X-linked congenital adrenal hypoplasia: Report of long clinical follow-up and description of a new complex variant in the NR0B1 gene.

Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.

Safety of withholding perioperative steroids for patients with pituitary resection with an intact hypothalamus-pituitary-adrenal axis: A meta-analysis of randomized clinical trials.

INTRODUCTION: Several observational studies have evaluated the effects of pre-operative steroids (STER) for transsphenoidal pituitary removal in patients with an intact hypothalamus-pituitary-adrenal axis. However, a consensus built upon randomized studies has not been previously performed. PURPOSE: To comprehensively evaluate the clinical effects of patients receiving STER when compared to those not receiving steroids (NOSTER) in transsphenoidal pituitary resection, a meta-analysis of randomized clinical trials (RCT) was conducted. METHODS: A systematic review of the literature of RCTs comparing STER and NOSTER was performed in accordance with the PRISMA guidelines. Databases, including PUBMED, Cochrane Library, Web of Science, and Embase were queried. The primary outcomes were adrenal insufficiency (AI) and diabetes insipidus (DI) post-operatively. RESULTS: A total of 4 final studies were included, in which 530 total patients were analyzed. The meta-analysis suggested that there was no significant difference between STER and NOSTER groups post-operatively related to transient AI (RR= 0.83, 95% CI [0.51-1.35], p = 0.45; I² = 52%), permanent AI (RR= 0.97, 95% CI [0.41-2.31], p = 0.95; I² = 0%), and permanent DI (RR= 0.62, 95% CI [0.16-2.33], p = 0.48; I² = 0%). Nevertheless, STER group had significantly lower rates of transient DI (RR= 0.60, 95% CI [0.38-0.95], p = 0.03; I² = 5%), and post-op hyponatremia (RR = 0.49, 95% CI [0.28-0.87], p = 0.02; I² = 0%). CONCLUSION: This study demonstrates evidence from RCTs that patients receiving pre-operative STER are both safe and effective pre-operatively for resection of pituitary adenomas with an intact hypothalamus-pituitary-adrenal axis.

Morning serum cortisol role in the adrenal insufficiency diagnosis with modern cortisol assays.

PURPOSE: To investigate the accuracy of cutoff values of the morning serum cortisol (MSC) using the cortisol stimulus test (CST) insulin tolerance test (ITT) and 250 mcg short Synacthen test (SST) as the reference standard tests, to better define its clinical role as a tool in the diagnostic investigation of adrenal insufficiency (AI) AI. METHODS: An observational study was conducted with a retrospective analysis of MSC in adult patients who had been submitted to a CST to investigate AI between January 2014 and December 2020. The normal cortisol response (NR) to stimulation was defined based on the cortisol assay. RESULTS: 371 patients underwent CST for suspected AI, 121/371 patients (32.6%) were diagnosed with AI. ROC curve analysis showed an area under the curve (AUC) for MSC of 0.75 (95% CI 0.69 - 0.80). The best MSC cutoff values to confirm AI were < 3.65, < 2.35 and < 1.5 mcg/dL with specificity of 98%, 99%, and 100%, respectively. MSC > 12.35, > 14.2 and > 14.5 mcg/dL had sensitivity of 98%, 99%, and 100%, respectively, being the best cutoff values to exclude AI. Almost 25% of patients undergoing CST for possible AI had MSC values between < 3.65 mcg/dL (6.7% of patients) and > 12.35 mcg/dL (17.5% of patients), making the formal CST testing unnecessary if we consider these cutoff values. CONCLUSION: With the most modern cortisol assays, MSC could be used as a diagnostic tool, with high accuracy to confirm or exclude AI, avoiding unnecessary CST; thus, reducing expenses and safety risks during AI investigation.

Paracoccidioidomycosis and Addison's syndrome - case report.

Paracoccidioidomycosis is caused by a fungus (Paracoccidioides brasiliensis), which is endemic to Brazil. It is most frequently found in the lungs, with haematogenous and lymphatic spread. The condition is more prevalent in men, between 30 and 60 years old, commonly rural workers. It is the third leading cause of death among chronic infectious diseases today. The systemic disease has an insidious and nonspecific course, with adrenal involvement being observed in 5% of cases and requiring the destruction of 80% of the glands for symptoms of adrenal insufficiency to appear. Isolated involvement of this gland is quite rare. In this case report, however, our patient presented wasting and adrenal insufficiency with isolated adrenal involvement by the fungus.

