Adrenal Failure Research Articles

Role of unilateral‐cannulating adrenal venous sampling for the subtyping of primary aldosteronism for adrenalectomy: Experience from a low‐volume center

AbstractBackgroundCurrent guidelines recommend adrenal venous sampling (AVS) for subtyping primary aldosteronism (PA). However, bilateral adrenal cannulation failure is common especially at low‐volume centers. The role of unilateral‐cannulating AVS in selecting patients for unilateral adrenalectomy is unclear.MethodsFifty consecutive patients underwent AVS between 2009 and 2023 and thirty‐three (66%) underwent unilateral adrenalectomy. We defined unilateral PA (uPA) by the normalized plasma aldosterone and the aldosterone–renin ratio following unilateral adrenalectomy. We examined the effectiveness of unilateral‐cannulating AVS in identifying uPA.Results88%, 50%, and 48% of patients had the left, right, and bilateral adrenal veins successfully cannulated, respectively. Among patients with bilateral successful cannulation, a lateralization index (LI) > 4 provided a sensitivity of 100% and a positive predictive value (PPV) of 86.7% for uPA. Thresholds for the contralateral suppression index (CSI) and relative aldosterone secretion index (RASI) were derived from this subgroup and applied to the entire cohort. CSI <0.5 demonstrated a sensitivity of 76.5% and PPV of 92.9% for uPA, whereas RASI >2.4 showed a sensitivity of 85.0% and PPV of 94.4% for uPA. With CSI <0.5 or RASI >2.4 combined, a higher PPV (95.5%) was achieved when compared to computed tomography and iodocholesterol scintigraphy (86.2% and 62.5%, respectively).ConclusionDespite unsuccessful bilateral cannulation, our study confirms that unilateral‐cannulating AVS can effectively select patients for unilateral adrenalectomy based on a combination of CSI or RASI criteria.

6826 Mevalonate Treatment Worsened Hypocholesterolemia During Prolonged Sepsis Without Affecting Adrenal And Muscle Function

Abstract Disclosure: L. De Bruyn: None. S. Derde: None. F. Van Beek: None. S. Vander Perre: None. I. Derese: None. L. Pauwels: None. G. Van den Berghe: None. L. Langouche: None. Introduction: Sepsis is hallmarked by an immediate and sustained reduction in total-, HDL- and LDL-cholesterol (-C), associated with illness severity and a potential contributor to the development of adrenal failure and muscle weakness. The underlying mechanisms that might be involved in sepsis-induced hypocholesterolemia are multifactorial and partly understood. We hypothesized that treatment with the cholesterol precursor mevalonate might improve cholesterol availability, thereby improving adrenal gland and skeletal muscle function. Our hypothesis was tested in a validated and clinically relevant mouse model of prolonged sepsis. Methods: In a catheterized mouse model of cecal ligation and puncture-induced, fluid resuscitated and antibiotics treated polymicrobial abdominal sepsis (5 d), septic mice received continuous infusion with either mevalonate (78 mg/d) or placebo solution, whereas healthy mice served as controls (N=50). Plasma total-C (HDL- + LDL-C), CORT and total bile acids were measured, in addition to ex vivo muscle force and adrenocortical cholesterol ester content. Gene expression markers of inflammation (Tnf-α, Il-6) were measured in the adrenal gland, as well as hepatic mRNA expression of cholesterol synthesis enzymes (Hmgcs1, Hmgcr, Fdft1). Metabolites of the mevalonate pathway (mevalonic acid, squalene, lanosterol, desmosterol and (7-dehydro) cholesterol) were quantified in the liver with LC-MS. Results: The sepsis-induced reduction in plasma total-C was further decreased in mevalonate-treated septic mice (26±3 mg/dL) as compared with placebo (53±3 mg/dL) and healthy controls (108±3 mg/dL) (p<0.0001). Metabolites of the mevalonate pathway were all increased in the liver after mevalonate treatment (p<0.01), whereas hepatic cholesterol content was decreased as compared with placebo (p<0.05). Also, gene expression markers of cholesterol synthesis enzymes were further decreased in the liver of mevalonate-treated septic mice as compared with placebo (p<0.05). In the context of the unexpected further reduction in plasma total-C, no additional effect on plasma CORT, total bile acids, and sepsis-induced loss of muscle force and depletion in adrenocortical cholesterol ester content was observed. In addition, the sepsis-induced rise in markers of adrenal inflammation (Tnf-α, Il-6) was not further affected by mevalonate treatment. Conclusion: Mevalonate treatment further reduced the sepsis-induced hypocholesterolemia in prolonged septic mice, potentially due to increased feedback inhibition on hepatic cholesterol biosynthesis, but without further affecting adrenal and muscle function. Other therapies such as substitution with bovine serum HDL-C are currently investigated to improve altered cholesterol availability during sepsis. Presentation: 6/2/2024

