimately improving outcomes and quality of life in patients with inflammatory dermatologic disorders. [ABSTRACT FROM AUTHOR]

The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK/MAPK, p38/MAPK, JNK/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Approximately 1% of the UK population take oral corticosteroids for ≥ 28 days each year, for broadly two reasons: deficiency in corticosteroid requiring replacement; or therapeutic corticosteroid for inflammatory conditions. Acute deficiency can occur at times of physiological stress (e.g. surgery), potentially leading to major complications. The Association of Anaesthetists' 2020 consensus guideline provides detailed advice for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency. This national audit aimed to assess compliance with this guideline. Methods: Data were collected from 59 Trusts over 14 consecutive days for all eligible patients undergoing procedures under the care of an anaesthetist. Patients who were prescribed ≥ 5 mg oral prednisolone equivalents pre‐operatively, in whom supplementary corticosteroid would be indicated, were compared with those prescribed < 5 mg oral prednisolone equivalents. Results: Operations for 21,731 patients were audited: 277 (1.3%) patients were taking therapeutic corticosteroids. Detailed peri‐operative data were collected for all patients receiving therapeutic corticosteroids: 201/277 (73%) were ASA physical status ≥ 3; 184/277 (66%) underwent elective procedures; and 252/277 (91%) were prescribed prednisolone pre‐operatively, of whom 219/277 (79%) were prescribed ≥ 5 mg oral prednisolone equivalents. In the patients who were prescribed ≥ 5 mg oral prednisolone equivalents, 186/219 (85%) received pre‐operative glucocorticoid supplementation and 97/219 (42%) received it postoperatively; however, only 67/219 (31%) and 43/219 (20%) respectively received glucocorticoid supplementation according to the guidelines. Overall, peri‐operative prescribing was compliant in 19/219 (9%) patients. A similar proportion, 30/219 (14%), received no supplementation. In the patients taking < 5 mg oral prednisolone equivalents pre‐operatively, 28/58 (48%) received inappropriate supplementation. Conclusions: Despite 125/277 (45%) of anaesthetists reporting Association of Anaesthetists' guidelines use, compliance remained low, with adherence in only 27/125 (22%) patients. Further research is required to identify the correct peri‐operative strategy for patients taking therapeutic corticosteroids. [ABSTRACT FROM AUTHOR]

Purpose: Patients with hypopituitarism are at increased cardiovascular risk, in part because of growth hormone deficiency (GHD), but probably also because of the overuse of glucocorticosteroids in concomitant adrenal insufficiency (AI). We hypothesized that patients with hypopituitarism that were on glucocorticosteroid replacement therapy for concomitant AI would have worse cardiovascular outcomes than those without. Methods: Retrospective nationwide cohort study. GHD patients from the Dutch National Registry of Growth Hormone Treatment in adults were grouped by the presence (AI; N = 1836) or absence (non-AI; N = 750) of concomitant AI, and differences between groups were analyzed for baseline characteristics and cardiovascular risk, at baseline and during GHRT. Results: At baseline, AI patients had higher levels of total and LDL cholesterol (both p < 0.01). During GHRT, AI patients were more likely to use cardiovascular drugs (p ≤ 0.01), but we did not find worse outcomes for blood pressure, body composition, lipid and glucose metabolism. The risk of developing peripheral arterial disease (HR 2.22 [1.06–4.65]) and non-fatal cerebrovascular events (HR 3.47 [1.60–7.52]) was higher in AI patients, but these differences disappeared in the models adjusted for baseline differences. Conclusion: We found no clear evidence to support our hypothesis that patients with hypopituitarism and concomitant AI have worse cardiovascular outcomes than non-AI patients. This suggests that glucocorticoid replacement therapy in AI may be safer than previously thought. However, cardiovascular burden, events and medication use at baseline and during GHRT (in unadjusted models) were higher in AI; so the lack of power, the important role of (adjusting for) other risk factors, and the inability to distinguish between glucocorticoid treatment regimens may have influenced the outcomes. [ABSTRACT FROM AUTHOR]

