Steroid hormone profiles and molecular diagnostic tools in pediatric patients with non-CAH primary adrenal insufficiency

Background There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. Objective Investigation of the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. Design Paediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targetedgene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Setting Eighteen pediatric endocrinology clinics. Patients Forty-one patients (17 females, median age: 3 months, range: 0-8 years) with non-CAH PAI of unknown etiology. Results A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to healthy control group, patients showed lower steroid concentrations, most significantly in cortisone, cortisol, and corticosterone (p<0.0001, area under the ROC curve: 0.96, 0.88, 0.87, respectively). Plasma cortisol<4 ng/mL, cortisone<11 ng/mL, and corticosterone<0.11 ng/mL had >95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology. Conclusion Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, while they are unlikely to point out a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, while little additional benefit is expected from WES.

Long-Term Outcomes of Conventional And Novel Steroid Replacement Therapy On Bone Health In Primary Adrenal Insufficiency

Purpose: To compare dual-release hydrocortisone (DR-HC) and conventional glucocorticoids (GCs) on bone metabolism in patients with primary adrenal insufficiency (PAI).Methods: Thirty-five patients with PAI maintained conventional GCs (group A), while other 35 were switched to DR-HC (group B). At baseline and after 18, 36 and 60 months of conventional GCs and DR-HC treatment, the clinical and bone metabolic parameters were evaluated. Results: After 60 months of follow-up, patients in group A had a significant increase in Body Mass Index (BMI) (p=0.004) and Waist Circumference (WC) (p=0.026) and a significant decrease in osteocalcin (p=0.002), bone alkaline phosphatase (p=0.029), lumbar spine bone mass density (BMD) T and Z scores (p<0.001 and p=0.001, respectively) than baseline. By contrast, patients in group B had a significant decrease in WC (p=0.047) and increase in bone alkaline phosphatase (p=0.019), lumbar spine BMD T score (p=0.032), femoral neck BMD T and Z scores (p=0.023 and p=0.036, respectively) than baseline. Conclusions: Long-term conventional steroid replacement therapy is associated with a decrease in BMD, notably at lumbar spine, and an increase in vertebral fractures rate. By contrast, DR-HC treatment is associated with improvement of BMD.

Atypical Presentation of Testicular Adrenal Rest Tumor (TART) Leading to Bilateral Partial Orchiectomy in a 31-Year-Old Adult Revealing Primary Adrenal Insufficiency with CYP11A1 Deficiency

Adrenogenital syndrome is commonly associated with a deficiency in 21-hydroxylase but can be present in other rare enzymatic blocks. We report here the case of a 31-year-old man who presented with bilateral painful testicle lesions leading to bilateral partial orchiectomy as they were suspected for malignancy. These lesions were finally identified as benign testicle adrenal rest tumors (TARTs), and the patient was actually belatedly diagnosed with primary adrenal insufficiency due to 2 mutations of the CYP11A1 gene encoding the cholesterol side-chain cleavage enzyme (P450scc); the mutations were 940G > A (p.Glu314Lys) and c.1393C > T (p.Arg465Trp). The same mutations were found in his 29-year-old sister, who was then also diagnosed for primary adrenal insufficiency. Deficiency in P450scc is an extremely rare genetic autosomal recessive disorder with around 40 described families in the literature and 30 different mutations. As the diagnosis of delayed onset of P450Scc mutation is difficult, this case illustrates the need for a systematic endocrinological assessment in any case of bilateral testicle lesions, thus avoiding unnecessary surgery.

Bilateral adrenal masses due to tuberculosis: how to diagnose without extra-adrenal tuberculosis

Summary Primary adrenal insufficiency is a rare disease and can masquerade as other conditions; therefore, it is sometimes incorrectly diagnosed. Herein, we reported the case of a 39-year-old Vietnamese male with primary adrenal insufficiency due to bilateral adrenal tuberculosis. The patient presented to the emergency room with acute adrenal crisis and a 3-day history of nausea, vomiting, epigastric pain, and diarrhoea with a background of 6 months of fatigue, weight loss, and anorexia. Abdominal CT revealed bilateral adrenal masses. Biochemically, unequivocal low morning plasma cortisol (<83 nmol/L) and high plasma adrenocorticotropic hormone levels were consistent with primary adrenal insufficiency. There was no evidence of malignancy or lymphoma. As the patient was from a tuberculosis-endemic area, extra-adrenal tuberculosis was excluded during the work up. A retroperitoneal laparoscopic left adrenalectomy was performed, and tuberculous adrenalitis was confirmed by the histopathological results. The patient was started on antituberculous therapy, in addition to glucocorticoid replacement. In conclusion, even without evidence of extra-adrenal tuberculosis, a diagnosis of bilateral adrenal tuberculosis is required. A histopathological examination has a significant role along with clinical judgement and hormonal workup in establishing a definitive diagnosis of adrenal tuberculosis without evidence of active extra-adrenal involvement. Learning points Primary adrenal insufficiency can be misdiagnosed as other mimicking diseases, such as gastrointestinal illness, leading to diagnostic pitfalls. Adrenal insufficiency can be confirmed with significantly low morning plasma cortisol levels of <83 nmol/L without a dynamic short cosyntropin stimulation test. Tuberculous adrenalitis is an uncommon treatable condition; however, it remains an important cause of primary adrenal insufficiency, especially in developing countries. In the absence of extra-adrenal involvement, adrenal biopsy plays a key role in the diagnostic process. Alternatively, adrenalectomy for histopathological purposes should be considered if CT scan-guided fine needle aspiration is infeasible in cases of small adrenal masses.