Impact of Dose Reduction of Topical Steroids to Manage Adrenal Insufficiency in Pediatric Eosinophilic Esophagitis.

OBJECTIVE: To evaluate the impact of type and dose of swallowed topical steroids (STS) and concurrent steroid therapy on the development and resolution of adrenal insufficiency (AI) in pediatric eosinophilic esophagitis (EoE). METHODS: We performed a retrospective case-control study of pediatric EoE subjects in a single tertiary care center, who were treated with STS for at least 3 months and diagnosed with AI based on a peak stimulated cortisol level of <18 µg/dL (500 nmol/L). Steroid forms and doses, and endoscopy data were collected at the time of AI diagnosis and AI resolution or the last known evaluation. Steroid formulations were converted to a fluticasone-equivalent dose for analysis. RESULTS: Thirty-two EoE subjects with AI were identified, and 20 had AI resolution, including 12 who remained on lower dose STS. Eight of the 32 patients were also treated with extended-release budesonide (ER budesonide), which resulted in a 7-fold higher total daily steroid dose, and thus were analyzed separately. When the 24 cases that were not on ER budesonide were compared to the 81 controls, no difference was found in the STS dose nor total daily steroid dose, although the inhaled steroid dose had marginal significance. Peak eosinophil counts tended to increase when STS doses were decreased, except in subjects on ER budesonide at AI diagnosis. CONCLUSION: Altering the total daily steroid regimen can lead to resolution of AI in patients with EoE, though this may come at the expense of disease control.

Crisis adrenal neonatal secundaria a hipoplasia hipofisaria / Neonatal Adrenal Crisis Secondary to Pituitary Hypoplasia

Introducción: La insuficiencia adrenal hipotálamo hipofisaria usualmente se manifiesta secundaria a tumores y, cuando resulta congénita se asocia, con frecuencia, con otras deficiencias hormonales. La crisis adrenal suele presentarse en su debut y puede resultar potencialmente mortal. Objetivo: Examinar el caso de una paciente con insuficiencia adrenal central que debutó con una crisis adrenal congénita. Presentación del caso: Recién nacida a término, padres no consanguíneos, hospitalizada a los 9 días de vida por clínica de una semana con múltiples episodios eméticos y apnea. Ingresó con deshidratación severa, hipotensa y estuporosa. Además, se encontró acidosis metabólica severa, hipoglucemia persistente, hiponatremia e insuficiencia prerrenal. Ante la no mejoría de su estado hemodinámico, a pesar del uso de cristaloides y vasopresores, finalmente mejoró con la administración de dosis altas de hidrocortisona. El diagnóstico de deficiencia de cortisol de origen central se realizó con un test dinámico de insulina y la resonancia magnética nuclear hipofisaria. Conclusiones: La crisis adrenal se debe tener presente como diagnóstico diferencial en episodios agudos con inestabilidad hemodinámica persistente e hipoglucemia de difícil manejo. Adicionalmente, hay que considerar que existen otras causas menos comunes de insuficiencia adrenal en neonatos como la hipoplasia hipofisaria(AU)

Introduction: Hypothalamic-pituitary adrenal insufficiency usually manifests secondary to tumors and, when congenital, is often associated with other hormonal deficiencies. Adrenal crisis usually occurs at its onset and can be life threatening. Objective: To review the case of a patient with central adrenal insufficiency who had an onset with a congenital adrenal crisis. Case presentation: Term newborn, non-consanguineous parents, hospitalized at 9 days of life for a week-long clinical presentation with multiple emetic episodes and apnea. She was admitted with severe dehydration, hypotensive and stuporous. In addition, severe metabolic acidosis, persistent hypoglycemia, hyponatremia and prerenal failure were found. Given the lack of improvement of her hemodynamic status, despite the use of crystalloids and vasopressors, she finally improved with the administration of high doses of hydrocortisone. The diagnosis of cortisol deficiency of central origin was made with a dynamic insulin test and pituitary nuclear magnetic resonance imaging. Conclusions: Adrenal crisis should be kept in mind as a differential diagnosis in acute episodes with persistent hemodynamic instability and difficult-to-manage hypoglycemia. Additionally, other less common causes of adrenal insufficiency in neonates, such as pituitary hypoplasia, should be considered(AU)

Central adrenal insufficiency: who, when, and how? From the evidence to the controversies - an exploratory review.