7438 DAX1/NR0B1 Related Adrenal Hypoplasia Congenita Without Hypogonadotropic Hypogonadism

Abstract Disclosure: R.L. Figueiredo: None. J.B. Drummond: None. A. Meireles: None. J.L. Machado: None. G. Vidigal: None. B.S. Rocha: None. Background: X-linked congenital adrenal hypoplasia (AHC) is a rare disease caused by genetic mutations in DXA1/NRB01 gene, which encodes a nuclear hormone receptor expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary gland, occurring in less than 1:12,500 live births (1,2). AHC is characterized by primary adrenal insufficiency (PAI) associated with hypogonadotropic hypogonadism (HH) and impaired spermatogenesis (oligospermia or azoospermia). Although DAX1/NR0B1 mutations can manifest with different phenotypes, HH is mostly present, which makes this present case a diagnostic challenge. Clinical case: A 23-year-old man presented with typical symptoms of adrenal insufficiency at the age of 7 (abdominal pain, dehydration, nausea, vomiting and cutaneous hyperpigmentation). Initial testing was consistent with primary adrenal failure: elevated ACTH levels (1250pg/mL, RR<46pg/mL) and very low serum cortisol (0.8mcg/dL, RR 3-20mcg/dL). Etiological investigation excluded autoimmune etiology (negative anti-adrenal and anti-21-hydroxylase antibodies) as well as adrenoleukodystrophy (normal very long chain fatty acid levels). Physical exam revealed normal virilization, testicular volume and penile length. The patient reported normal libido and sexual function. Hormonal evaluation showed normal total testosterone (424 and 713ng/dL, RR 165 to 753ng/dL) as well as calculated free testosterone (7.2 and 11.4ng/mL, RR>3.8ng/mL) levels. Abdominal CT showed signs of bilateral adrenal hypoplasia. We then proceeded to genetic testing that revealed a pathological variant c.625C>T:p (Gln 209*) in hemizygosity in exon 1 of the DAX 1/NR0B1 gene. This is a nonsense mutation that introduces a premature stop codon. This variant is not present on the global and Brazilian genetic databases (gnomAD and ABraOM) and has not been previously described in the literature. The patient is currently being treated for adrenal insufficiency with the lowest tolerated dose of prednisone (7.5mg/day) and fludrocortisone 0.1mg/day. Conclusion: Etiological investigation of patients with PAI is essential to understand the evolution of the disease, monitoring extra-adrenal manifestations and the possibility of genetic counseling for the family. An intact hypothalamic-pituitary gonadal axis should not preclude genetic evaluation for a DAX/NR0B1 mutation in patients with PAI and suspected AHC. Further studies will clarify if this specific mutation carries a genotype-phenotype correlation in patients with AHC without HH.

Endocrine Petrified Ear: Associated Endocrine Conditions in Auricular Calcification/Ossification (A Sample-Focused Analysis).

