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Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , NCT03088540. Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1–31·8; 149 [52%] of 284 died) versus 13·3 months (10·5–16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46–0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2–8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3–6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42–0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1–9·3) and overall survival of 15·1 months (11·3–18·7). The most common grade 3–4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. Regeneron Pharmaceuticals and Sanofi. [ABSTRACT FROM AUTHOR]

Autoimmune Addison's disease (AAD) is treated with daily oral hormone replacements for cortisol and aldosterone. The current treatment is sub-optimal, and frequently results in supra- and infra-physiological cortisol levels that might negatively affect the brain and cognitive functioning. It is currently unclear if the brains of these patients need to be better protected. The present study investigates brain function during working memory in young adults with AAD compared to healthy controls. All participants (56 AAD (33 females), 62 controls (39 females), 19–43 years), underwent MRI brain scanning while performing a visuo-spatial and verbal working memory task. No main group differences in accuracy, reaction time or brain activity during the tasks were found. These findings suggest that patients perform equal to controls, and achieve similar levels of brain activity during working memory. However, variations in the patient population may have confounded this outcome. Controlled studies on larger cohorts are therefore needed to confirm these findings and test if having AAD affects the brain on the long term. • Brain activity during verbal and visuo-spatial working memory was assessed in patients with autoimmune Addison's disease. • Patients did not differ from healthy controls in performance on the working memory tasks. • Patients did not differ from healthy controls in brain activity during the working memory tasks. • Patients that experienced more mental fatigue had stronger activity in the cerebellum and occipital cortex. [ABSTRACT FROM AUTHOR]

Uncontrolled endocrine pathology can cause significant adverse complications during a patient's perioperative journey. With an ageing population, increasing comorbidity, and rising obesity rates, the incidence of endocrine disease in elective and emergency work is likely to increase. A thorough understanding of diagnosis and management perioperatively is essential to prevent any excess morbidity and mortality. The perioperative period may precipitate endocrine emergencies which require rapid diagnosis and life-saving treatments. This article will cover the management of diabetes, thyroid and adrenal disease in the perioperative period with reference to recently published national guidance. [ABSTRACT FROM AUTHOR]

• Reviewed various methods of detecting cortisol including electrochemical, etc. • Electrochemical immunosensing offered high sensitivity and low detection limits. • The review investigates the intricate connection between cortisol and cancer. • In-silico modeling, and machine learning were covered for cortisol detection. • Stress monitoring and healthcare advancement through cortisol detection. Cortisol, a crucial steroid hormone synthesized by the adrenal glands, has diverse impacts on multiple physiological processes, such as metabolism, immune function, and stress management. Disruption in cortisol levels can result in conditions like Cushing's syndrome and Addison's disease. This review provides an in-depth exploration of cortisol, covering its structure, various forms in the body, detection methodologies, and emerging trends in cancer treatment and detection. Various techniques for cortisol detection, including electrochemical, chromatographic, and immunoassay methods were discussed and highlighted for their merits and applications. Electrochemical immunosensing emerges as a promising approach, which offered high sensitivity and low detection limits. Moreover, the review delves into the intricate relationship between cortisol and cancer, emphasizing cortisol's role in cancer progression and treatment outcomes. Lastly, the utilization of biomarkers, in-silico modeling, and machine learning for electrochemical cortisol detection were explored, which showcased innovative strategies for stress monitoring and healthcare advancement. [ABSTRACT FROM AUTHOR]

In human patients with hypoadrenocorticism, a secondary dilated cardiomyopathy is noted that has been reported to resolve with replacement steroid therapy. A similar secondary dilated cardiomyopathy in dogs with hypoadrenocorticism has not been previously described. We present three dogs concurrently diagnosed with hypoadrenocorticism and ventricular dilation with systolic dysfunction. Two dogs were presented with clinical signs consistent with biventricular congestive heart failure and a third dog was presented with signs of acute hypoadrenocorticism without congestive heart failure. All dogs recovered to normal cardiac size and function with therapy. Hypoadrenocorticism should be considered as a differential diagnosis in dogs that present with ventricular dilation and systolic dysfunction if there are other indicators in the clinical and laboratory testing. Additionally, a thorough cardiac evaluation should be recommended for dogs that are found to have a heart murmur at the time of diagnosis of hypoadrenocorticism. [ABSTRACT FROM AUTHOR]

• Genetic susceptibility to vitiligo links to multiple autoimmune diseases via blood metabolites. • Integrating metabolomic and genomic data unveils vitiligo's etiological links with immunological conditions. • Discoveries yield diagnostic markers and treatment targets for vitiligo and related autoimmune diseases. This study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites. We performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases. Our findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08–1.27), psoriasis (OR 1.10; 95 % CI 1.04–1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23–1.63), pernicious anemia (OR 1.23; 95 % CI 1.12–1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11–1.26), alopecia areata (OR 1.22; 95 % CI 1.10–1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12–1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated. We substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities. [ABSTRACT FROM AUTHOR]

