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Maternal primary adrenal insufficiency (PAI) during pregnancy, due to either Addison disease (AD) or congenital adrenal hyperplasia (CAH), is rare. Only few studies have examined the subsequent important outcomes of maternal glucocorticoid and mineralocorticoid deficiencies during pregnancy upon the fetus and the neonate. Therefore, this systematic review and meta-analysis evaluated the impact of these deficiencies, with data from PubMed/Medline, Cochrane/CENTRAL, and Google Scholar. A total of 31 studies were included for qualitative analysis and 11 for quantitative analysis. Studies examining the prevalence of spontaneous abortion, preterm birth, the occurrence of small for gestational age (SGA) neonates, as well as the neonatal birth weight were included. The systematic review revealed a substantial number of spontaneous abortions, preterm births and SGA neonates in pregnant women with PAI. The meta-analysis showed a mean spontaneous abortion prevalence of 18%, 18% and 17% in women with PAI, AD or CAH, respectively. The mean preterm birth prevalence was 11% when women with AD or CAH were analyzed together, and 13% and 9% in women with AD or CAH, respectively, when these women were analyzed separately. The mean prevalence of SGA neonates was 8% when women with AD or CAH were analyzed together, and 5% and 10% in women with AD or CAH, respectively, when these women were analyzed separately. The mean fetal birth weight was within normalcy in all women with PAI, as well as in women with AD or CAH. In conclusion the executed systematic review of 31 studies followed by a meta-analysis of 11 studies in pregnant women with PAI has shown a greater prevalence of pregnancies with negative outcome (spontaneous abortion, preterm birth) and of negative fetal outcome (SGA) in women with either AD or CAH, as compared to control pregnant women. [ABSTRACT FROM AUTHOR]

We describe a rare case of acute mania in the setting of autoimmune adrenalitis. A 41-year-old male with no previous psychiatric diagnoses presented with impulsivity, grandiosity, delusions of telepathy, and hyperreligiosity following a previous hospitalization for an acute adrenal crisis and 2 subsequent days of low-dose corticosteroid treatment. Workups for encephalopathy and lupus cerebritis were negative, raising concern that this presentation might represent steroid-induced psychosis. However, discontinuation of corticosteroids for 5 days did not resolve the patient's manic episode, suggesting that his clinical presentation was more likely new onset of a primary mood disorder or a psychiatric manifestation of adrenal insufficiency itself. The decision was made to restart corticosteroid treatment for the patient's primary adrenal insufficiency (formerly known as Addison disease), coupled with administration of both risperidone and valproate for mania and psychosis. Over the following 2 weeks, the patient's manic symptoms resolved, and he was discharged home. His final diagnosis was acute mania secondary to autoimmune adrenalitis. Although acute mania in adrenal insufficiency is quite rare, clinicians should be aware of the range of psychiatric manifestations associated with Addison disease so that they can pursue the optimal course of both medical and psychiatric treatment for these patients.

A man in his 20s with a history of acute disseminated encephalomyelitis (ADEM) was brought into the emergency department (ED) after his family found him at home collapsed on the floor unresponsive with a blood glucose of 28 mg/dL at the field. In the ED, the patient was tachycardic, tachypnoeic and hypotensive, requiring pressors and intubation at 9 hours and 12 hours after arrival, respectively. Laboratory results revealed a positive COVID-19 test, serum sodium of 125 mmol/L and persistent hypoglycaemia. The patient was given a high dose of dexamethasone for COVID-19 treatment 1 hour before pressors were started. He was then continued on a stress dose of intravenous hydrocortisone with rapid clinical improvement leading to his extubation, and discontinuation of vasopressors and glucose on day 2 of admission. The patient received his last dose of intravenous hydrocortisone on day 4 in the early afternoon with the plan to order adrenal testing the following morning prior to discharge. On day 5, the aldosterone 1250 pg/mL, and ACTH stimulation test showed cortisol levels of 3 and 3 µg/dL at 30 and 60 min, respectively. The anti-21-hydroxylase antibody was positive. The patient was discharged on hydrocortisone and fludrocortisone. The patient's symptoms, elevated ACTH, low cortisol and presence of 21-hydroxylase antibodies are consistent with autoimmune Addison's disease. This is the first case reporting autoimmune Addison's disease in a patient with COVID-19 with a history of ADEM. The case highlights the importance of considering adrenal insufficiency as a diagnostic differential in haemodynamically unstable patients with COVID-19.