Petrified ear (PE), an exceptional entity, stands for the calcification ± ossification of auricular cartilage (CAC/OAC); its pathogenic traits are still an open matter. Endocrine panel represents one of the most important; yet, no standard protocol of assessments is available. Our objective was to highlight most recent PE data and associated endocrine (versus non-endocrine) ailments in terms of presentation, imagery tools, hormonal assessments, biopsy, outcome, pathogenic features. This was a comprehensive review via PubMed search (January 2000-March 2024). A total of 75 PE subjects included: 46 case reports/series (N = 49) and two imagery-based retrospective studies (N = 26) with CAC/OAC prevalence of 7-23% (N = 251) amid routine head/temporal bone CT scans. Endocrine PE (EPE): N = 23, male/female ratio = 10.5; average age = 56.78, ranges: 22-79; non-EPE cohort: N = 26; male/female ratio = 1.88, mean age = 49.44; ranges: 18-75 (+a single pediatric case).The longest post-diagnosis follow-up was of 6-7 years. The diagnosis of PE and endocrine anomalies was synchronous or not (time gap of 10-20 years). A novel case in point (calcified EPE amid autoimmune poly-endocrine syndrome type 2 with a 10-year post-diagnosis documented follow-up) was introduced. We re-analyzed EPE and re-classified another five subjects as such. Hence, the final EPE cohort (N = 50) showed: adrenal insufficiency was the most frequent endocrine condition (36%) followed by hypopituitarism (22%) and hypothyroidism (18%); 39% of the patients with adrenal failure had Addison's disease; primary type represented 72% of all cases with hypothyroidism; an endocrine autoimmune (any type) component was diagnosed in 18%. We propose the term of "endocrine petrified ear" and a workflow algorithm to assess the potential hormonal/metabolic background in PE.

Schmidt's Syndrome: An Uncommon Cause of Spontaneous Hypoglycemia

AbstractSchmidt's syndrome, or autoimmune polyendocrine syndrome type 2 (APS-2), is an uncommon disorder characterized by the co-occurrence of autoimmune thyroiditis and adrenalitis. APS-2 is defined as a combination of Addison's disease, autoimmune thyroid disease, and/or type 1 diabetes mellitus. It is an autosomal dominantly inherited polygenic disorder with incomplete penetrance; the candidate genes include but are not limited to HLA-DR3, HLA-DR4, CTLA-4, PTPN22, and CD25-IL-2. Autoimmune thyroiditis, often Hashimoto's disease, results in hypothyroidism. Primary adrenal failure results in enhanced secretion of adrenocorticotrophic hormone melanocyte and co-secretion of melanocyte-stimulating hormone, contributing to hyperpigmentation. Mineralocorticoid deficiency results in salt wasting, fatigue and cramps, postural hypotension, and hyperkalemia. Cortisol, an insulin counter-regulatory hormone, plays a pivotal role in maintaining euglycemia; deficiency predisposes to the development of hypoglycemia. We here report a rare presentation of Schmidt's syndrome as hypoinsulinemic hypoglycemia in a middle-aged male patient. Management includes treatment of acute hypoglycemic episodes with glucose or glucagon, long-term glucocorticoids and mineralocorticoids for adrenal insufficiency, and thyroid hormone supplements for hypothyroidism. This case report and brief overview aim to contribute to the scientific understanding of Schmidt's syndrome/APS-2. Additionally, here we briefly outline the diagnostic challenges in hypoglycemia evaluation, including the utilization of Whipple's triad and the gold standard supervised 72-hour fast and evaluation for primary adrenal and thyroid insufficiencies.

Chapter 8 - Adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and progressive myelopathy in adulthood, although the age of onset and rate of progression are highly variable. In addition, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop myelopathy, but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In this chapter, clinical spectrum of ALD is discussed in detail.

Bilateral adrenal hemorrhage: learning notes from clinical practice and literature review.

Adrenal hemorrhage is a rare, but important, diagnosis to recognize, in particular when there is involvement of both adrenal glands. Bilateral adrenal hemorrhage can in fact lead to adrenal insufficiency, with dramatic consequences if not promptly recognized and treated. It is normally caused by systemic conditions that lead to the vasoconstriction and thrombosis of the adrenal vein. Oftentimes, the clinical diagnosis of this condition can be very challenging, as its signs and symptoms are generalized and nonspecific (abdominal pain, nausea, and fatigue). Here, we present the cases of two patients admitted to the Emergency Department in 2016 and 2022 with acute abdominal pain, having recently undergone surgery and subsequently prescribed low-molecular-weight heparin. In both cases, laboratory results revealed neutrophilic leukocytosis and an unexplained anemia. Due to the persistence of abdominal pain despite medication, a CT scan was performed, showing an enlargement of both adrenal glands suggestive of bilateral adrenal hemorrhage. Adrenal function was tested that correlated with a diagnosis of adrenal insufficiency, and both patients were promptly treated with parenteral hydrocortisone as a result. On 5 years' follow-up from the acute event, the second patient's adrenal function had returned to normal, and he has not needed further adrenal replacement therapy; the first patient however demonstrated persistence of adrenal failure requiring replacement therapy. In this paper, through our experience and a literature analysis, we will aim to outline some clues to identify patients at potential risk of bilateral adrenal hemorrhage.