• X-linked adrenoleukodystrophy is caused by mutations in the gene, ABCD1. • p.Arg163Cys substitution caused by c.487C>T in exon 1 is a novel missense mutation. • There is no correlation between the genotype and phenotype of adrenoleukodystrophy. • Axonal neuropathy with multifocal demyelination is common in adrenoleukodystrophy. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder that primarily affects the white matter of central nervous system and the adrenal cortex. It is caused by mutations in the adenosine triphosphate-binding cassette, subfamily D, member 1 (ABCD1) gene that results in elevated plasma levels of very long chain fatty acids (VLCFAs). The disease is characterized by an unpredictable variation in phenotypic expressions, including childhood cerebral form (CCALD) and adrenomyeloneuropathy (AMN). Genetic analysis is a reliable method for the diagnosis of X-ALD. We reported a 46-year-old male admitted to Department of Neurology, Chang Gung Memorial Hospital with progressive paraparesis and Addison's disease, which was diagnosed when he was around 20-year-old. Plasma levels of VLCFA showed that his C26:0, C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated. A novel missense mutation (p.Arg163Cys) caused by the nucleotide change c.487C > T in exon 1 was identified in the ABCD1 gene of the proband and his subclinical family members. In this article, we reviewed the mutations that had been reported at the same position with different phenotypes. Given that the nerve conduction study (NCS) of the proband demonstrated a rare finding of demyelinating polyneuropathy with conduction blocks, we also reviewed the findings of NCS in patients with AMN in literature. [ABSTRACT FROM AUTHOR]

• 36 anti-anti-adrenal cortex autoantibodies (ACA) positive patients investigated. • Anti-ZnT8 autoantibodies (ZnT8A) are present in 19% of ACA positive patients. • 70% of these patients are associated with coexisting T1D regardless of age. • ZnT8A should be incorporated in the diagnosis of autoimmune Addison's patients. Patients with autoimmune Addison's disease (AAD) can develop other autoimmune diseases. They often display autoantibodies other than anti-adrenal cortex autoantibodies (ACA) which could be of interest in predicting the development of other diseases such as type 1 diabetes (T1D). Among the well-established autoantibodies associated with T1D, anti-ZnT8 autoantibodies (ZnT8A) could be found in absence of anti-GADA and anti-IA2A. Thus, the aim of our study was to evaluate the prevalence of ZnT8A in a cohort of AAD patients. The presence of ZnT8A was studied in 36 patients (19 children and 17 adults) displaying ACA. ZnT8A were detected in both children and adults with an overall prevalence of 19%. The results also indicated that ZnT8A were associated with coexisting T1D in more than 70% of this population regardless of age. Even if the titer of ZnT8A for the one third of patients without T1D was low, they have to be followed due to the potential risk of developing T1D. ZnT8A in those cases could also be a marker of autoimmunity associated to the adrenal gland destruction in AAD. As ZnT8A screening has been included in the diagnostic investigation of T1D, it should also be incorporated in the autoantibodies screening panel of the AAD population. [ABSTRACT FROM AUTHOR]

Corticosteroids have been used for the treatment of a great variety of diseases. Therefore, the relationship between high doses of cortisol and infections has been widely known and prophylactic therapy has been established. Adrenocortical carcinoma is a rare malignancy with poor prognosis, so little is known about how to deal with the complications resulting from hormone excess such as Cushing's syndrome. Here we report a case of an 82-year-old woman who presented with a 1-day history of dyspnea and was finally diagnosed as disseminated cryptococcosis at autopsy. The patient had received a diagnosis of metastatic adrenocortical carcinoma and Cushing's syndrome three months earlier. The findings of this study indicate the relation between severe hypercortisolemia due to adrenocortical carcinoma and opportunistic infections. In the setting of adrenocortical carcinoma with Cushing's syndrome, clinicians should maintain a high index of suspicion for opportunistic infections including cryptococcosis, which are potentially treatable by early detection and prompt intervention. [ABSTRACT FROM AUTHOR]

• A 73-year-old man had hyperpigmentation on the dorsum of the tongue. • His-symptoms were consistent with addison's disease from metastatic adrenal tumors. • Hyperpigmentation in addison's disease can occur anywhere due to various stimuli. • Hyperpigmentation could indicate susceptibility to acute adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Uncontrolled endocrine pathology can cause significant adverse complications during a patient's perioperative journey. With the ageing population, increasing comorbidity and rising obesity rates, the incidence of endocrine disease in elective and emergency work is likely to increase. A thorough understanding of diagnosis and management perioperatively is essential to prevent any excess morbidity and mortality. The perioperative period may precipitate endocrine emergencies which require rapid diagnosis and life-saving treatments. This article will cover the management of diabetes, thyroid and adrenal disease in the perioperative period. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. In this study, we performed Sanger sequencing of AIRE in Iranian patients to identify different variants and probable new mutations corresponding to a clinical diagnosis of APS-1. After analyzing 14 AIRE exons, we detected a novel insertion mutation in exon 2 in a patient who presented with severe APS-1, Lys50AsnfsX168. Furthermore, the known mutations in AIRE , including Arg139X, Arg257X, and Leu323SerfsX51, were detected in enrolled patients. According to our results, sequencing analysis of AIRE provides a useful screening method to diagnose patients with incomplete or unusual clinical presentations of APS-1. [ABSTRACT FROM AUTHOR]

Chronic adrenal insufficiency (AI) is an established risk factor for adrenal crisis (AC). However, the proportion of patients with newly diagnosed chronic AI during admission for AC is unclear. This retrospective cohort study used a Japanese claims database involving 7.39 million patients at 145 acute care hospitals between 2003 and 2014. Study patients with AC met these criteria: 1) newly coded in claims as AI; 2) glucocorticoid therapy administered; 3) admission; and 4) age ≥ 18 years. We investigated the prevalence of underlying chronic AI and assessed in-hospital mortality. Additionally, we explored risk factors for in-hospital mortality through multivariate analysis using a Cox proportional hazards model. Among 504 patients with AC, chronic AI was diagnosed before and during admission in 73 (14.5%) and 86 (17.1%) patients, respectively. In-hospital mortality rates were 1.4% and 5.8%, respectively, lower than that of the total population (14.1%). Significant risk factors for increased mortality were: age (hazard ratio [HR] 1.45/10 years; 95% confidence interval [CI] 1.17–1.78), requiring mechanical ventilation (HR 3.81; 95% CI 1.88–7.72), vasopressor administration (HR 2.05; 95% CI 1.16–3.64), sepsis (HR 3.79; 95% CI 1.57–9.14), AI-related symptoms (HR 2.00; 95% CI 1.02–3.93), and liver disease (HR 3.24; 95% CI 1.10–9.58). Relative to patients without chronic AI, those diagnosed before admission tended to survive to discharge; however, the difference with those diagnosed during admission was not significant. Hospital admission due to nonspecific AI-related symptoms was associated with an increased risk of in-hospital mortality. • Adrenal crisis may indicate underlying chronic adrenal insufficiency. • The proportions of newly- versus previously-diagnosed chronic AI cases were similar. • Pre-existing chronic AI is related to a favorable outcome. • AI-related symptoms are a significant risk factor for in-hospital death. [ABSTRACT FROM AUTHOR]