Central adrenal insufficiency (CAI) is a life-threatening disorder. This occurs when ACTH production is insufficient, leading to low cortisol levels. Since corticosteroids are crucial to many metabolic responses under organic stress and inflammatory conditions, CAI recognition and prompt treatment are vital. However, the diagnosis of CAI is challenging. This is not only because its clinical presentation is usually oligosymptomatic, but also because the CAI laboratory investigation presents many pitfalls. Thus, the clarification of when to use each test could be helpful in many contexts. The CAI challenge is also involved in treatment: Several formulations of synthetic steroids exist, followed by the lack of a biomarker for glucocorticoid replacement. This review aims to access all available literature to synthesize important topics about who should investigate CAI, when it should be suspected, and how CAI must be treated.

Crisis suprarrenal: prevención, corticoterapia y elección del fármaco, revisión de la evidencia actual y recomendaciones / Adrenal crisis: prevention, corticotherapy and choice of the drug, review of current evidence and recommendations

INTRODUCCIÓN. La crisis suprarrenal se refiere a la insuficiencia suprarrenal aguda; la cual es un trastorno en el que la corteza adrenal no produce suficientes hormonas esteroides (en especial cortisol) para satisfacer las demandas del cuerpo, de acuerdo al mecanismo fisiopatológico se la puede clasificar como primaria, secundaria y terciaria, siendo más común en pacientes con insuficiencia suprarrenal primaria. Es una emergencia potencialmente mortal que requiere tratamiento inmediato. OBJETIVO. Establecer una estrategia de prevención y tratamiento de la crisis suprarrenal, así como la farmacoterapia ideal y sus alternativas válidas. MATERIAL Y MÉTODOS. Se realizó una revisión bibliográfica en varias revistas virtuales de alto carácter científico como Cochrane Library, Cochrane Systematic Reviews Database, MEDLINE a través de PubMed y ClinicalTrial.gov. Se seleccionaron revisiones sistemáticas con o sin metaanálisis, ensayos clínicos y recomendaciones de expertos relacionados con prevención y tratamiento de crisis suprarrenal en general. RESULTADOS. Se obtuvieron 1819 resultados, de los cuales se seleccionaron 20 artículos con mayor validez y replicabilidad en el medio para establecer un protocolo unificado de actuación. CONCLUSIÓN. El objetivo de la terapia es el tratamiento de la hipotensión y reversión de las anomalías electrolíticas y de la deficiencia de cortisol. Se deben infundir por vía intravenosa grandes volúmenes (1 a 3 litros) de solución salina al 0,9% o dextrosa al 5% en solución salina al 0,9% y la administración de hidrocortisona (bolo de 100 mg), seguido de 50 mg cada 6 horas (o 200 mg / 24 horas como infusión continua durante las primeras 24 horas). Si no se dispone de hidrocortisona, las alternativas incluyen prednisolona, prednisona y dexametasona.

INTRODUCTION. Adrenal crisis refers to acute adrenal insufficiency; which is a disorder in which the adrenal cortex does not produce enough steroid hormones (especially cortisol) to meet the body's demands, according to the pathophysiological mechanism it can be classified as primary, secondary and tertiary, being more common in patients with primary adrenal insufficiency. It is a life-threatening emergency that requires immediate treatment. OBJECTIVE. To establish a strategy for the prevention and treatment of adrenal crisis, as well as the ideal pharmacotherapy and its valid alternatives. MATERIAL AND METHODS. A literature review was performed in several highly scientific virtual journals such as Cochrane Library, Cochrane Systematic Reviews Database, MEDLINE through PubMed and ClinicalTrial.gov. Systematic reviews with or without meta-analysis, clinical trials and expert recommendations related to prevention and treatment of adrenal crisis in general were selected. RESULTS. A total of 1819 results were obtained, from which 20 articles with greater validity and replicability in the setting were selected to establish a unified protocol for action. CONCLUSIONS. The aim of therapy is the treatment of hypotension and reversal of electrolyte abnormalities and cortisol deficiency. Large volumes (1 to 3 liters) of 0.9% saline or 5% dextrose in 0.9% saline and administration of hydrocortisone (100 mg bolus), followed by 50 mg every 6 hours (or 200 mg / 24 hours as a continuous infusion for the first 24 hours) should be infused intravenously. If hydrocortisone is not available, alternatives include prednisolone, prednisone, and dexamethasone.