Autoimmune diseases and their prevalence in Saudi Arabian patients with type 1 diabetes mellitus.

To evaluate the prevalence of autoimmune disorders among young and adult populations diagnosed with type 1 diabetes mellitus (T1DM) in Al-Madinah Al-Munawarah, Saudi Arabia, and assess the potential impact of these conditions on other comorbidities. A retrospective, descriptive study examined autoimmune disorders in T1DM youth and adults. A total of 2258 verified T1DMs were tested. Analyzed hospital and laboratory data. Autoimmune T1DM was investigated clinically and laboratory. A total of 2258 T1DM adults, adolescents, and children were investigated; 500 (22.2%) were under 12, 540 (23.9%) were 13-17, and 1218 (53.9%) were 18 plus. Autoimmune with T1DM was 67.4%. Gender and age affect prevalence. 25.7% of adult females had autoimmune thyroiditis. Children and adolescents have greater rates of celiac disease than adults of both genders. Adrenal insufficiency was more frequent in adults. Adult males had 28.5% polyglandular autoimmune diseases, and women had 19.7%. Type 1 DM and other autoimmune illnesses increase the risk of nephropathy, CVD, and hypoglycemia. Bloodstream biomarkers linked to these disorders corroborate this. Autoimmune diseases in Saudi patients with T1DM exhibited specificity with respect to gender and age. Al-Madinah Al-Munawwarah have a heightened prevalence of autoimmune diseases among young individuals diagnosed with T1DM, such as celiac disease and autoimmune thyroiditis. Conversely, older individuals in the region have been observed to exhibit a greater incidence of adrenal failure and polyglandular autoimmune disorders. Autoimmune diseases that result in nephropathy, CVD, and hypoglycemia are highly prevalent based on biomarker levels.

Hormonal imbalance in patients with chronic kidney disease in the pre-dialysis and dialysis periods (part 2)

In the previous article, we presented the results of literature review showing the changes in hormone concentrations (parathyroid hormone, insulin, growth factor, prolactin) in patients with chronic renal failure (CRF) at the pre-dialysis and dialysis stages, described pathological relationships between renal failure and serum hormones concentrations, as well as changes in their biological effects. In this article, that continues the general topic, we provide the results of literature review that shows changes in serum concentrations of thyroid, adrenal, sex hormones and the features of the functioning of hypothalamus-pituitary-peripheral glands axis in patients with CRF. The presence of close pathogenic interactions of renal functional condition with hormonal activity of the thyroid gland was evaluated, as well as the ability of thyroid gland to influence the CRF progression both during pre-dialysis and dialysis sta­ges of CRF. Most patients with CRF have low serum triiodothyronine and thyroxine levels. It means that CRF is a pathological condition associated with thyroid hypofunction that progressively worsening as glomerular filtration rate decreases. For patients receiving dialysis treatment, hypothyroidism is associated with higher mortality. Secondary adrenal insufficiency is usually progresses in patients on renal replacement therapy. Non-diagnosed chronic adrenal failure may be life-threating that’s why the analysis of adrenal function is especially actual for patients on both pre-­dialysis and dialysis stages of CRF. Secondary adrenal insufficiency caused by long-lasting treatment with corticoids is a diagnostic problem for patients on dialysis treatment, because many nephrological diseases are treated by corticoids, and immunosuppressive therapy protocols used after the kidney transplantation are usually include prednisone. As the endocrine dysfunction progresses in patients with CRF, sexual dysfunction develops due to sex hormone imbalance. Abnormal androgen concentration is a typical fin­ding in CRF. A negative correlation was found between endogenic testosterone concentration and CRF stages I–V that indicated an abnormal profile of male sex hormones. There are gender-specific features of the development and progression of clinical symptoms of hormonal imbalance. The number of experimental studies show that continuous estradiol treatment may prevent the development of glomerulosclerosis. The results of clinical trials concluded that lower CRF progression and the lower incidence of CRF observed in young females compared to males, as well as the absence of gender protection in post-menopausal period, shows the important role of female sex hormones.