BACKGROUND: Type 2 polyglandular autoimmune syndrome is a rare condition characterized by at least two glandular failures induced by autoimmunity, which always includes Addison's disease, plus type 1 diabetes mellitus and/or autoimmune thyroid diseases. CLINICAL CASE: A 38-year-old female patient with a history of type 1 diabetes mellitus who was admitted to Internal medicine service with a diagnosis of "septic shock of urinary origin", without elevation of acute phase reactants or data of systemic inflammatory response, with gastrointestinal symptoms, plus hyperchromic lesions in mucosa, electrolyte disturbance sodium 119.13 mEq/L, potassium 6.1 mEq/L, cortisol levels 1.63 µg/dL and antithyroperoxidase titers greater than 2000 ng/dL, leading to a diagnosis of autoimmune polyglandular syndrome type II. CONCLUSIONS: Autoimmune polyglandular syndrome should be considered in all patients with primary glandular disease, as in this case, with the purpose of perform a timely diagnosis, treatment, and follow-up of this affection to avoid fatal complications such as adrenal crises, present in this case. [ABSTRACT FROM AUTHOR]

Context: Individuals with autoimmune Addison disease (AAD) take replacement medication for the lack of adrenal-derived glucocorticoid (GC) and mineralocorticoid hormones from diagnosis. The brain is highly sensitive to these hormones, but the consequence of having AAD for brain health has not been widely addressed. Objective: The present study compared resting-state functional connectivity (rs-fc) of the brain between individuals with AAD and healthy controls. Methods: Fifty-seven patients with AAD (33 female) and 69 healthy controls (39 female), aged 19 to 43 years were scanned with 3-T magnetic resonance imaging (MRI). Results: Independent component and subsequent dual regression analyses revealed that individuals with AAD had stronger rs-fc compared to controls in 3 networks: the bilateral orbitofrontal cortex (OFC), the left medial visual and left posterior default mode network. A higher GC replacement dose was associated with stronger rs-fc in a small part of the left OFC in patients. We did not find any clear associations between rs-fc and executive functions or mental fatigue. Conclusion: Our results suggest that having AAD affects the baseline functional organization of the brain and that current treatment strategies of AAD may be one risk factor. [ABSTRACT FROM AUTHOR]

Background/Objective: Infiltrative fungal infections are an unusual cause of primary adrenal insufficiency (AI). Our objective is to present a long-term follow-up of a patient with AI due to cryptococcal adrenalitis. Case Report: A 47-year-old woman presented in January 2004, with 50-lb weight loss, nausea, emesis, and headache with diplopia. During the 6 months prior to her presentation the patient had multiple admissions for evaluation of recurrent nausea and emesis. Prior to the most recent of these admissions, the patient developed a headache; evaluation of her cerebrospinal fluid revealed the presence of Cryptococcus, and she was treated with a 2-week course of amphotericin B. Physical examination demonstrated a temperature of 101.1 °F, heart rate of 110 bpm, and blood pressure of 94/65 mm Hg. She appeared ill and was underweight with dry mucous membranes and photophobia. Laboratory tests revealed random cortisol of 0.5 μg per dL. CT imaging showed bilateral adrenal gland enlargement and fine needle aspiration of the adrenal gland revealed encapsulated budding yeast. Stress dose intravenous glucocorticoids were administered and switched to oral hydrocortisone and fludrocortisone because the patient clinically improved with a second course of amphotericin B. Further evaluation in 2017 revealed persistently enlarged adrenal glands, positive cryptococcus antigen, and low IgG levels. Discussion: Our literature review noted few publications of AI caused by disseminated cryptococcus with no long-term follow-up of these cases beyond a 1- to 4-year time frame. Conclusion: Patients with AI due to disseminated fungal infection need long-term follow-up to assess for resolution of adrenal enlargement and evaluation of immunocompromised status.

