scholarly journals Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia

2019 ◽  
Vol 104 (11) ◽  
pp. 5065-5072 ◽  
Author(s):  
Manon Engels ◽  
Karijn J Pijnenburg-Kleizen ◽  
Agustini Utari ◽  
Sultana M H Faradz ◽  
Sandra Oude-Alink ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Clinical Signs ◽  
Adrenal Hyperplasia ◽  
Blood Concentrations ◽  
Adrenal Steroid ◽  
17 Hydroxyprogesterone ◽  
Cortisol Deficiency ◽  
Steroid Precursor

Abstract Context and Objective We describe the clinical features and biochemical characteristics of a unique population of severely affected untreated patients with congenital adrenal hyperplasia (CAH) from an Indonesian population with proven cortisol deficiency but without clinical signs of cortisol deficiency. We evaluated the in vitro glucocorticoid activity of all relevant adrenal steroid precursors occurring in patients with CAH. Design Cross-sectional cohort study and translational research. Intervention/Main Outcome Measures Adrenal steroid precursor concentrations before and 60 minutes after ACTH administration to 24 untreated patients with CAH (3 to 46 years) with proven cortisol deficiency (<500 nmol/L post-ACTH) measured by liquid chromatography–tandem mass spectrometry were compared with six control patients (Mann-Whitney U test). Glucocorticoid receptor (GR) activation was determined by dual-luciferase assays in human embryonic kidney cells transfected with the GR and exposed to increasing amounts of adrenal steroid precursors for 24 hours. Results Blood concentrations of the steroid precursors 11-deoxycortisol (457 nmol/L, P = 0.003), 11-deoxycorticosterone (55 nmol/L, P = 0.003), 17-hydroxyprogesterone (610 nmol/L, P < 0.001), progesterone (29 nmol/L, P < 0.001), and 21-deoxycortisol (73 nmol/L) were strongly elevated compared with control subjects. The GR was activated with comparable potency to cortisol by corticosterone and 21-deoxycortisol or with 4 to 100 times lower potency by 11-hydroxyprogesterone, 11-deoxycortisol, aldosterone, 11-deoxycorticosterone, progesterone, and 17-hydroxyprogesterone. Conclusions We identified strongly elevated adrenal steroid precursor concentrations in blood from untreated patients with CAH and demonstrated glucocorticoid activity of these adrenal precursors in vitro, suggesting a possible role of these precursors in the clinical phenotype of these patients. Further studies are necessary to evaluate the role of these precursors in more detail.

scholarly journals Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia

2014 ◽  
Vol 3 (2) ◽  
pp. 67-74 ◽  
Author(s):  
Ingeborg Brønstad ◽  
Lars Breivik ◽  
Paal Methlie ◽  
Anette S B Wolff ◽  
Eirik Bratland ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Gene Encoding ◽  
Salt Wasting ◽  
Functional Studies ◽  
Norwegian Population ◽  
Liquid Chromatography Tandem Mass ◽  
17 Hydroxyprogesterone

In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with CAH, of which p.L388R and p.E140K were associated with salt wasting (SW), p.P45L with simple virilising (SV) and p.V211M+p.V281L with SV to non-classical (NC) phenotypes. We aimed to characterise the novel variants functionally utilising a newly designed in vitro assay of 21OH enzyme activity and structural simulations and compare the results with clinical phenotypes. CYP21A2 mutations and variants were expressed in vitro. Enzyme activity was assayed by assessing the conversion of 17-hydroxyprogesterone to 11-deoxycortisol by liquid chromatography tandem mass spectroscopy. PyMOL 1.3 was used for structural simulations, and PolyPhen2 and PROVEAN for predicting the severity of the mutants. The CYP21A2 mutants, p.L388R and p.E140K, exhibited 1.1 and 11.3% of wt 21OH enzyme activity, respectively, in vitro. We could not detect any functional deficiency of the p.P45L variant in vitro; although prediction tools suggest p.P45L to be pathogenic. p.V211M displayed enzyme activity equivalent to the wt in vitro, which was supported by in silico analyses. We found good correlations between phenotype and the in vitro enzyme activities of the SW mutants, but not for the SV p.P45L variant. p.V211M might have a synergistic effect together with p.V281L, explaining a phenotype between SV and NC CAH.