Reactive systemic vasculitis in the course of a coronavirus OC43 infection: a case report

This case report details a severe systemic failure following a coronavirus OC43 (HCoV-OC43) infection. A 78-year-old man, who had been vaccinated against SARS-CoV-2, was hospitalized for a flu-like infection and abdominal pain, revealing bilateral hemorrhagic adrenal infarctions with secondary adrenal failure. Imagery examinations showed adrenal necrosis and multiple ischemic cerebral strokes. A multiplex retro-transcriptase polymerase chain reaction (RT-PCR) became positive for HCoV-OC43. Cardio-vascular, infectious, and auto-immune exams were negative. A steroid medication finally allowed clinical improvement, and the diagnosis of reactional vasculitis was retained. An unknown pathogenicity of HCoV-OC43 is possible, considering that RT-PCR research is rarely made. The hypothesis of cross-reactions with SARS-CoV-2 antivaccine antibodies is also feasible. At last, the possible former virulence of HCoV-OC43 is being researched, in the event that this virus is connected to the 1889 Russian influenza pandemic. The development of multiplex RT-PCR would enable the study of other HCV-OC43 infections.

The importance of under-treating adrenal failure in order to allow normal adrenal function following unilateral adrenalectomy for Cushing's syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father.

Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G>C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family. The importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance. In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation. With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.

RECOMMENDATIONS FOR SCREENING AND MANAGEMENT OF ENDOCRINOPATHIES AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION

Endocrine disorders after hematopoietic stem cell transplantation result from the interaction between the underlying disease, host characteristics and treatment, including exposure to pre- and peri-transplant agents (chemotherapy and radiotherapy). In addition, post-transplantation factors, including graft-versus-host disease, and its treatment, especially glucocorticoids, also contribute to hormone deficiencies or endocrine disorders. Endocrinological alterations can be divided into six main groups: 1) Growth disorders; 2) Thyroid diseases; 3) Gonadal dysfunction; 4) Adrenal failure; 5) Osteometabolic disorders; 6) Obesity and metabolic syndrome. The purpose of this article is to update screening recommendations and management approaches for the various endocrine diseases, defining populations at risk, recommendations during follow-up, and treatment strategies, with attention to controversial issues.

Immunohistochemically ACTH positivity in an adrenal adenoma that mimicks pheochromocytoma in terms of clinical and radiological findings

Abstract Introduction Ectopic ACTH secretion is a rare cause of endogenous hypercortisolism. Herein, a case of an immunhistochemically ACTH (+) adrenocortical adenoma with typical pheochromocytoma-like clinical and imaging findings on admission is presented. Clinical Case A 41 years-old male was admitted because of an incidentally detected adrenal mass. He complained about attacks of hypertension, headache and facial flashing that occurred unregularly for the last four years although he was on candesartan. Hypertension was common in his family with no sudden death. BMI was 36.61kg/m2, blood pressure was 130/80mmHg. The only pathologic finding was fire-red flashing at his face. Abdominal MRI exhibited a mass, 91×89×86mm in size, at left adrenal gland, compatible with pheochromocytoma. His 24 hours urinary metanephrine was 375.49mcg (44–261), normetanephrine was 786.26mcg (119–451). Routine laboratory tests, electrolytes were normal. Following two-weeks of preparation with hydration and doxazosin, an open-left adrenalectomy was performed safely. His postoperative follow-up was uneventful. Hypertension resolved completely. 24-hour urinary metanephrines returned to normal, 5-HIIA was normal, as well. Pathological examination of the operation specimen was reported as adrenocortical neoplasia, 420 gr. in weight. Only necrosis was positive considering about Weiss criteria. Chromogranin-A and synaptophysin were positive. Ki-67 index was below 1%. The unexpected pathological results alarmed us for measurement of adrenal steroids. DHEA-S was low [60.60mcg/dl (80–560)], total testosterone normal [3.08ng/ml (2.41–8.27)], early-morning cortisol was 9.56µg/dL. Short synacthen test was performed, stimulated cortisol was 12.14µg/dL, which was compatible with adrenal failure. Prednisolon 5mg/day was introduced. He was considered as adrenal Cushing syndrome and preoperative mildly high metanephrines were attributed to induction of Phenylethanolamine N Methyltransferase activity in adrenal medulla by high cortisol in neighbourhood. At follow-up visits, he seemed well with any complaints. His periodic abdominal imagings were normal. He was compliant to glucocorticoid replacement, but surprisingly his baseline cortisol levels kept being low, dropped to lower levels; even to 2.7mcg/dl. At third post-operative year, he still required prednisolon, his plasma ACTH was 320pg/ml and early-morning cortisol was 4.8mcg/dl. His baseline medical records were re-evaluated, contralateral adrenal seemed normal at diagnosis. ACTH immunohistochemical staining of operation specimen was performed and was found positive. Conclusion This case has serious take home messages. First, glucocorticoid axis should be evaluated for each adrenal mass regardless of clinical and imaging findings. Second, although it is very rare, ectopic ACTH secretion should be kept in mind in cases, who exhibit long-lasting adrenal failure with even worsening cortisol levels following adrenalectomy.