Fluconazole-Induced adrenal insufficiency following allogeneic hematopoietic cell transplant.

INTRODUCTION: Adrenal insufficiency (AI) is a potentially life-threatening endocrine abnormality rarely associated with azole antifungals. Patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) are at high risk of invasive fungal infection and frequently receive azoles. Signs and symptoms of AI, such as gastrointestinal symptoms, lethargy, and electrolyte disturbances frequently overlap with common alloHCT toxicities, such that azole-induced AI may be under-reported in this population. CASE REPORT: We report the first published case of azole-induced AI following alloHCT. The patient presented with orthostasis and nonspecific gastrointestinal and failure to thrive symptoms in the setting of roughly 6 weeks of fluconazole prophylaxis. The patient was found to have primary AI diagnosed via low serum cortisol and inadequate response to cosyntropin. MANAGEMENT & OUTCOME: AI symptoms resolved with hydrocortisone supplementation and recurred upon rechallenge with fluconazole. The patient had fluconazole permanently discontinued with resolution of symptoms. We rate this case as a probable adverse drug reaction on the Naranjo scale. DISCUSSION: AI may be underreported and misdiagnosed in the alloHCT population given the presence of multiple toxicities with overlapping features. Clinicians must be diligent in investigating adrenal function in patients undergoing alloHCT on azole antifungals who present with symptoms of AI.

Allgrove syndrome with amyotrophy.

Allgrove syndrome is an autosomal recessive disease mostly caused by mutations in the AAAS gene. It has variable clinical features but its cardinal features comprise the triad of achalasia, alacrimia and adrenal insufficiency. It typically develops during the first decade of life, but some cases have second and third decades onset. We describe a 25-year-old woman with Allgrove syndrome who had progressive amyotrophy, achalasia, dry eyes and adrenal insufficiency since childhood. Awareness of its neurological manifestations and multisystem features helps to shorten the time for diagnosis and allow appropriate symptomatic treatment.

[A Novel Pathogenic variant in NR0B1 gene associated with Congenital Adrenal Hypoplasia]. / Nueva Variante Patogénica en el Gen NR0B1 Asociada a Hipoplasia Adrenal Congénita.

X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency. Mutations in the NR0B1 gene cause a loss of function in the DAX1 receptor, which activates genes involved in the development and function of the hypothalamic-pituitary-gonadal axis. Objective: To describe a case of adrenal hypoplasia congenita secondary to a mutation in the NR0B1 gene and identified the differential diagnoses of the pediatric patient with adrenal insufficiency and hypogonadotropic hypogonadism. Clinical Case: A 4-year-old male patient with no relevant history and from a rural area was admitted to the emergency room due to a 15-days of emesis, asthenia, adynamia, myalgia, and ataxic gait. On the physical examination, hypotension, hyponatremia, and hyperkalemia, as well as mucosal hyperpigmentation and bilateral cryptorchidism were observed, therefore, adrenal crisis was diagnosed, starting fluid resuscitation with saline solution, hydrocortisone, and fludrocortisone, which stabilized the patient. Adrenal hyperplasia congenita, innate metabolic error, and infectious or autoimmune etiology were ruled out as etiology. A clinical exome test was performed which iden tified the variant c.1275A > T; p.Arg425Ser (Transcript ENST00000378970.5) in the NR0B1 gene consistent with X-linked adrenal hypoplasia congenita. Management of the patient continued with glucocorticoids and mineralocorticoids with favorable clinical course at 7 years of follow-up. Con clusion: A novel pathogenic variant associated with X-linked adrenal hypoplasia is described. Variants in the NR0B1 gene should be a differential diagnosis in a male patient with the association of primary adrenal insufficiency and hypogonadism.

Severe oral ulcerative and lichenoid lesions associated with adrenal insufficiency in a patient treated with nivolumab: Report of a case and review of literature.

Nivolumab, an antibody against anti-programmed death type 1, has been used for treatment of advanced non-small cell lung cancer with improvement of overall survival. Usually, diarrhea, cutaneous rash, and pruritus are reported as the most common immune-related adverse effects of nivolumab therapy. Oral lesions and secondary adrenal insufficiency sometimes occur but usually are rare events. We report a case of a patient treated with nivolumab who then showed persistent oral ulcerative and lichenoid lesions, which were refractory to topical corticosteroids. The oral lesions were concomitant to nivolumab-induced adrenal insufficiency. These adverse events led to nivolumab discontinuation, which favored oral lesion healing and adrenal insufficiency remission. Through a brief review of the literature concerning nivolumab toxicity in the oral cavity, we discuss the clinical aspect and management of these lesions.