Autoantibodies directed against the P450 side chain cleavage enzyme (P450scc) have been recently described in dogs affected with hypoadrenocorticism, consistent with an immune-mediated pathogenesis of this endocrinopathy. In human autoimmune Addison’s disease, autoantibodies may have a predictive value, being detectable before clinical signs developing, and have been shown to persist for a period of time after diagnosis. Furthermore, an autoantibody positive status post-diagnosis has been associated with successful remission of Addison’s disease following B-cell depletion, suggesting active immunopathology in these cases. The current study was designed to investigate changes in serum P450scc autoantibody status over time in dogs diagnosed with spontaneous hypoadrenocorticism. P450scc autoantibodies were measured using a species-specific radioimmunoprecipitation assay in an initial cohort of 213 dogs, indicating a prevalence of 24%. Thirty two of these dogs had repeat samples (n = 80 in total) available for analysis. Five dogs were consistently P450scc autoantibody positive in all samples, for up to 425 days following first sampling. Three dogs were initially autoantibody positive, then became seronegative at later time points. One dog, a 1 year old female entire standard poodle, was initially negative for P450scc autoantibodies, but seroconverted 18 months after diagnosis. The remaining 23 dogs with multiple samples available were consistently P450scc autoantibody negative. Persistence was not associated with sex (p = .673). This study demonstrates persistence of P450scc autoantibodies in a subset of dogs affected with hypoadrenocorticism and seroconversion over one year post-diagnosis. P450scc autoantibody reactivity in human autoimmune Addison’s disease has been associated with sex, with females having a higher prevalence, possibly due to P450scc expression in the ovary acting as an additional source of antigenic stimulation. However, there was no sex difference in autoantibody persistence in the dogs affected with hypoadrenocorticism. Autontibody persistence in dogs with hypoadrenocorticism might represent persistent pathology, due to residual antigenic stimulation and autoimmune inflammation in the adrenal gland. [ABSTRACT FROM AUTHOR]

Addison’s disease is a rare autoimmune disorder leading to adrenal insufficiency and life-long glucocorticoid dependency. Vitamin D receptor (VDR) polymorphisms and vitamin D deficiency predispose to Addison’s disease. Aim of the current study was, to investigate potential anti-inflammatory vitamin D effects on monocytes in Addison’s disease, focusing on inflammatory CCL-2 and IL6 , as well on monocyte CD14 markers. Addison’s disease is genetically linked to distinct HLA susceptibility alleles. Therefore we analyzed, whether HLA genotypes differed for vitamin D effects on monocyte markers. CD14 + monocytes were isolated from Addison’s disease patients (AD, n = 13) and healthy controls (HC, n = 15) and stimulated with 1,25-dihydroxyvitamin D 3 and IL1β as an inflammatory stimulant. Cells were processed for mRNA expression of CCL-2, IL6 and CD14 and DNA samples were genotyped for major histocompatibility class (MHC) class II-encoded HLA- DQA1-DQB1 haplotypes. We found a downregulation of CCL-2 after vitamin D treatment in IL1β-stimulated monocytes both from AD patients and HC (AD p < 0.001; HC p < 0.0001). CD14 expression however, was upregulated in both HC and AD patients after vitamin D treatment (p < 0.001, respectively). HC showed higher CD14 transcription level than AD patients after vitamin D treatment (p = 0.04). Compared to IL1β-induced inflammation, HC have increased CD14 levels after vitamin D treatment (p < 0.001), whereas the IL1β-induced CD14 expression of AD patients’ monocytes did not change after vitamin D treatment (p = 0.8). AD patients carrying HLA high-risk haplotypes showed an increased CCL-2 expression after IL1β-induced inflammation compared to intermediate-risk HLA carriers (p = 0.05). Also HC monocytes’ CD14 transcription after IL1β and vitamin D co-stimulation differed according to HLA risk profile. We show that vitamin D can exert anti-inflammatory effects on AD patients’ monocytes which may be modulated by HLA risk genotypes. [ABSTRACT FROM AUTHOR]

Patients with autoimmune Addison's disease (AAD) are unable to produce glucocorticoids (GCs), mineralocorticoids (MCs) and androgens from the adrenal cortex and therefore require life-long treatment with GCs and MCs. Due to the sensitivity of the brain to cortisol and androgens, brain function might be affected in patients, as the replacement regime cannot mimic the natural rhythmicity of hormonal secretion. Alterations in brain function might predispose to cognitive or mood disturbances. The present study investigated resting-state functional connectivity (rs-fc) in patients with AAD. Resting-state fMRI data was collected from 57 (33 females) patients with AAD and 69 (39 females) control participants, aged 19-43 years. Resting-state brain networks were identified with independent component analysis (FSL MELODIC). Dual-regression analysis was applied to test for group differences in rs-fc in these networks. Within the patient group we tested the association between rs-fc and glucocorticoid replacement dose in mg/m2/day. Significant clusters were identified with threshold free cluster enhancement and considered to be significant at p<0.05. Patients with AAD had increased fc in the bilateral medial orbitofrontal cortex compared to controls. A higher glucocorticoid replacement dose was associated with stronger functional connectivity in several networks in the prefrontal cortex in patients. AAD seems to be associated with stronger fc at rest in an area known to contain a high density of GC receptors. Further research is needed to investigate if this increased activity is part of an adaptive mechanism or if it predisposes to disturbances in mood and executive functioning. [ABSTRACT FROM AUTHOR]