ODP055 The methylation pattern of a unique Bilateral para-overian Adrenal Rest Tumor in a girl with Nicotinamide Nucleotide Transhydrogenase mutation

Abstract Background Patients with NNT (Nicotinamide Nucleotide Transhydrogenase) gene mutations, a rare cause of glucocorticoid and mineralocorticoid deficiency require hormone replacement therapy. Adrenal Rest Tumor (ART) in females, reported so far only in noncompliant patients with congenital adrenal hyperplasia and elevated ACTH levels, is very rare (<20 cases world-wide). This study characterizes the pathophysiology, the molecular ontogeny and methylation analysis of a unique ART in a female with adrenal failure due to the G200S mutation in NNT Clinical presentation and Method: A 15-year-old girl, with homozygous G200S NNT-mutation followed for adrenal insufficiency reappeared to follow-up with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (> 1500 pmol/l). Pelvic MRI and Ultrasound demonstrated one sided paraovarian round tumor with pathological vascularization. Laparoscopic exploration revealed bilateral para ovarian mesosalpinx masses involving the serosa of the Fallopian tube, (3 and 1 cm in diameter). The testosterone level normalized within one day after surgical removal of those masses (0.2 nmol/l). Results Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1, inhibin and the pituitary marker ACTH. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the positive Gene expression of Cyp17a1, Cyp21a2 and Mc2r cDNA but not Pomc suggesting adrenal but not pituitary origin of the tissue. We further profiled the epigenomic profile of several adrenal rest tumors from both ovarian and testes origins using the Infinium Methylation EPIC array. We characterized the adrenal-specific features by comparing the tumors from the two different originating sites to published methylation array data on healthy adrenal tissue. We further investigated cancer-specific methylation changes to identify activated cancer pathways, and used the methylation arrays to identify somatic copy number alterations. Finally, we analyzed the likely developmental origin of these tumors by comparing to published methylation array data of developmental and adult reproductive tissues. Conclusion This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue that was caused by incompliance to treatment in a patient with NNT gene mutation. The laparoscopic surgical findings indicate that imaging techniques may be insufficient in identification of such rest tumors and call for laparoscopy when clinical findings are suggestive. An early detection of this tumor could preserve fertility. Using histopathology markers cDNA studies and epigenomic profiling by methylation studies, our study shows for the first time that female ART originates from adrenal cells. The growth of a functional androgen producing "tumor" indicates that functional NNT protein is NOT required for androgen synthesis in contrast to glucocorticoids and that a zona reticularis similar tissue in ART is responsive to ACTH stimulation. Presentation: No date and time listed

Growth alterations in rare forms of primary adrenal insufficiency: a neglected issue in paediatric endocrinology.