Background and Objectives: Adrenal insufficiency (AI) can be a significant concern in patients with transfusion-dependent homozygous beta thalassemia (bThal) due to the chronic disease burden and frequent blood transfusions that these patients require. The prevalence of AI in this population remains unclear, with studies often lacking control groups for comparison. This meta-analysis aimed to estimate the proportion of patients with transfusion-dependent bThal who exhibit evidence of AI. Materials and Methods: A systematic review following PRISMA guidelines identified 19 studies for analysis. Results: Despite the variability in the diagnostic methods used to ascertain AI, the meta-analysis revealed that approximately one-third of patients had evidence of AI, with the prevalence rising to 50% in studies focused on adults with bThal. Conclusions: These findings suggest an increased risk of AI in patients with bThal compared to the general population. Clinicians should consider tailored management strategies, including glucocorticoid coverage during surgical procedures, to mitigate the risk of adrenal crises in this vulnerable patient group. Further research is needed to optimize adrenal surveillance and management in patients with bThal. [ABSTRACT FROM AUTHOR]

Oral hormone replacement therapy has been and continues to be the cornerstone of adrenocortical insufficiency management. However, the introduction of continuous subcutaneous hydrocortisone infusion (CSHI) shows great potential for advancing the management of adrenocortical insufficiency. It resembles the circadian rhythm of physiological cortisol secretion and was shown to have a promising outcome in terms of quality of life (QOL) and clinical outcomes in the literature. We conducted a systematic search strategy including MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and the online trials registers at ClinicalTrials.gov without geographic restrictions. Research investigations where self-reported quality of life (QOL) was assessed as a variable in adult individuals with confirmed adrenal disease, treated by CSHI, and results were presented in English. All articles included were published between 2014 and 2023, even though we had no timeframe limitations in our inclusion criteria. A total of six studies were included, with 63 subjects enrolled, and the average age was 40 years, a study showed a significant reduction in the average total daily dose of HC from 47.5 mg to 31.4 mg on CSHI, while other two studies estimated a reduction in the hospitalization rate due to adrenal crisis from 2.6 to 1.3 admissions per year on CSHI. Most of the studies on subjective well-being and quality of life have shown significant improvement. Overall, CSHI shows great potential as a treatment method for Adrenal insufficiency. It improves the quality of life and lowers hospitalization rates, resulting in increased patient satisfaction and acceptance. Additional comprehensive research is necessary to strengthen these discoveries, gain a deeper understanding of the effectiveness and safety of this treatment approach, and provide guidance for medical practitioners. [ABSTRACT FROM AUTHOR]

The clinical presentation of adrenal insufficiency, a condition causing adrenal hormone deficiency, is characterised by non-specific symptoms and signs: consequently, an important diagnostic delay is often evident which correlates with an increased mortality. This case report shows how the clustering of some symptoms and signs may hamper the diagnostic suspicion for this condition: serum electrolyte alterations and weight loss, when associated to recurrent infections and, in female patients, an empty sella may further guide the clinician towards a diagnosis of adrenal insufficiency. Accordingly, a clinical approach taking into account gender medicine could improve the diagnostic workup. [ABSTRACT FROM AUTHOR]

Background It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDEs) and hospitalization rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events. Aim Study temporal trends of AI related AE in the I-CAH Registry. Methods In 2022, data on the occurrence of AI-related AE in children aged <18 years with 21-hydroxylase deficiency CAH were compared to data collected in 2019. Results In 2022, a total of 513 children from 38 centers in 21 countries with a median of 8 children (range 1-58) per center had 2470 visits evaluated over a 3-year period (2019-2022). The median SDE per patient year in 2022 was 0 (0-2.5) compared to 0.3 (0-6) in 2019 (P =.01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the 2 cohorts. Of the 38 centers in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%), and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalization compared to 299 of 1099 SDEs (27%) in the 2019 cohort (P =.02). Conclusion The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring. [ABSTRACT FROM AUTHOR]