Background X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with leukodystrophy, myeloneuropathy and adrenocortical insufficiency. We performed a retrospective cohort study to evaluate long-term outcome of patients with X-ALD. Method All patients with X-ALD diagnosed between 1989 and 2012 were included. Electronic patient charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, neuroimaging, long-term outcome and treatment. Results Forty-eight patients from 18 unrelated families were included (15 females; 33 males). Seventeen patients were symptomatic at the time of the biochemical diagnosis including 14 with neurocognitive dysfunction and 3 with Addison disease only. Thirty-one asymptomatic individuals were identified by positive family history of X-ALD. During follow-up, eight individuals developed childhood cerebral X-ALD (CCALD), one individual developed adrenomyeloneuropathy (AMN), six individuals developed Addison disease only, and five individuals remained asymptomatic. Direct sequencing of ABCD1 confirmed the genetic diagnosis in 29 individuals. Seven patients with CCALD underwent hematopoietic stem cell transplantation (HSCT). Nine patients lost the follow-up. There was no correlation between clinical severity score, Loes score and elevated degree of elevated very long chain fatty acid (VLCFA) levels in CCALD. Conclusion Our study reports forty-eight new patients with X-ALD and their long-term outcome. Only 35% of the patients presented with neurological features or Addison disease. The remaining individuals were identified due to positive family history. Close monitoring of asymptomatic males resulted in early HSCT to prevent progressive lethal neurodegenerative disease. Identification of patients with X-ALD is important to improve neurodevelopmental outcome of asymptomatic males. [ABSTRACT FROM AUTHOR]

Objectives Recent guidelines recommend a diagnosis of adrenal insufficiency when a stimulated peak cortisol level falls below 500 nmol/L. This may not be valid using a highly specific cortisol immunoassay or liquid chromatography-mass spectroscopy (LCMS/MS). We sought to determine the diagnostic threshold for adrenal insufficiency using a new and widely available, highly specific cortisol immunoassay. Design All patients having a dynamic test of adrenal reserve had results measured using the historical cortisol assay (Roche Cortisol) and the newer assay (Roche Cortisol II). Measurements Subjects were categorized according to the traditional assay (normal > 500 nmol/L) with clinical case adjudication where necessary. Results from Cortisol II assay were concomitantly measured along with cortisol levels measured by LCMS/MS. ROC curve analysis was performed to generate new diagnostic thresholds. Results The Roche Cortisol II compared favourably with measures by LCMS/MS, generating cortisol levels approximately 30% lower than the older immunoassay. Many normal subjects had peak cortisols as low as 300 nmol/L with Cortisol II. The optimized diagnostic threshold for adrenal insufficiency was 350 nmol/L with a sensitivity of 91% and specificity 97%. Use of the old diagnostic threshold with the Cortisol II assay would have inappropriately doubled the rate of patient-classification as adrenal insufficient. Conclusions Transition to a more specific cortisol assay requires revision of diagnostic thresholds for dynamic tests of adrenal insufficiency. With the Roche Cortisol II assay, a cut-off of 350 nmol/L should replace the traditional 500 nmol/L although some healthy subjects may be very close to this level. [ABSTRACT FROM AUTHOR]

Background Standard replacement therapy for Addison’s disease (AD) does not restore a normal circadian rhythm. Periods of sub- and supra- physiological cortisol levels experienced by patients with AD likely induce disrupted sleep. Given that healthy sleep plays an important role in memory consolidation, the novelty of the current study was to characterise, using objective measures, the relationship between sleep and memory in patients with AD, and to examine the hypothesis that poor sleep is a biological mechanism underlying memory impairment in those patients. Methods We used a within-subjects design. Ten patients with AD and 10 matched healthy controls completed standardised neuropsychological tests assessing declarative memory (Rey Auditory Verbal Learning Test) and procedural memory (Finger Tapping Task) before and after a period of actigraphy-measured sleep, and before and after a period of waking. Results Relative to healthy controls, patients with AD experienced disrupted sleep characterised by poorer sleep efficiency and more time spent awake. Patients also showed impaired verbal learning and memory relative to healthy controls ( p = 0.007). Furthermore, whereas healthy controls’ declarative memory performance benefited from a period of sleep compared to waking ( p = 0.032), patients with AD derived no such benefit from sleep ( p = 0.448). Regarding the procedural memory task, analyses detected no significant between-group differences (all p ’s < 0.065), and neither group showed significant sleep-enhanced performance. Conclusions We demonstrated, using actigraphy and standardized measures of memory performance, an association between sleep disturbances and cognitive deficits in patients with AD. These results suggest that, in patients with AD, the source of memory deficits is, at least to some extent, disrupted sleep patterns that interfere with optimal consolidation of previously-learned declarative information. Hence, treating the sleep disturbances that are frequently experienced by patients with AD may improve their cognitive functioning. [ABSTRACT FROM AUTHOR]