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Mara Carsote,1,2 Claudiu Nistor3,4 1Department of Endocrinology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 2Department of Gonads and Infertility, “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania; 3Department 4 – Cardio -Thoracic Pathology, Thoracic Surgery II Discipline, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 4Thoracic Surgery Department, “Dr. Carol Davila” Central Emergency University Military Hospital, Bucharest, RomaniaCorrespondence: Mara Carsote, Aviatorilor Ave, 34-38, Sector 1, Bucharest, 011683, Romania, Tel +40744 851 934, Email carsote_m@hotmail.comAbstract: We aim to overview Addison’s disease (AD) with regard to current diagnosis and management. This is a narrative review of full-length articles published in English between January 2022 and December 2022 (including online ahead of print versions) in PubMed-indexed journals. We included original studies in living humans regardless of the level of statistical significance starting from the key search terms “Addison’s disease” or “primary adrenal insufficiency” in title or abstract. We excluded articles with secondary adrenal insufficiency. Briefly, 199 and 355 papers, respectively were identified; we manually checked each of them, excluded the duplicates, and then selected 129 based on their clinical relevance in order to address our 1-year analysis. We organized the data in different subsections covering all published aspects on the subject of AD. To our knowledge, this is the largest AD retrospective from 2022 on published data. A massive role of genetic diagnosis especially in pediatric cases is highlighted; the importance of both pediatric and adult awareness remains since unusual presentations continue to be described. COVID-19 infection is a strong player amid this third year of pandemic although we still not do have large cohorts in this particular matter as seen, for instance, in thyroid anomalies. In our opinion, the most important topic for research is immune checkpoint inhibitors, which cause a large panel of endocrine side effects, AD being one of them.Keywords: Addison disease, cortisol, primary adrenal insufficiency, synacthen, congenital adrenal hyperplasia, immune checkpoint inhibitor, COVID-19

Abstract Background We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease. Case presentation An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease. Conclusions In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the “healthy” adrenal tissue residue than a direct secretory activity by the adrenal tumor.

Complete heart block is a commonly encountered entity in clinical cardiology practice, which may be secondary to a variety of diseases including metabolic disorders. Here, we report the case of a 60-year-old female patient who presented with persistent symptomatic complete heart block despite the correction of electrolyte disorder and required admission for permanent pacemaker implantation. The etiologic investigation revealed underlying adrenal insufficiency due to tuberculosis. The clinical and biological presentation of adrenal insufficiency is variable with a difficult etiologic assessment. Although cardiac manifestations are rare, significant electrocardiographic abnormalities can be observed in untreated adrenal insufficiency, such as conduction abnormalities. Hence, in our case, we highlight one of the rare etiologies of conductive disorders and the complexity of the extrapulmonary manifestations of tuberculosis that clinicians should be aware of it.

BackgroundPrimary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies.ResultsOur study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility.ConclusionOur findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune-related adverse events (irAEs). Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI-irAE. MATERIALS AND METHODS: Suspected PAI-irAE cases were identified using VigiBase, the World Health Organizations pharmacovigilance database of individual case safety reports. RESULTS: From September 2, 2008, through October 5, 2018, a total of 50,108 ICI-associated ADRs were reported. Since 2008, there were 451 cases of PAI-irAE identified of which 45 were definite PAI and 406 possible PAI. Patients were mainly male (58.1%) with a median age of 66 years (range, 30-95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6-576). ICI-associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between definite versus possible PAI group. CONCLUSION: Our study represents the largest clinical description and characterization of PAI-irAE. Although ICI-associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242 IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitor (ICI)-associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life-threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI-related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI-PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.