Background: Secondary adrenal insufficiency (SAI) may occur in patients after unilateral adrenalectomy for adrenal-dependent hypercortisolism (HC) or primary aldosteronism (PA). This study aimed to assess whether postoperative day (POD) 1 basal cortisol was predictive of an abnormal cosyntropin stimulation test (CST) result and the need for glucocorticoid replacement (GR). Methods: A retrospective review of consecutive patients who underwent unilateral adrenalectomy for HC, PA, or both between September 2014 and September 2022 was performed. On POD1, CST was performed for all the patients with HC, and before 2021 for all the patients with PA. The patients with an abnormal CST result were deemed at risk of SAI and discharged with GR. Receiver operating characteristic (ROC) curves were generated to evaluate the sensitivity (SN) and specificity (SP) of basal cortisol thresholds to predict an abnormal CST result. Results: The patients underwent unilateral adrenalectomy for overt hypercortisolism (OH; n = 42), mild autonomous cortisol excess (MACE; n = 70), mixed PA/HC (n = 22), or PA (n = 73). On POD1, CST was performed for 152 patients (93% OH, 96% MACE,73% PA/HC, 41% PA), and 80 patients (53%) had SAI (67% OH, 55% MACE, 44% PA/HC, 33% PA). The SN and SP of a basal cortisol level of 10 µg/dL or lower to predict an abnormal CST were respectively 92% and 77% for OH, 94% and 73% for MACE, 100% and 85% for PA, and 100% and 67% for PA/HC. The optimal basal cortisol level for predicting an abnormal CST for patients with PA or PA/HC was 5 µg/dL or lower (SN/SP, 100%). Conclusions: After unilateral adrenalectomy for HC, PA, or mixed PA/HC, POD1 CST improved identification of patients at risk for SAI compared with basal cortisol levels alone. The authors recommend that POD1 CST be performed to determine the risk for SAI and the need for postoperative GR after unilateral adrenalectomy for patients with HC. [ABSTRACT FROM AUTHOR]

This article discusses a rare genetic disorder called MIRAGE syndrome, which is characterized by various symptoms including myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital phenotypes, enteropathy, achalasia, alacrimia, endocrinopathies, and immune dysregulation. The article presents a case study of a 5-year-old boy with MIRAGE syndrome who had a novel SAMD9 variant and unique pulmonary findings. The patient experienced recurring episodes of febrile illness and improved with immunoglobulin replacement therapy. The article also discusses the potential mechanisms underlying the anti-inflammatory effects of immunoglobulin therapy and suggests that it may benefit other patients with MIRAGE syndrome. [Extracted from the article]

Primary adrenal insufficiency (PAI) is a rare medical condition, characterized by a deficiency in adrenal hormones. Although rare, PAI is a life-threatening disease requiring prompt recognition and treatment. However, symptoms of PAI are often non-specific and diagnosis can be challenging, causing frequent diagnostic delays. In adults, autoimmunity is the most common cause of PAI in industrialized countries, whereas in children, the most frequent etiology is represented by congenital defects of steroidogenesis and, in particular, by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. A few recent case series from different countries have reported that autoimmunity is the second most common etiology of PAI in the pediatric age group. However, data on autoimmune PAI in children are still scant and the exact epidemiology, clinical manifestations, and long-term outcomes of this condition have yet to be defined. The scope of this review is to summarize the current knowledge on the etiology, presentation, and treatment of autoimmune PAI in childhood and to increase physicians' awareness of the signs that should raise an early suspicion of this condition. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic ablative radiation (SAbR) is a focused, high-dose radiation technique used to treat cancers that have spread to the adrenal glands. One of the feared consequences of this therapy is causing adrenal insufficiency in patients, which is a lack of adrenal function; however, the rates and severity at which this occurs in patients are still poorly studied. We studied patients with 66 treated adrenal glands using SAbR, which demonstrated that this technique was effective at controlling cancer sites with a control rate of 75% at 1 year. The risk of patients developing adrenal insufficiency in the entire cohort was significant at 14%, with a median time of 4.3 months. There was a higher risk in patients who had both adrenal glands treated with SAbR, or who had received a prior surgical removal of their other adrenal gland prior to SAbR therapy, with 44% of these patients developing adrenal insufficiency. Background: Adrenal metastases are often treated with stereotactic ablative radiation (SAbR). We aimed to assess the incidence, timing, and factors associated with the development of primary adrenal insufficiency (PAI) following SAbR. Methods: A retrospective cohort study comprised 66 consecutive patients (73% men, median age 61 years) who underwent SAbR for adrenal metastasis. Results: The series encompassed metastases from renal cell carcinoma (41%), lung tumors (38%), colorectal adenocarcinoma (9%), melanoma (5%), and others (7%). Median follow-up was 17 months from SAbR. Nine (14%) patients developed PAI at a median of 4.3 months (range, 0.7–20.2). The incidence of PAI was 44% in patients with prior adrenalectomy receiving unilateral SAbR, 44% with bilateral SAbR, 2% with unaffected contralateral gland, and 0% with bilateral metastases treated with unilateral SAbR. PAI was associated with prior adrenalectomy (odds ratio [OR] 32) and bilateral SAbR (OR 8.2), but not age, sex, metastasis size, or biological effective dose. Post-SAbR 6-month and 1-year local control rates were 82% and 75%, respectively. Conclusions: Patients undergoing SAbR for adrenal metastasis are at high risk of developing PAI. PAI is associated with bilateral SAbR and contralateral adrenalectomy. PAI is unlikely with a remaining unaffected adrenal gland or in the setting of bilateral adrenal metastases with unilateral SAbR. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionMitotane is the cornerstone of adjuvant adrenocortical cancer (ACC) treatment. However, its use is burdened with frequent adverse events.A retrospective analysis of adverse events was performed in 26 ACC patients adjuvantly treated with mitotane.Mitotane toxicity was present in all patients (100%). Two (7.7%) patients developed 1–3 adverse events, 15 (57.7%) experienced 4–6 adverse events and 9 (34.6%) patients had more than 6 adverse events. Two (7.7%) patients discontinued mitotane due to adverse events.Careful monitoring and timely management are essential for ensuring mitotane treatment adherence and maximizing its benefits. [ABSTRACT FROM AUTHOR]