• Chronic corticosterone treatment induced hyperacusis and active sound avoidance. • DPOAE, cochlear CAP and acoustic startle reflex unaffected by corticosterone. • Corticosterone induced sound-evoked hyperactivity in auditory cortex. • Glucocorticoid receptors upregulated in auditory cortex by corticosterone. • Corticosterone disrupted the HPA axis and blunted the reactive stress response. Hyperacusis, a debilitating loudness intolerance disorder, has been linked to chronic stress and adrenal insufficiency. To investigate the role of chronic stress, rats were chronically treated with corticosterone (CORT) stress hormone. Chronic CORT produced behavioral evidence of loudness hyperacusis, sound avoidance hyperacusis, and abnormal temporal integration of loudness. CORT treatment did not disrupt cochlear or brainstem function as reflected by normal distortion product otoacoustic emissions, compound action potentials, acoustic startle reflexex, and auditory brainstem responses. In contrast, the evoked response from the auditory cortex was enhanced up to three fold after CORT treatment. This hyperactivity was associated with a significant increase in glucocorticoid receptors in auditory cortex layers II/III and VI. Basal serum CORT levels remained normal after chronic CORT stress whereas reactive serum CORT levels evoked by acute restraint stress were blunted (reduced) after chronic CORT stress; similar changes were observed after chronic, intense noise stress. Taken together, our results show for the first time that chronic stress can induce hyperacusis and sound avoidance. A model is proposed in which chronic stress creates a subclinical state of adrenal insufficiency that establishes the necessary conditions for inducing hyperacusis. [ABSTRACT FROM AUTHOR]

Background Increased frequency of glucose intolerance, dyslipidaemia, and obesity has been reported in subjects treated for adrenocortical failure (Addison's disease, AD). Glucocorticoid substitution is difficult to adjust and patients display variable responses to steroid dosage. Since local regeneration markedly contributes to the available cortisol pool, the activity of 11β-hydroxysteroid dehydrogenase type 1 ( HSD11B1 gene) may be involved in adverse metabolic profile. Our aim was to explore if HSD11B1 polymorphisms might impact on individual requirements for glucocorticoid replacement and its metabolic effects. Methods This cross-sectional analysis comprised 152 AD patients (aged 47.1 ± 15.1 years) receiving regular glucocorticoid substitution. Their daily hydrocortisone dosage (mean 25.5 ± 5.5 mg) had been based upon clinical features. Stratification by the HSD11B1 genotypes (rs846910, rs3753519 and rs12086634) enabled comparisons with regard to patients' anthropometric, hormonal, and metabolic characteristics. Results In rs3753519-stratified analysis, carriers of the minor allele presented significantly increased BMI ( p < 0.001), fasting plasma glucose ( p < 0.001) and HOMA-IR ( p = 0.021) compared to the wild-type homozygotes, although the HOMA-IR association disappeared when adjusted for age, gender, BMI, and hydrocortisone dose. In contrast, homozygous carriers of two common rs12086634 alleles displayed elevated serum triglycerides ( p = 0.035), total, and LDL cholesterol ( p = 0.001 and 0.003, respectively) but only total cholesterol association survived after correction for multiple comparisons. Finally, no association of rs846910 with any clinical or laboratory parameter was found. Conclusion Our study provides support for plausible implication of the HSD11B1 polymorphisms in susceptibility to develop undesirable effects of glucocorticoid replacement. Further analyses are warranted to validate the role of HSD11B1 variants in clinical practice. [ABSTRACT FROM AUTHOR]

The number of women with endocrine conditions embarking on pregnancy is growing as more choose to delay conception or require assisted reproduction techniques. It is therefore increasingly important for clinicians to have an understanding of common endocrine disorders and how these may impact on pregnancy and fetal development. Over-investigation and subsequent medicalization and treatment of sub-clinical endocrine conditions, which have uncertain clinical impact for the fetus or mother, is a cause for concern and debate surrounding this practice is ongoing. Vitamin D deficiency is increasing in prominence due to the rise in childhood rickets; this startling re-emergence has led to more work on the prevalence of vitamin D deficiency and identified a higher than expected percentage of women affected. For this reason, national advice has called for routine vitamin D supplementation in pregnancy, and diagnosis and treatment of those most at risk. This review also briefly discusses the management of other rarer endocrine conditions, which can lead to significant maternal and fetal morbidity if the diagnosis is delayed or overlooked. [ABSTRACT FROM AUTHOR]

Background and Aims Allgrove syndrome is characterized by achalasia, alacrima, and adrenal insufficiency as well as being associated with progressive neurological signs. This is an autosomal recessive disorder due to mutations in the AAAS gene located on chromosome 12q13. The AAAS gene encodes a protein of 546 amino acids, ALADIN. Mutations in this genwere reported in families from North Africa and Europe. Our objective is to conduct a clinical, molecular and genetic study of 26 Tunisian patients with Allgrove syndrome. Methods We report 26 Tunisian patients with between two and four clinical features associated with Allgrove syndrome. Blood samples were collected and isolated DNA derived from subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR and sequencing. PCR-RFLP method was performed to identify the frequent mutations found. Results Sequencing of the AAAS gene revealed a major homozygous mutation (c.1331+1G>A) in 25 patients and R286X mutation in one patient. The presence of a major mutation in several unrelated affected individuals suggests the presence of a founder effect in Tunisia and allows for a fast and targeted molecular diagnosis. Conclusions We created an easy and rapid molecular enzymatic protocol based on PCR-RFLP using MvaI restriction enzyme that directly targets this major mutation and can be used for prenatal diagnosis and genetic counseling for Tunisian families at risk. To the best of our knowledge, this is the first major series report of Allgrove syndrome in Tunisia. [ABSTRACT FROM AUTHOR]