High aldosterone and cortisol levels in salt wasting congenital adrenal hyperplasia: a clinical conundrum

2017 ◽  
Vol 30 (12) ◽  
Author(s):  
Sirisha Kusuma Boddu ◽  
Sheeja Madhavan
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Cross Reactivity ◽  
Adrenal Hyperplasia ◽  
Salt Wasting ◽  
Adrenal Steroid ◽  
Wasting Syndrome ◽  
Serum Aldosterone ◽  
Diagnostic Confusion ◽  
Cortisol Levels ◽  
17 Hydroxyprogesterone

AbstractBackground:Salt wasting syndrome (hyponatremia, hyperkalemia, dehydration, metabolic acidosis) in early infancy could be caused by either mineralocorticoid deficiency as in congenital adrenal hyperplasia (CAH) and adrenal insufficiency or mineralocorticoid resistance as in pseudohypoaldosteronism (PHA). In salt wasting CAH, serum aldosterone and cortisol levels are expected to be low. Cross reactivity between high levels of adrenal steroid precursors and aldosterone has recently been reported resulting in elevated aldosterone levels in CAH, leading to difficulty in differentiating between CAH and PHA.Case presentation:We report four such cases of salt wasting CAH, where high aldosterone levels and high normal cortisol levels led to initial diagnostic confusion with PHA. Diagnosis of CAH was later established on the basis of significantly elevated adrenocorticotropic hormone (ACTH) stimulated 17-hydroxyprogesterone (17-OHP) values.Conclusions:By reporting these cases we draw attention to the possibility that high levels of adrenal steroid precursors can cross react with aldosterone and cortisol, and underscore the significance of ACTH stimulated 17-OHP values in differentiating CAH and PHA.

scholarly journals Nonsense variant of NR0B1 causes hormone disorders associated with congenital adrenal hyperplasia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Da-Bei Fan ◽  
Li Li ◽  
Hao-Hao Zhang
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Energy Homeostasis ◽  
Hypogonadotropic Hypogonadism ◽  
Chinese Family ◽  
Orphan Nuclear Receptor ◽  
Inherited Disease ◽  
Adrenal Hyperplasia ◽  
Infancy And Early Childhood ◽  
Disordered Energy

AbstractCongenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene. The DAX-1 protein (encoded by NR0B1) is a vertebrate-specific orphan nuclear receptor and is also a transcriptional factor for adrenal and reproductive development. CAH usually causes adrenal insufficiency in infancy and early childhood, leading to hypogonadotropic hypogonadism in adulthood; however, few adult cases have been reported to date. In this study, we examined a Chinese family with one adult patient with CAH, and identified a putative variant of NR0B1 gene via next-generation sequencing (NGS), which was confirmed with Sanger sequencing. A novel nonsense variant (c.265C>T) was identified in the NR0B1 gene, which caused the premature termination of DAX-1 at residue 89 (p.G89*). Furthermore, mutant NR0B1 gene displayed a partial DAX-1 function, which may explain the late pathogenesis in our case. Additionally, qPCR revealed the abnormal expression of four important genes identified from ChIP-seq, which were associated with energy homeostasis and steroidogenesis, and were influenced by the DAX-1 mutant. In addition, hormone disorders can be caused by DAX-1 mutant and partially recovered by siRNA of PPARGC1A. Herein, we identified a novel nonsense variant (c.265C>T) of NR0B1 in a 24-year-old Chinese male who was suffering from CAH. This mutant DAX-1 protein was found to have disordered energy homeostasis and steroidogenesis based on in vitro studies, which was clinically consistent with the patient’s phenotypic features.