Introduction: Adrenoleukodystrophy (ALD) patients exhibit three primary clinical phenotypes: primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral demyelination due to the accumulation of saturated very long-chain fatty acids in the adrenal cortex and central nervous system white matter and axons. We investigated the diagnosis of adrenal insufficiency (AI) and the use of mineralocorticoid treatment in male ALD patients. Methods: A retrospective chart review of electronic medical records was conducted for all ALD patients at a single institution between January 1, 2011, and December 6, 2021. Results: Among the 437 ALD patients, 82% were male and 18% were female. Of the male ALD patients, 60% (213 out of 358) had a diagnosis of AI, and 39% (84 out of 213) of those with AI were prescribed mineralocorticoid replacement therapy. Conclusion: AI is highly prevalent among ALD patients, with approximately 40% of those with a diagnosis of AI undergoing mineralocorticoid replacement therapy. Further research is warranted to delineate the characteristics of patients predisposed to developing mineralocorticoid deficiency within the context of ALD and AI. [ABSTRACT FROM AUTHOR]

The proopiomelanocortin (Pomc)‐derived peptides, including adrenocorticotropic hormone and α‐melanocyte stimulating hormone (α‐Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early‐onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation‐mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress‐induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early‐onset childhood obesity due to Pomc dysfunction. [ABSTRACT FROM AUTHOR]

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants. [Display omitted] Boonsawat et al. establish germline missense variants in the tumor suppressor gene ZNRF3 as a cause of neurodevelopmental disorders (NDDs) with microcephaly or macrocephaly, depending on the functional/domain-specific effects of the variants on Wnt/β-catenin signaling. This study finds that ZNRF3 haploinsufficiency does not cause NDDs but rather other phenotypes. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the risk of adverse events (AEs) in breast cancer patients treated with pembrolizumab combined with paclitaxel versus those receiving pembrolizumab or paclitaxel monotherapy, using the FDA Adverse Event Reporting System (FAERS) database. Methods: Data were extracted from the FAERS database for breast cancer patients treated with pembrolizumab combined with paclitaxel or with pembrolizumab or paclitaxel monotherapy from Q1 2016 to Q2 2023. Disproportionation analysis was performed by calculating the reporting odds ratio (ROR) with corresponding 95% confidence interval (95% CI), the information component (IC), and the lower bound of the information component 95% confidence interval (IC025) to identify potential safety signals. Results: No significant difference in AEs was observed between the combined treatment group and the pembrolizumab monotherapy group. However, the combined treatment group exhibited a substantial increase in AE risk compared to the paclitaxel monotherapy group. The most significant increases in AE risk were adrenal insufficiency (ROR = 189.94, 95% CI 25.41-1419.7, IC = 3.37, IC025 = 1.59), hypophysitis (ROR = 99.46, 95% CI 12.72-777.4, IC = 3.31, IC025 = 1.44), and myocarditis (ROR = 69.5, 95% CI 8.55-565.23, IC = 3.25, IC025 = 1.33). The time-to-event for combined treatment was 35 (34-70) days, for pembrolizumab was 43 (35-90) days, and for paclitaxel was 42 (37-76) days. The combination therapy group demonstrated significantly shorter intervals to the onset of adrenal insufficiency (p = 0.008), myocarditis (p < 0.001), and immune-related enterocolitis (p = 0.009). Conclusion: Analysis of the FAERS database indicates that combination therapy significantly elevates the risk of adrenal insufficiency, myocarditis, hypophysitis, and immune-related enterocolitis compared to paclitaxel monotherapy. These findings provide critical insights for clinicians in predicting and managing potential AEs associated with this treatment regimen. [ABSTRACT FROM AUTHOR]