Primary adrenal insufficiency (PAI) occurs in 1 in 5 to 7000 adults. Leading etiologies are autoimmune adrenalitis in adults and congenital adrenal hyperplasia (CAH) in children. Oral replacement of cortisol is lifesaving, but poor quality of life, repeated adrenal crises, and dosing uncertainty related to lack of a validated biomarker for glucocorticoid sufficiency persists. Adrenocortical cell therapy and gene therapy may obviate many of the shortcomings of adrenal hormone replacement. Physiological cortisol secretion regulated by pituitary adrenocorticotropin could be achieved through allogeneic adrenocortical cell transplantation, production of adrenal-like steroidogenic cells from either stem cells or lineage conversion of differentiated cells, or for CAH, gene therapy to replace or repair a defective gene. The adrenal cortex is a high-turnover organ and thus failure to incorporate progenitor cells within a transplant will ultimately result in graft exhaustion. Identification of adrenocortical progenitor cells is equally important in gene therapy, for which new genetic material must be specifically integrated into the genome of progenitors to ensure a durable effect. Delivery of gene-editing machinery and a donor template, allowing targeted correction of the 21-hydroxylase gene, has the potential to achieve this. This review describes advances in adrenal cell transplants and gene therapy that may allow physiological cortisol production for children and adults with PAI. [ABSTRACT FROM AUTHOR]

Background: We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease. Case presentation: An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease. Conclusions: In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the "healthy" adrenal tissue residue than a direct secretory activity by the adrenal tumor. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndrome type 2 (APS2) is characterized by autoimmune adrenal insufficiency (AI) in conjunction with autoimmune thyroid disease (AITD) and/or type 1 diabetes mellitus (T1DM). The aim is to report an 11-year-old girl with concurrence of Addison disease, celiac disease and thyroid autoimmunity. She initially presented at the age of 5 with vomiting, dehydration, hyponatremia, hyperkalemia and low glucose. She recovered with intravenous hydration but the diagnosis was not established. She presented again at the age of 11 with hyperpigmentation, weakness and signs of impending adrenal crisis. Diagnosis of autoimmune AI was established together with celiac disease and thyroid autoimmunity. Thus, she met criteria for APS, being the third pediatric case report of APS2 with this combination. This case is notable for the atypical age of onset, given that APS2 is rare in the pediatric population. Furthermore, it depicts the insidious course of Addison disease with symptoms fluctuating for years before diagnosis. [ABSTRACT FROM AUTHOR]

الملخص: أهداف البحث: لمقارنة الممارسة الحالية على مستوى المملكة مع دراستنا المؤسسية السابقة حول هذا الموضوع. أيضا، لتحديد ما إذا كان تخصص أو درجة الطبيب ترتبط بميله نحو بروتوكول معين عند إجراء اختبار سيناكتين القصير. طرق البحث: قمنا باستطلاع رأي الأطباء المسجلين لدى المجلس الصحي السعودي لتحديد مختلف البروتوكولات المتبعة عند اجراء اختبار سيناكتين القصير بالمملكة العربية السعودية. النتائج: تلقينا ۱٦٢ردا. من هؤلاء، كان ٦٦ (٤۱٪) مشاركا من أطباء الغدد الصماء، والباقي من أطباء الباطنة. كان ٦۱ (۳٨٪) من المستجيبين من درجة استشاري، بينما كان الباقي من درجة غير استشاري. اعتبر الأطباء الخلل الأيضي مثل انخفاض ضغط الدم (٧٨٪), نقص صوديوم الدم (٦٥٪), نقص السكر في الدم (٥٩٪), و فرط البوتاسيوم (٥٤٪) هي الأسباب الرئيسية لإجراء الاختبار. اعتمد اغلب الأطباء بروتوكول اختبار سيناكتين القصير، لقياس هرمون الكورتيزول الأساسي في الدم (٩٠٪) والهرمون الموجه للغدة الكظرية (٧٨٪) في يوم الاختبار. قام ٧٥٪ من الأطباء بقياس كلا من هرمون الكورتيزول في الدم بعد ۳٠ و٦٠ دقيقة بعد حقن الهرمون الموجه للغدة الكظرية. من هؤلاء، أفاد ۱۳ ٪ من الأطباء أن مستويات الكورتيزول كانت أقل من الحد الأدنى المقبول بعد ۳٠ دقيقة ولكنها وصلت فقط بعد ٦٠ دقيقة. جاءت نتائج ٩٠٪ من اختبار سيناكتين القصير التي تم إجراؤها طبيعية. اعتبر ٩۳٪ من الأطباء أن مستوى هرمون الكورتيزول المحفز البالغ ٥٥٠ نانومول⁄ لتر هو الحد الدنى الطبيعي لوظائف الغدة الكظرية. الاستنتاجات: أكدت هذه الدراسة أن قياس هرمون الكورتيزول في الدم بعد ٦٠ دقيقة يجب أن يكون جزءا من بروتوكول اختبار سيناكتين القصير لتجنب وجود نتائج إيجابية كاذبة. وعلاوة على ذلك، يتعين على الأطباء مراعاة الأسباب الأخرى لهذا الخلل الأيضي قبل الترتيب لإجراء اختبار سيناكتين القصير خصوصا مع وجود احتمال منخفض ما قبل الاختبار. Abstract: Objectives: This study aimed to compare the current Kingdom-wide practice with our prior institutional study on use of the short synacthen test (SST), and to determine whether physician specialty or grade is associated with a tendency toward using a particular protocol. Method: We surveyed clinicians registered with the Saudi Medical Council to determine the different SST protocols used within KSA. Results: We received 162 responses, 66 (41%) from endocrinologists and the remainder from internists. A total of 61 (38%) respondents were consultants, whereas the rest were non-consultant grade. The clinicians indicated metabolic derangements, such as hypotension (78%), hyponatremia (65%), hypoglycemia (59%), and hyperkalemia (54%), as the main reasons for performing the test. Most clinicians used the SST protocol, which measures baseline serum cortisol (90%) and ACTH (78%) on the test day. A total of 75% of the physicians measured both the 30- and 60-minute serum cortisol after ACTH injection. Of these clinicians, 13% reported that the cortisol levels were below the pass threshold at 30 min but reached the pass threshold only at 60 min. The SST was normal 90% of the time when performed. A total of 93% of the clinicians considered a stimulated cortisol level of 550 nmol/L to be the threshold for normal adrenal function. Conclusion: The survey confirms that 60-min serum cortisol should be part of the SST protocol to avoid false-positive results. Moreover, clinicians should consider other causes of these metabolic derangements before requesting a SST, particularly in patients with a low pretest probability.