Primary adrenal insufficiency (PAI) is an endocrine disorder characterized by direct adrenal failure, with consequent glucocorticoid, and eventually mineralocorticoid, deficiency. In children, the main cause of PAI is congenital adrenal hyperplasia (CAH), due to a loss of function of adrenal steroidogenic enzymes, but also rarer forms, including autoimmune polyglandular syndrome, adrenoleucodistrophy, adrenal hypoplasia congenita, familial glucocorticoid deficiency, and Allgrove's Syndrome, may be observed. In PAI children, growth alterations represent a major issue, as both inadequate and excessive glucocorticoid replacement treatment may lead to reduced growth rate and adult height impairment. However, growth abnormalities are poorly studied in rare forms of paediatric PAI, and specific studies on growth rate in these children are currently lacking. In the present review, the currently available evidence on growth alterations in children with rare PAI forms will be summarized, with a major focus on comorbidities with a potential impact on patients' growth rate.

Addison’s disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculosis or MAC pulmonary disease, in a subject with type 2 diabetes mellitus: case report

BackgroundAddison’s disease is primary adrenal dysfunction and is characterized by decrease of cortisol level and increase of adrenocorticotropic hormone (ACTH) level. It is known that infection is one of main causes of Addison’s disease. Among various infections, tuberculous infection accounts for the majority of them. Recently the number of subjects with non-tuberculous mycobacterial infection has been increased, and the infection can also bring about Addison’s disease. Mycobacterium avium complex (MAC) pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection.Case presentationAn 83-year-old female was suspected of having adrenal failure in our outpatient care and hospitalized in our institution. There was pigmentation in her face, hands and legs, especially in auricle and nail beds in her hands and legs. In rapid ACTH load test (0.25 mg of 1–24 ACTH), cortisol level was not increased at all. An abdominal computed tomography (CT) showed swelling of both adrenal glands accompanied by calcification. QuantiFERON test was negative and mycobacterium tuberculosis complex was negative in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of adrenal tuberculosis. It is known that MAC pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection. In this subject, however, anti-MAC antibody was negative and MAC-related bacteria were not detected in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of MAC pulmonary disease. Mycobacterium abscessus (Mab) was positive in bronchial lung lavage fluid culture. Based on these data, we diagnosed this subject with Addison’s disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculous or MAC pulmonary disease. Decreased sodium level and increased eosinophil number were normalized and appetite loss was markedly mitigated after starting hydrocortisone therapy. A chest CT which was taken about 6 months later showed drastic reduction of consolidation in the upper lobe of the left lung although calcification in the adrenal gland was still observed.ConclusionsWe should bear in mind the possibility of Addison’s disease triggered by another type of infection rather than adrenal tuberculosis or MAC pulmonary disease.

Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations.

Overexpression of CYP11A1 recovers cell cycle distribution in renal cell carcinoma Caki-1

BackgroundClear cell renal carcinoma is commonly known for its metastasis propensity to outspread to other organs and is asymptomatic in the early stage. Recent studies have shown that deficiencies in CYP11A1 expression can lead to fatal adrenal failure if left untreated and are associated with downstream regulation in various cancer types. However, the molecular mechanisms of CYP11A1 and kidney cancer proliferation remain unclear.MethodsNormal and renal carcinoma cell lines (HEK293 and Caki-1) were transfected with plasmid encoding CYP11A1 to overexpress the P450scc protein. Cell cycle distribution was investigated using flow cytometry. The expression of proteins related to C-Raf/ERK/JNK/p38 signaling pathways was examined using western blot.ResultsWe observed that CYP11A1 overexpression suppressed the cyclin B1 and cell-division cycle 2 expression while cyclin-dependent kinases 2 and 4 were unaffected. Cancer cell migration and invasion were suppressed along with epithelial-intermediate metastatic markers Snail and Vimentin. In addition, in CYP11A1-overexpressing Caki-1 cells, cdc2/cyclinB1 was downregulated while the phosphorylation of cdc25c, a G2/M arrest-related upstream signal, was increased. The intrinsic-mitochondrial apoptosis markers were not significantly altered. We also identified that the C-Raf/ERK/JNK/p38 pathway is an important pro-apoptotic mechanism in CYP11A1-overexpressing cell-based models. Our results suggest that CYP11A1 overexpression recovered the disturbed cell cycle arrest distribution in renal carcinoma cell line Caki-1 through G2/M arrest and C-Raf/ERK/JNK pathway.ConclusionsOur findings may suggest promising new therapeutic targets to suppress kidney cancer proliferation without affecting normal cells, eventually improving the survival of patients with cancer.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.