Introduction: Variants in genes that play a role in maintaining cellular redox homeostasis in adrenocortical cells may be associated with glucocorticoid deficiency, and it is unclear whether these cases may be associated with a wider phenotype. However, to date, only 1 case of a genetic variant in thioredoxin reductase type 2 (TXNRD2) in a South Asian kindred with familial glucocorticoid deficiency has been reported. Case Presentation: The index case was diagnosed with selective glucocorticoid deficiency at 10 years of age. He had a history of a small penis and a right undescended testis, which subsequently required an orchidopexy. The parents were of Pakistani origin and first cousins. The boy's gonadal function was normal and autosomal recessive missense homozygous variants p.Val361Met;Val361Met in TXNRD2 were identified in him by whole-genome sequencing. Functional studies were performed using peripheral blood mononuclear cells from the patient, unaffected parents, and four age-matched healthy boys. Compared to the carriers and controls, the case had lower TXNRD2 protein on immunoblotting using anti-TXNRD2 antibody (1.3-fold), 95% CI: 1.8 (1.5–2.1), lower mRNA expression of TXNRD2 on quantitative RT-PCR (1.6-fold), 95% CI: 1.1 (0.7–1.4), and a lower glutathione:oxidized glutathione ratio (6.7-fold), 95% CI: 2.0 (1.6–2.4). Conclusions: In addition to confirming the critical role that TXNRD2 serves in maintaining adrenal function, by reporting the findings of atypical genitalia, this case further extends the phenotype. Established Facts: Nicotinamide nucleotide transhydrogenase (NNT) and TXNRD2 genes play a role in maintaining cellular redox homeostasis in adrenocortical cells and have been identified as genetic causes of glucocorticoid deficiency with or without mineralocorticoid deficiency. To date, a single report of familial glucocorticoid deficiency in a South Asian kindred has been described to be associated with a genetic variant in TXNRD2. [ABSTRACT FROM AUTHOR]

Objective To summarize the clinical characteristics and outcomes of corona virus disease 2019 (COVID-19) in patients with adrenal insufficiency (AI), and analyze the risk factors of outcomes. Methods The clinical data of COVID-19 patients with AI in Peking Union Medical College Hospital in December 2022 were analyzed retrospectively and the patients were followed up to collect outcomes of their diseases. Results Among 28 COVID-19 patients with AI, 20 cases (71.4%) received basal corticosteroid replacement. Among the 18 patients with community-acquired COVID-19, 11 cases (61.1%) increased the corticosteroid dosage proactively at home. The most common symptoms of COVID-19 were fever (96.4%), gastrointestinal symptoms (82.1%) and consciousness disturbance (78.6%). Occurrence of severe consciousness disturbance was associated with older age and lower basal corticosteroid replacement dose(P＜0.05). Adrenal crisis(AC) occurred in 20 patients(71.4%), which was associated with lower basal corticosteroid replacement dose, hypochloremia, lower eosinophil, lower platelet, and longer activated partial thromboplastin time(APTT)(P＜0.05). 2 patients died during hospitalization.26.3 % (5/19) of surviving patient′s recovered consciousness longer than 48 hours. Delayed recovery of consciousness was associated with lower systolic pressure, higher blood creatinine, and higher fibrinogen(P＜0.05). Long COVID-19 symptoms such as fatigue and poor appetite occurred in 48.0 % (12/25) of patients. Among patients with increased corticosteroid dosage, 50.0 % (12/24) had their dose reduced to baseline within 3 weeks. Conclusions COVID-19 patients with AI have a high frequency of consciousness disturbance and AC. AI patients are lack of awareness of adjusting corticosteroid dosage proactively in case of infection stress, thus education of “sick day rules” for AI patients should be strengthened in clinical practice. [ABSTRACT FROM AUTHOR]