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT Perioral pigmentation is a commonly encountered condition in the skin Out Patient Department (OPD), occurring due to a variety of primary as well as secondary causes. The affection of the perioral skin being readily visible negatively impacts the patient’s quality of life. As the etiology of perioral pigmentation is multifactorial, treatment modalities vary according to the cause. The perioral skin, because of its location close to the mouth, is exposed to various allergens associated with food, saliva, toothpaste, cosmetics, etc., which can all lead to allergic manifestations resolving with pigmentation. Certain other dermatoses like melasma can first present with pigmentation over the perioral region. Infections like chikungunya and dengue and infestation with Demodex mite can also lead to pigmentation at this site. Perioral pigmentation can also be a marker of underlying systemic disease. Localized lentigines-like pigmentation can be associated with various cancer predisposition syndromes like Peutz-Jeghers syndrome. Diffuse pigmentation can occur due to Addison disease, vitamin deficiencies, or can be drug-induced. All these causes of pigmentation are seen more commonly in type IV and V skin. Currently, very little literature is available elucidating the cause of perioral pigmentation and the diagnostic approach. This article reviews the causes of perioral pigmentation and highlights their important features.

Daniela Nisticò,1 Benedetta Bossini,1 Simone Benvenuto,1 Maria Chiara Pellegrin,1 Gianluca Tornese2 1University of Trieste, Trieste, Italy; 2Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, ItalyCorrespondence: Gianluca TorneseDepartment of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste, 34137, ItalyTel +39 040 3785470Email gianluca.tornese@burlo.trieste.itAbstract: Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason.Keywords: adrenal gland, primary adrenal insufficiency, central adrenal insufficiency, Addison disease, children, adrenal crisis, hydrocortisone