Background The brain is a major target organ for cortisol considering its high density of glucocorticoid receptors. Several states of hypothalamus–pituitary–adrenal dysregulation point towards impairments in cognitive functioning. However, there is a very limited body of research on the effects of hypocortisolism on cognitive functioning. Aim To evaluate cognitive functioning in patients with hypocortisolism (i.e., primary adrenal insufficiency (PAI)) and to examine the possible effect of postponing early-morning hydrocortisone intake on cognitive functioning. Methods Thirty-one patients with PAI on regular morning hydrocortisone intake and 31 healthy matched controls underwent nine neuropsychological tests, evaluating memory and executive functioning. In addition, the effect of normal timing and postponement of morning hydrocortisone intake on neuropsychological tests were assessed in an additional 29 patients with PAI. Results Compared to controls, patients with PAI performed worse on auditory and visual memory tasks (all P ≤ 0.024) and executive functioning tasks (all P ≤ 0.012). In contrast, patients performed better on a concentration and an attention task (both P < 0.05). Postponement of hydrocortisone intake in the morning did not affect the outcomes of neuropsychological tests. Conclusion Patients on long-term hydrocortisone replacement for PAI show mild cognitive deficits compared to controls. There was no effect of postponement of regular hydrocortisone intake on cognition. [ABSTRACT FROM AUTHOR]

Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. In fact, hydrocortisone replacement in AD patients likely induces disrupted sleep. Given that healthy sleep plays an important role in improving quality of life, optimizing cognition, and ensuring affect regulation, the aim of this study was to investigate whether poor quality of life, mood alterations, and memory complaints reported by AD patients are associated with their disrupted sleep patterns. Sixty patients with AD and 60 matched healthy controls completed a battery of self-report questionnaires assessing perceived physical and mental health (Short-Form 36), mood (Beck Depression Inventory—II), sleep quality (Pittsburgh Sleep Quality Index), and cognition (Cognitive Failures Questionnaire). A latent variable model revealed that although AD had a significant direct effect on quality of life, the indirect effect of sleep was significantly greater. Furthermore, although AD had no direct effect on cognitive functioning, the indirect effect of sleep was significant. The overall model showed a good fit (comparative fit index = 0.91, root mean square of approximation = 0.09, and standardized root mean square residual = 0.05). Our findings suggest that disrupted sleep, and not the disease per se, may induce poor quality of life, memory impairment, and affect dysregulation in patients with AD. We think that improving sleep architecture may improve cognitive, affective, and physical functioning. [ABSTRACT FROM AUTHOR]

Summary Background Patients with primary adrenal insufficiency (AI) need to replace glucocorticoids and mineralocorticoids that act on glucocorticoid (GR) and mineralocorticoid receptors (MR). Both receptors are highly expressed in the hippocampus and are closely associated with cognitive function, which might be impaired by insufficient or increased GR and MR stimulation. However, little is known about cognitive function in patients with AI. Methods It was examined whether patients with AI exhibit worse cognitive function compared to sex-, age-, and education-matched controls. Cognitive function (executive function, concentration, verbal memory, visual memory, working memory, and autobiographical memory) was assessed in 30 patients with AI (mean age 52.4 yrs. ±14.4, n = 21 women, mean duration of illness 18.2 yrs. ±11.1) and 30 matched controls. We also measured depressive symptoms, body mass index (BMI), and blood pressure. Results Patients with AI showed more depressive symptoms, had a greater BMI and lower systolic blood pressure compared to controls. Adjusted analyses controlling for these variables revealed that patients with AI performed significantly worse in verbal learning ( F = 7.8, p = .007). Executive function, concentration, working memory, verbal memory, visuospatial memory, and autobiographical memory did not differ between groups. Conclusions No clinically relevant cognitive impairment was found in patients with AI compared to matched controls. Even long-term glucocorticoid and mineralocorticoid substitution over almost two decades appears to have only subtle effects on cognition in patients with AI. [ABSTRACT FROM AUTHOR]

Adrenal insufficiency (glucocorticoid deficiency) comprises a group of rare diseases, including primary adrenal insufficiency, secondary adrenal insufficiency and congenital adrenal hyperplasia. Lifesaving glucocorticoid therapy was introduced over 60 years ago, but since then a number of advances in treatment have taken place. Specifically, little is known about short- and long-term treatment effects, and morbidity and mortality. Over the past decade, systematic cohort and registry studies have described reduced health-related quality of life, an unfavourable metabolic profile and increased mortality in patients with adrenal insufficiency, which may relate to unphysiological glucocorticoid replacement. This has led to the development of new modes of replacement that aim to mimic normal glucocorticoid physiology. Here, evidence for the inadequacy of conventional glucocorticoid therapy and recent developments in treatment are reviewed, with an emphasis on primary adrenal insufficiency. [ABSTRACT FROM AUTHOR]

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Abstract: We described a 38-year-old woman of rapidly progressive dementia with white matter encephalopathy and death. She had Addison's disease but the adrenal glands were hyperplastic. Brain magnetic resonance imaging revealed diffuse white matter lesion predominantly in the frontal lobe with band-like contrast enhancement. l-Methyl-11C-methionine positron emission tomography revealed accumulation of tracer in bilateral frontal lobes. Stereotactic biopsy demonstrated demyelination changes. A number of urinary organic acids were elevated. Adrenoleukodystrophy was diagnosed by elevated plasma very long chain fatty acid and ABCD1 gene mutation (C1544C/T). Adrenoleukodystrophy should be considered as a differential diagnosis in women with rapidly progressive white matter encephalopathy. [Copyright &y& Elsevier]

Highlights: [•] Abnormal DNA methylation is frequently observed in autoimmune diseases. [•] We identified multiple differentially methylated regions (DMRs) in AAD patients. [•] We used DNA from CD4+ T cells in combination with MeDIP. [•] Many of the DMRs localized to genes involved in immune regulation and autoimmunity. [ABSTRACT FROM AUTHOR]