Enfoque perioperatorio de la insuficiencia suprarrenal en el contexto de un paciente con síndrome poliglandular: Reporte de caso / Adrenal Insufficiency in a patient with polyglandular syndrome perioperative management

Adrenal insufficiency is a deficiency in the secretion of steroid hormones, mainly glucocorticoids from the adrenal gland. It can be classified in primary when the alteration occurs at the level of the adrenal gland; or secondary, due to a central defect that compromises corticotropin (ACTH) or corticotropin-releasing hormone (CRH) secretion. Adrenergic suppression and compromised response to stress characteristic of patients with adrenal deficiency constitute a potentially fatal clinical condition, especially in operating rooms, where it becomes a challenge for the entire surgical team, particularly the anesthesiologist, where is essential to carry out a comprehensive pre-anesthetic assessment, creating an anesthetic plan focused on correct adrenergic substitution, which is decisive in the patient's prognosis.

La insuficiencia suprarrenal es una entidad caracterizada por una deficiencia en la secreción de hormonas esteroideas, principalmente glucocorticoides desde la glándula adrenal. Se puede clasificar en primaria cuando la alteración se produce a nivel de la glándula adrenal; o secundaria, debido a un defecto central que compromete la secreción de corticotropina (ACTH), o de hormona liberadora de corticotropina (CRH). La supresión adrenérgica y el compromiso en la respuesta ante el estrés característica en los pacientes con déficit adrenal, constituye una condición clínica potencialmente mortal, especialmente en salas de cirugía, donde se convierte en un desafío para todo el equipo quirúrgico en particular el anestesiólogo, donde es imprescindible realizar una valoración preanestésica integral creando un plan anestésico enfocado en la correcta suplencia adrenérgica que es determinante en el pronóstico del paciente.

Adrenalitis tuberculosa: a propósito de una actualización / Tuberculous adrenalitis: in regard to a recent update

Introducción: la insuficiencia suprarrenal primaria (IA) descrita por Thomas Addison en 1855 atribuía como principal causa a la infección por tuberculosis (TBC) diseminada, pero con el paso del tiempo ha disminuido en los países desarrollados. En aquellos en vías de desarrollo se mantiene alta esta etiología infecciosa, en especial en pacientes con VIH. Objetivo: realizar una revisión narrativa de la literatura reciente sobre la adrenalitis por TBC, incluyendo el enfoque, manejo y seguimiento en los casos de insuficiencia suprarrenal primaria (IA). Materiales y métodos: búsqueda y análisis de los artículos disponibles en los últimos 5 años bajo los descriptores en ciencias de la salud (DeCS) enfermedad de Addison, tuberculosis, insuficiencia suprarrenal primaria y adrenalitis en español en las bases de Google scholar y LILACS, y en inglés en PubMed y ClinicalKey. Conclusiones: la insuficiencia adrenal o adrenalitis por TBC ha descendido como causa de IA primaria, pero en el contexto de reemergencia de infección por VIH, continúa siendo una causa importante de IA en países en desarrollo. En estos casos además de la suplencia con corticosteroides el tratamiento de la causa específica es de importancia para impactar en la respuesta clínica, la supervivencia y la calidad de vida.

Introduction: primary adrenal insufficiency (AI) was described by Thomas Addison in 1855, and the vast majority of cases were attributable to disseminated tuberculosis (TB), but TB has decreased in developed countries over time. Conversely, in developing countries, this infectious etiology remains high, especially in patients with HIV infection. Objective: to perform a narrative review of the recent literature on tuberculous adrenalitis, including the approach, management and follow-up in cases of primary adrenal insufficiency (AI). Materials and methods: search and analysis of articles available over the past 5 years, using Health Sciences Descriptors (DeCS), Addison ́s disease, tuberculosis, primary adrenal insufficiency and adrenalitis, in Spanish in the Google scholar and LILACS databases, and in English in the PubMed and ClinicalKey databases. Conclusions: adrenal insufficiency or adrenalitis due to TB has decreased as a cause of primary AI, but in the context of the resurgence of HIV infection, TB remains an important cause of AI in developing countries. In these cases, in addition to corticosteroid replacement therapy, treatment of the specific cause is important to impact clinical response, survival and quality of life.