Objective Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC. Methods Patients with hPCC due to pathogenic variants in RET , VHL , NF1 , MAX , and TMEM127 from 12 European centers (1974–2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality. Results The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA. In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET , VHL , and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09). Conclusion In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation. [ABSTRACT FROM AUTHOR]

Objective Primary hypophysitis might be challenging to diagnose, and there is a lack of evidence regarding optimal treatment strategies due to rarity of the disease. We aim to investigate the clinical features and compare the outcomes of different management strategies of primary hypophysitis in a large group of patients recruited on a nationwide basis. Design A retrospective observational study. Methods The demographic, clinical, and radiologic features and follow-up data were collected in study protocol templates and analyzed. Results One hundred and thirteen patients (78.8% female, median age: 36 years) were included. Lymphocytic (46.7%) and granulomatous hypophysitis (35.6%) were the prevailing subtypes out of 45 patients diagnosed after pathologic investigations. Headache (75.8%) was the most common symptom, and central hypogonadism (49.5%) was the most common hormone insufficiency. Of the patients, 52.2% were clinically observed without interventions, 18.6% were started on glucocorticoid therapy, and 29.2% underwent surgery at presentation. Headache, suprasellar extension, and chiasmal compression were more common among glucocorticoid-treated patients than who were observed. Cox regression analysis revealed higher hormonal and radiologic improvement rates in the glucocorticoid-treated group than observation group (hazard ratio, 4.60; 95% CI, 1.62-12.84 and HR, 3.1; 95% CI, 1.40-6.68, respectively). The main indication for surgery was the inability to exclude a pituitary adenoma in the presence of compression symptoms, with a recurrence rate of 9%. Conclusion The rate of spontaneous improvement might justify observation in mild cases. Glucocorticoids proved superior to observation in terms of hormonal and radiologic improvements. Surgery may not be curative and might be considered in indeterminate, treatment-resistant, or severe cases. [ABSTRACT FROM AUTHOR]

This literature review, in light of the presented case report, explores the complex interplay between gabapentin (GBP), a gamma-aminobutyric acid (GABA) analog, and the hypothalamic–pituitary–adrenal (HPA) axis in patients undergoing major surgical procedures. It specifically investigates the potential impact of GBP on cortisol levels, stress responses, and infection risk, illustrated by a detailed clinical case. This review combines a comprehensive literature search with a case report of a 17-year-old male with osteosarcoma who experienced transient adrenal insufficiency and infections while receiving GBP. The case is analyzed in the context of the existing literature on GBP and the HPA axis. The findings highlight the intricate relationship between GBP use, adrenal insufficiency, and infection susceptibility. It underscores the need for further research and clinical vigilance when prescribing GBP to patients with underlying medical conditions, particularly in the context of major surgical procedures. The review underscores the need for further research and clinical vigilance when prescribing GBP, particularly in perioperative settings. In conclusion, GBP's effects on the HPA axis and immune responses are complex and multifaceted. Clinicians should exercise caution when prescribing GBP, especially for patients with underlying conditions undergoing major surgery. Further research is needed to elucidate the mechanisms of GBP's influence on cortisol levels and stress responses. [ABSTRACT FROM AUTHOR]

Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype–phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database. [ABSTRACT FROM AUTHOR]

Adrenalectomy is the gold standard for canine adrenal tumours, but not always recommended due to patient age, underlying conditions and perioperative mortality. Ethanol ablation is an alternative in human medicine for poor surgical candidates. A 13‐year‐old neutered female toy‐poodle with hypercortisolism presented with severe haematuria. Ultrasonography revealed left adrenal and right kidney tumours. Due to high surgical risk, simultaneous laparotomic right nephroureterectomy and ethanol ablation of the left adrenal tumour were performed. Post‐ethanol injection complications included transient hypertension and arrhythmia, which resolved spontaneously. The adrenal tumour size decreased within 2.5 months, and cortisol levels normalised within 8 days, remaining stable for 12 months. No hypercortisolism signs were observed without trilostane until death from renal insufficiency. Autopsy showed that the ablated left adrenal gland was an adrenocortical tumour and had shrunk. Ethanol ablation may be a feasible alternative to adrenalectomy for high‐risk canine patients. [ABSTRACT FROM AUTHOR]

Background: 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. Aim: To review SST requesting patterns and practices across public hospitals in Queensland. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]