Abstract: Autoimmune adrenalitis, or autoimmune Addison disease (AAD), is the most prevalent cause of primary adrenal insufficiency in the developed world. AAD is rare and can easily be misdiagnosed as other conditions. The diagnosis depends on demonstrating inappropriately low cortisol production and the presence of high titers of adrenal cortex autoantibodies (ACAs), along with excluding other causes of adrenal failure using other tests as necessary. The treatment corticosteroid replacement, and the prognosis following the treatment is the same as the normal population. Spontaneous recovery of adrenal function has been described but is rare. [Copyright &y& Elsevier]

Abstract: Autoimmune polyendocrine syndromes (APS), also called polyglandular autoimmune syndromes (PGAS), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organs, although non-endocrine organs can be affected. The two major autoimmune polyendocrine syndromes, (type1–type2/APS-1 and APS-2), both have Addison's disease as a prominent component. Further autoimmune polyendocrine syndromes include APS3 and APS4. The major autoimmune polyendocrine syndromes have a strong genetic component with the type 2 syndrome occurring in multiple generations and the type I syndrome in siblings. It is well recognized that more than 20years may elapse between the onset on one endocrinopathy and the diagnosis of the next, for example, almost 40–50% of subjects with Addison's disease will develop an associated endocrinopathy. The discovery of the polyendocrine autoimmune syndromes offered the possibility to understand autoimmune disorders with particular interest for type 1A diabetes and the neuroendocrine immunology (NEI) is further contributing to understand the links. [Copyright &y& Elsevier]

Sub-optimal replacement of glucocorticoids (GC) in autoimmune Addison's disease (AAD) may affect cognitive functioning. The present study therefore sought to investigate cognitive performance and self-reported problems with executive functions in a cohort of young adult patients with AAD. 67 patients with AAD (39 females), mean age 32 yrs. (range 19–41), and 80 control participants (43 females), mean age 29 yrs. (range 19–43), completed neuropsychological tests estimating verbal and non-verbal intellectual ability, learning, memory and executive functioning, in addition to self-report scales assessing problems with executive functions, fatigue and symptoms of anxiety and depression. Patients performed within the average range on all cognitive tests compared to population norms. However, female AAD patients reported more problems than controls with both hot (emotion regulation) and cold (cognitive regulation) executive functions in daily life. Moreover, experienced problems with executive functions in both male and female patients were associated with increased mental fatigue and lower GC replacement doses. Despite average performance in neuropsychological tests by both sexes, young adult female patients with AAD experience problems with executive functions in daily life. Coping with mental fatigue and optimization of pharmacotherapy may be important factors to be addressed in order to provide timely support for patients. Future research is needed to further determine other risk factors for experiencing executive function impairments in AAD. • We compared patients with Autoimmune Addison's disease (AAD) to healthy controls. • Patients did not differ from controls on a range of cognitive tests. • Female patients reported to experience problems with executive function. • Experienced problems correlated with mental fatigue and a lower medication dose. [ABSTRACT FROM AUTHOR]

Extramedullary hematopoiesis occurs in the setting of hematologic disorders or malignancies when the activity of the bone marrow is insufficient to generate blood cells. We report a unique case of adrenal extramedullary hematopoiesis diagnosed in a 16 year old female with a history of anti-Diego antibody and congenital dyserythropoietic anemia. She presented with an enlarging adrenal mass and underwent surgical resection. Pathology revealed extramedullary hematopoiesis. On literature review, we identified only two prior existing cases of adrenal extramedullary hematopoiesis in pediatric patients, with no prior case reports of adrenal extramedullary hematopoiesis occurring in patients with anti-Diego antibody or in those with congenital dyserythropoietic anemia. [ABSTRACT FROM AUTHOR]

To the Editor: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by glucocorticoid deficiency and increased adrenocorticotropic hormone (ACTH) with absence of mineralocorticoid deficiency.[1] The 18-month-old girl was taken to the pediatric clinic due to fever persisting for 1 day and cyanotic lips after birth. Plasma renin-aldosterone activity and gonadal hormones were normal, and cranial, uterus, and ovary ultrasonography results were normal. [Extracted from the article]

This article describes a case of confirmed adrenocorticotropic hormone (ACTH)-secreting macroadenoma in Addison's disease due to adrenal tuberculosis. The patient was a 58-year-old woman with Addison's disease who presented with headache and blurred vision over two months. Endocrine tests revealed elevated plasma ACTH. Lumbar spine X-ray showed fusion of the L4-S1 vertebrae, consistent with previous tuberculosis infection.

Summary: Hypoadrenocorticism or Addison's disease (AD) is a functional disorder in which insufficient mineralocorticoid and glucocorticoid hormones are produced by the adrenal cortex. Human AD is usually attributed to lymphoplasmacytic adrenalitis with autoimmune destruction of the adrenal cortex. Lymphoplasmacytic adrenalitis is also reported in some descriptions of canine AD; however, the histological aspects of adrenalitis or adrenocortical atrophy have not been well characterized because microscopical examination is not required for diagnosis of AD. In this study, sections of adrenal glands from 33 dogs with adrenalitis were compared with those of 37 dogs without adrenal lesions. The affected dogs were classified clinically as having AD (n = 3), being suspected of having AD (n = 17), not having AD (n = 11) or were unclassified (n = 2). The adrenal inflammation was lymphoplasmacytic in 17 dogs, lymphocytic in four, lymphohistiocytic in one, granulomatous in three and neutrophilic in eight cases. Adrenal glands from control dogs lacked leucocyte infiltration and had a cortical to medullary area ratio of 1.1–7.2. All three dogs with AD, 8/17 dogs with suspected AD and 1/11 dogs without AD had a cortical to medullary area ratio <1.1. Because the area ratio was correlated (r = 0.94) with a linear cortical to medullary thickness ratio, a thickness ratio <1.1 could also indicate severe adrenocortical atrophy. Severe adrenocortical atrophy was associated typically with lymphoplasmacytic infiltration and nearly complete loss of cortical cells; however, the zona glomerulosa was partially spared in three dogs with lymphoplasmacytic adrenalitis and severe cortical atrophy. In contrast, non-lymphoid inflammation was generally part of systemic disease, multifocal and was unaccompanied by severe adrenocortical atrophy. [Copyright &y& Elsevier]