Endocrine Disorders and Genital Infections Impair Gynecological Health in APECED (APS-1)

ObjectiveIn autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) defects in the autoimmune regulator gene lead to impaired immunotolerance. We explored the effects of immunodeficiency and endocrinopathies on gynecologic health in patients with APECED.DesignCross-sectional cohort study combined with longitudinal follow-up data.MethodsWe carried out a gynecologic evaluation, pelvic ultrasound, and laboratory and microbiologic assessment in 19 women with APECED. Retrospective data were collected from previous study visits and hospital records.ResultsThe study subjects’ median age was 42.6 years (range, 16.7-65.5). Sixteen patients (84%) had premature ovarian insufficiency, diagnosed at the median age of 16.5 years; 75% of them used currently either combined contraception or hormonal replacement therapy. In 76% of women, the morphology and size of the uterus were determined normal for age, menopausal status, and current hormonal therapy. Fifteen patients (79%) had primary adrenal insufficiency; three of them used dehydroepiandrosterone substitution. All androgen concentrations were under the detection limit in 11 patients (58%). Genital infections were detected in nine patients (47%); most of them were asymptomatic. Gynecologic C. albicans infection was detected in four patients (21%); one of the strains was resistant to azoles. Five patients (26%) had human papillomavirus infection, three of which were high-risk subtypes. Cervical cell atypia was detected in one patient. No correlation between genital infections and anti-cytokine autoantibodies was found.ConclusionsOvarian and adrenal insufficiencies manifested with very low androgen levels in over half of the patients. Asymptomatic genital infections, but not cervical cell atypia, were common in female patients with APECED.

An unusual presentation of primary adrenal insufficiency with new onset type 1 diabetes: case report and review of the literature

Objectives To describe an atypical presentation of primary adrenal insufficiency in conjunction with new onset type 1 diabetes. Case presentation Here, we describe a case of new-onset type 1 diabetes (T1D) presenting simultaneously with an unusual presentation of primary adrenal insufficiency in a previously healthy 16-year-old. He was admitted for a typical presentation of diabetic ketoacidosis, but with extreme hyponatremia. An extensive workup revealed a low aldosterone level, appropriate cortisol level, and positive 21-hydroxylase antibodies. While the phenomenon of multiple autoimmune conditions developing in the same patient is well-described, this particular case has several atypical aspects. Our patient’s case highlights the danger of relying on random serum cortisol in the setting of acute illness to rule out adrenal insufficiency. Conclusions Adrenal insufficiency can present as isolated hypoaldosteronism without hypocortisolemia and can manifest as severe hyponatremia in the context of diabetic ketoacidosis. Workup for an unusual presentation of T1D should include a 21-hydroxylase antibody, as well as thyroid and celiac disease studies.

POSACONAZOLE INDUCED PSEUDOHYPERALDOSTERONISM WITH CONCURRENT ACUTE PRIMARY ADRENAL INSUFFICIENCY-A CASE REPORT

In this covid 19 pandemic,there were increased incidence of Mucormycosis and thereby increase in usage of antifungals especially oral posaconazole which is more recently available in tablet form.There are already enough case reports of the incidence of new onset hypertension and hypokalemia with supressed renin and aldosterone which is termed as “Posaconazole induced pseudohyperaldosteronism”.We describe here about a similar case that presented with hypertensive urgency as Acute pulmonary edema with an associated primary adrenal insufciency.The potential mechanism include inhibition of 11 β HSD which degrades cortisol to cortisone,thereby increasing the levels of cortisol that stimulates Mineralocorticoid receptor.Also there is inhibition of steroidogenesis at the level of adrenal which in our patient presented with features of Acute adrenal insufciency.

Case Report: Neonatal Cholestasis as Early Manifestation of Primary Adrenal Insufficiency

Neonatal cholestasis (NC) may be due to multiple surgical and non-surgical causes, some of which are potentially fatal. The list of potential causes of NC is long, and the systematic search for each of them is challenging in infants, especially when overt signs of underlying disease are lacking. Endocrinological diseases as causes of NC are rare and sometimes misdiagnosed. We report the case of an infant with prolonged cholestatic jaundice due to adrenal insufficiency suspected because of a single episode of hypoglycemia occurring at birth in the absence of clinical signs of adrenal impairment. Clinical exome analysis identified a new homozygous variant in MC2R gene as a putative responsible for familial glucocorticoid deficiency (FGD). Adrenal insufficiency should always be considered in all cholestatic infants, even in the absence of specific symptoms, since early recognition and treatment is essential to prevent life-threatening events.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.