ObjectivePatients with adrenal insufficiency (AI) may be exposed to supraphysiological glucocorticoids levels during standard treatment with cortisone acetate (CA) or immediate-release hydrocortisone (IR-HC). Recent studies, predominantly including patients in IR-HC treatment, suggested that modified-release hydrocortisone (MRH) provide a more physiological cortisol rhythm, improving metabolic control and quality of life. Our primary aim was to assess clinical and biochemical modifications in patients shifted from CA to MRH.Design/MethodsWe designed a retrospective longitudinal study, enrolling 45 AI patients (22 primary and 23 secondary AI) treated exclusively with CA thrice daily, shifted to MRH once daily; 29/45 patients concluded at least 18-months follow-up (MRH-group). We recruited 35 AI patients continuing CA as a control group (CA-group). Biochemical and clinical data, including metabolic parameters, bone quality, and symptoms of under- or overtreatment were collected. In 24 patients, a daily salivary cortisol curve (SCC) performed before and one month after shifting to MRH was compared to healthy subjects (HS).ResultsNo significant changes in glycometabolic and bone parameters were observed both in MRH and CA-groups during a median follow-up of 35 months. A more frequent decrease in blood pressure values (23.1% vs 2.8%, p=0.04) and improvement of under- or overtreatment symptoms were observed in MRH vs CA-group. The SCC showed a significant steroid overexposure in both CA and MRH-groups compared to HS [AUC (area under the curve) = 74.4 ± 38.1 nmol×hr/L and 94.6 ± 62.5 nmol×hr/L respectively, vs 44.1 ± 8.4 nmol×hr/L, p

This review highlights oral anomalies with major clinical impact in Addison disease (AD), including dental health and dermatologic features, through a dual perspective: pigmentation issues and AD comorbidities with oral manifestations. Affecting 92% of AD patients, cutaneomucosal hyperpigmentation is synchronous with or precedes general manifestations by up to a decade, underlying melanocytic infiltration of the basal epidermal layer; melanophages in the superficial dermis; and, rarely, acanthosis, perivascular lymphocytic infiltrate, and hyperkeratosis. Intraoral pigmentation might be the only sign of AD; thus, early recognition is mandatory, and biopsy is helpful in selected cases. The buccal area is the most affected location; other sites are palatine arches, lips, gums, and tongue. Pigmented oral lesions are patchy or diffuse; mostly asymptomatic; and occasionally accompanied by pain, itchiness, and burn-like lesions. Pigmented lingual patches are isolated or multiple, located on dorsal and lateral areas; fungiform pigmented papillae are also reported in AD individuals. Dermoscopy examination is particularly indicated for fungal etiology; yet, it is not routinely performed. AD's comorbidity burden includes the cluster of autoimmune polyglandular syndrome (APS) type 1 underlying AIRE gene malfunction. Chronic cutaneomucosal candidiasis (CMC), including oral CMC, represents the first sign of APS1 in 70–80% of cases, displaying autoantibodies against interleukin (IL)-17A, IL-17F ± IL-22, and probably a high mucosal concentration of interferon (IFN)-γ. CMC is prone to systemic candidiasis, representing a procarcinogenic status due to Th17 cell anomalies. In APS1, the first cause of mortality is infections (24%), followed by oral and esophageal cancers (15%). Autoimmune hypoparathyroidism (HyP) is the earliest endocrine element in APS1; a combination of CMC by the age of 5 years and dental enamel hypoplasia (the most frequent dental complication of pediatric HyP) by the age of 15 is an indication for HyP assessment. Children with HyP might experience short dental roots, enamel opacities, hypodontia, and eruption dysfunctions. Copresence of APS-related type 1 diabetes mellitus (DM) enhances the risk of CMC, as well as periodontal disease (PD). Anemia-related mucosal pallor is related to DM, hypothyroidism, hypogonadism, corresponding gastroenterological diseases (Crohn's disease also presents oral ulceration (OU), mucogingivitis, and a 2–3 times higher risk of PD; Biermer anemia might cause hyperpigmentation by itself), and rheumatologic diseases (lupus induces OU, honeycomb plaques, keratotic plaques, angular cheilitis, buccal petechial lesions, and PD). In more than half of the patients, associated vitiligo involves depigmentation of oral mucosa at different levels (palatal, gingival, alveolar, buccal mucosa, and lips). Celiac disease may manifest xerostomia, dry lips, OU, sialadenitis, recurrent aphthous stomatitis and dental enamel defects in children, a higher prevalence of caries and dentin sensitivity, and gingival bleeding. Oral pigmented lesions might provide a useful index of suspicion for AD in apparently healthy individuals, and thus an adrenocorticotropic hormone (ACTH) stimulation is useful. The spectrum of autoimmune AD comorbidities massively complicates the overall picture of oral manifestations. [ABSTRACT FROM AUTHOR]