The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations that are features of the syndrome, including insulin resistance, central obesity, and hyperlipidaemia. Clinical practice must integrally evaluate the effects of the intricate and tight relationship between the liver and the endocrine system, in order to better address all manifestations, complications, and prevent deterioration of one or the other organ-system. [ABSTRACT FROM AUTHOR]

Abstract: Endocrine disorders are commonly encountered in pregnancy. To optimize pregnancy outcome, it is essential to understand the physiology underlying these conditions. Clinicians should be aware of which investigations are required for diagnosis and monitoring during pregnancy as well as current guidance on which treatments are safe to use. The most common endocrine disorder encountered in pregnancy is diabetes, followed by hypo and hyperthyroidism. Rarer endocrine disorders including pituitary dysfunction, adrenal and parathyroid disease are as important to be aware of due to the potential for significant maternal and fetal morbidity or mortality if not diagnosed or managed appropriately. Over recent years awareness of the potential adverse effects of vitamin D deficiency has driven the guidance for vitamin D supplementation for pregnant and lactating women. This review focuses on the physiology and current management of thyroid dysfunction and the rarer endocrine disorders in pregnancy, and includes current guidance on vitamin D supplementation. [Copyright &y& Elsevier]

Abstract: Corticosteroids emerged in the late 1940s, at a time when steroid chemistry began to offer new therapeutic approaches. Extractive chemistry (T. Reichstein), chemical synthesis (E.C. Kendall) and clinical investigations (P. Hench) were combined to result in the discovery of cortisone in 1948, leading to a long series of related derivatives. Besides their first applications to treat Addison''s disease and rheumatic or inflammatory diseases, corticosteroids could easily correct many metabolic and functional symptoms. Fluoridation of the steroid skeleton allowed the development of more active and better tolerated molecules. Corticosteroids have revolutionized the treatment of allergic diseases or immunity troubles, graft rejection, many dermatological, respiratory, digestive, eye diseases, etc. It is used today in all areas of therapeutic. [Copyright &y& Elsevier]

Recent studies have suggested an association between intestinal microbiota composition and human disease, however causality remains to be proven. With hindsight, the application of fecal transplantation (FMT) does indeed suggest a causal relation between interfering with gut microbiota composition and a resultant cure of several disease states. In this review, we aim to show the available evidence regarding the involvement of intestinal microbiota and human (autoimmune) disease. Moreover, we refer to (mostly case report) studies showing beneficial or adverse effects of fecal transplantation on clinical outcomes in some of these disease states. If these findings can be substantiated in larger randomized controlled double blind trials also implementing gut microbiota composition before and after intervention, fecal transplantation might provide us with novel insights into causally related intestinal microbiota, that might be serve as future diagnostic and treatment targets in human disease. [ABSTRACT FROM AUTHOR]

Abstract: Triple A (or Allgrove) syndrome is an autosomal recessive genetic disorder. Patients typically suffer from chronic adrenal insufficiency due to resistance to ACTH (Addison''s disease), achalasia of the cardia, and defective tear formation (alacrima). The syndrome is caused by mutations in the AAAS gene which encodes the protein ALADIN, a constituent of eukaryotic nuclear pore complexes. The multi-systemic nature and variable manifestations of the triple A syndrome often confound its diagnosis and limit our understanding of its exact pathogenesis. We performed mutational screening of the AAAS gene in a Greek family of four individuals, including an affected propositus with typical symptoms of late-onset triple A syndrome. Our results are consistent with an autosomal recessive pattern of inheritance within the family, caused by a functional c.43C>A mutation in exon 1 of the AAAS gene. All members of the family were also homozygous for a silent c.855C>T nucleotide change within exon 9 of the AAAS gene, representing a common single nucleotide polymorphism. The compromising c.43C>A mutation is predicted to cause a p.Gln15Lys amino acid substitution in the ALADIN protein. However, it has been suggested that the functional impact of this mutation may be more severe, causing a shift in the reading frame of AAAS gene via formation of an aberrant premature donor splice site within exon 1. We propose that mutational analysis of the AAAS gene should be considered in adult patients with one or more clinical signs of the disease, as diagnosis of late-onset cases can be ambiguous. [Copyright &y& Elsevier]

Abstract: Addison’s disease is a prototypic organ-specific autoimmune disease affecting the adrenal cortex. The CXC chemokine ligand 10 (CXCL10) is expressed early in viral infections, and is produced by primary adrenocortical cells stimulated by certain cytokines. CXCL10 is also elevated in the serum of Addison’s disease patients. We therefore investigated if the viral RNA substitute polyinosine–polycytidylic acid (poly (I:C)) could influence the cytokine induced production of CXCL10 by adrenocortical cells. We found that poly (I:C) could induce CXCL10 in NCI-H295R adrenocortical carcinoma cells, either alone or synergistically along with cytokines interferon-γ and tumor necrosis factor-α. This effect was found to be mediated by toll-like receptor 3 and both nuclear factor κB (NFκB) and signal transducer and activator of transcription-1 (STAT1), but not type I interferons, seemed to be involved. We propose that the combination of environmental and endogenous factors presented here, could contribute to the multifactorial pathogenesis of autoimmune Addison’s disease. [Copyright &y& Elsevier]