scholarly journals Importance and Antimicrobial Resistance of Mycoplasma bovis in Clinical Respiratory Disease in Feedlot Calves

Animals ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1470
Author(s):  
Ana García-Galán ◽  
Juan Seva ◽  
Ángel Gómez-Martín ◽  
Joaquín Ortega ◽  
Francisco Rodríguez ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Clinical Signs ◽  
Antimicrobial Treatment ◽  
Mycoplasma Bovis ◽  
Bacterial Disease ◽  
Feedlot Calves ◽  
Fixed Panel

Bovine respiratory disease (BRD) is an important viral and/or bacterial disease that mainly affects feedlot calves. The involvement of Mycoplasma bovis in BRD can lead to chronic pneumonia poorly responsive to antimicrobial treatment. Caseonecrotic bronchopneumonia is a pulmonary lesion typically associated with M. bovis. In Spain, M. bovis is widely distributed in the feedlots and circulating isolates are resistant to most antimicrobials in vitro. However, the role of this species in clinical respiratory disease of feedlot calves remains unknown. Furthermore, available data are relative to a fixed panel of antimicrobials commonly used to treat BRD, but not to the specific set of antimicrobials that have been used for treating each animal. This study examined 23 feedlot calves raised in southeast Spain (2016–2019) with clinical signs of respiratory disease unresponsive to treatment. The presence of M. bovis was investigated through bacteriology (culture and subsequent PCR), histopathology and immunohistochemistry. The pathogen was found in 86.9% (20/23) of the calves, mainly in the lungs (78.26%; 18/23). Immunohistochemistry revealed M. bovis antigens in 73.9% (17/23) of the calves in which caseonecrotic bronchopneumonia was the most frequent lesion (16/17). Minimum inhibitory concentration assays confirmed the resistance of a selection of 12 isolates to most of the antimicrobials specifically used for treating the animals in vivo. These results stress the importance of M. bovis in the BRD affecting feedlot calves in Spain.

Effect of hydrocortisone dose schedule on adrenal steroid secretion in congenital adrenal hyperplasia

1985 ◽  
Vol 106 (1) ◽  
pp. 137-142 ◽  
Author(s):  
Jorg Winterer ◽  
George P. Chrousos ◽  
D. Lynn Loriaux ◽  
Gordon B. Cutler
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Dose Schedule ◽  
Adrenal Hyperplasia ◽  
Steroid Secretion ◽  
Adrenal Steroid

scholarly journals The role of imaging in congenital adrenal hyperplasia

2014 ◽  
Vol 58 (7) ◽  
pp. 701-708 ◽  
Author(s):  
Sara Reis Teixeira ◽  
Paula Condé Lamparelli Elias ◽  
Marco Túlio Soares Andrade ◽  
Andrea Farias Melo ◽  
Jorge Elias Junior
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Tumors ◽  
Adrenal Hyperplasia ◽  
Salt Wasting ◽  
Testicular Adrenal Rest Tumors ◽  
High Incidence ◽  
Adrenal Rest ◽  
Hormonal Evaluation

Congenital adrenal hyperplasia (CAH) is an autossomic recessive disorder caused by impaired steroidogenesis. Patients with CAH may present adrenal insufficiency with or without salt-wasting, as well as various degrees of virilization and fertility impairment, carrying a high incidence of testicular adrenal rest tumors and increased incidence of adrenal tumors. The diagnosis of CAH is made based on the adrenocortical profile hormonal evaluation and genotyping, in selected cases. Follow-up is mainly based on hormonal and clinical evaluation. Utility of imaging in this clinical setting may be helpful for the diagnosis, management, and follow-up of the patients, although recommendations according to most guidelines are weak when present. Thus, the authors aimed to conduct a narrative synthesis of how imaging can help in the management of patients with CAH, especially focused on genitography, ultrasonography, computed tomography, and magnetic resonance imaging.

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