Perioral pigmentation is a commonly encountered condition in the skin Out Patient Department (OPD), occurring due to a variety of primary as well as secondary causes. The affection of the perioral skin being readily visible negatively impacts the patient's quality of life. As the etiology of perioral pigmentation is multifactorial, treatment modalities vary according to the cause. The perioral skin, because of its location close to the mouth, is exposed to various allergens associated with food, saliva, toothpaste, cosmetics, etc., which can all lead to allergic manifestations resolving with pigmentation. Certain other dermatoses like melasma can first present with pigmentation over the perioral region. Infections like chikungunya and dengue and infestation with Demodex mite can also lead to pigmentation at this site. Perioral pigmentation can also be a marker of underlying systemic disease. Localized lentigines-like pigmentation can be associated with various cancer predisposition syndromes like Peutz-Jeghers syndrome. Diffuse pigmentation can occur due to Addison disease, vitamin deficiencies, or can be drug-induced. All these causes of pigmentation are seen more commonly in type IV and V skin. Currently, very little literature is available elucidating the cause of perioral pigmentation and the diagnostic approach. This article reviews the causes of perioral pigmentation and highlights their important features. [ABSTRACT FROM AUTHOR]

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Background: Autoimmunity accounts for 90% of cases of primary adrenal insufficiency (Addison disease (AD)). Affected people present a significant co‐occurrence of autoimmune conditions; hence, clustering of autoimmunity is also predicted among their relatives. Aims: To evaluate the burden of autoimmunity in families of people with AD. Methods: A total of 116 individuals with AD was surveyed regarding the occurrence of 23 autoimmune diseases among their relatives. Results: A total of 74.1% of persons with AD reported at least one relative with an autoimmune disorder – 257 cases were diagnosed in 221 relatives. Hashimoto thyroiditis was found in 100 individuals, followed by Graves disease and vitiligo, in 25 and 24 relatives respectively. Type 1 diabetes was diagnosed in 23 relatives, psoriasis in 15, rheumatoid arthritis in 12, pernicious anaemia in 11, multiple sclerosis in 8, and premature menopause in 8 women. AD was found in seven relatives, alopecia in six and celiac disease in five. Other conditions were rare. Significant correlation was noticed between the number of autoimmune conditions in AD proband and the number of affected relatives (P = 0.031). A total of 66.4% of people with AD had a first‐degree relative suffering from autoimmunity. Autoimmune conditions were more frequent among females: sisters (P < 0.001), mothers (P = 0.002) and grandmothers (P = 0.002). Conclusions: Considerable prevalence of autoimmune conditions in relatives of people with AD confirms substantial risk of autoimmunity, especially in females and relatives of patients affected by multiplex autoimmunity. Our data corroborate the recommendation of active screening for autoimmune disorders, particularly thyroid disease, among AD family members. [ABSTRACT FROM AUTHOR]

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Background/Objective: The multisystemic effects of COVID-19 are becoming evident. In the adrenal gland, adrenal hemorrhage and infarction after COVID-19 infection have been reported. Our objective is to present a case of autoimmune adrenal insufficiency diagnosed after COVID-19 infection, without the evidence of a hemorrhage or an infarction. Case Report: A 64-year-old woman with hypothyroidism and type 2 diabetes presented with a 1-week history of abdominal pain, nausea, and vomiting. She had experienced asymptomatic COVID-19 infection 5 months prior and reported an unintentional 30-lb weight loss. The home medications included enalapril, atorvastatin, and levothyroxine. A physical examination was notable for hypotension, epigastric tenderness, and mucocutaneous hyperpigmentation. Laboratory tests revealed a serum sodium level of 117 mmol/L (range, 18 μg/dL). This was followed by a high-dose, 250-μg adrenocorticotropic hormone (ACTH) stimulation test, which revealed that the cortisol level was 2.3, 2.9, and 2.6 μg/dL (ref, >18 μg/dL) at baseline, 30 minutes, and 60 minutes, respectively. The ACTH level was 1944 pg/mL (range, 7.2-63.3 pg/mL), the aldosterone level was