Reverse circadian glucocorticoid treatment in prepubertal children with congenital adrenal hyperplasia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ilja Dubinski ◽  
Susanne Bechtold Dalla-Pozza ◽  
Martin Bidlingmaier ◽  
Nicole Reisch ◽  
Heinrich Schmidt
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Pubertal Development ◽  
Adrenal Crisis ◽  
Adrenal Hyperplasia ◽  
Glucocorticoid Treatment ◽  
Steroid Synthesis ◽  
Prepubertal Children ◽  
Salt Wasting ◽  
17 Hydroxyprogesterone

Abstract Objectives Children with salt-wasting congenital adrenal hyperplasia (CAH) have an impaired function of steroid synthesis pathways. They require therapy with glucocorticoid (GC) and mineralocorticoid hormones to avoid salt-wasting crisis and other complications. Most commonly, children receive hydrocortisone thrice daily with the highest dose in the morning, mimicking the regular physiology. However, reverse circadian treatment (RCT) had been suggested previously. In this study, we aimed to determine the efficacy of RCT in prepubertal children with CAH by comparing the salivary 17-hydroxyprogesterone (s17-OHP) levels individually. Methods In this retrospective study, we analyzed the records of children with classical CAH and RCT who were monitored by s17-OHP levels. The study included 23 patients. We identified nine prepubertal children with RCT schemes (three boys and six girls) and compared the s17-OHP levels in the morning, afternoon, and evening. The objective of this study was to demonstrate the non-effectiveness of RCT in terms of lowering the morning s17-OHP concentration. In addition, we compared s17-OHP day profiles in six patients on RCT and non-RCT therapy (intraindividually). Results Eight of nine children with RCT showed higher s17-OHP levels in the morning compared to the evening. In addition, none of the children showed a significant deviation of development. Three children were overweight. No adrenal crisis or pubertal development occurred. Comparison of RCT and non-RCT regimens showed no difference in 17-OHP profiles. Conclusions Our data do not support the use of RCT schemes for GC replacement in children with CAH due to lack of benefits and unknown long-term risks.

scholarly journals Late consequences of classic congenital adrenal hyperplasia and its long-term poor control in men (case report and literature review)

2020 ◽  
Vol 16 (4) ◽  
pp. 90-102 ◽  
Author(s):  
Boris M. Shifman ◽  
Larisa K. Dzeranova ◽  
Ekaterina A. Pigarova ◽  
Anatoly N. Tiulpakov ◽  
Natalia S. Fedorova
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive Disorder ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Glucocorticoid Treatment ◽  
Salt Wasting ◽  
Adult Age ◽  
Chronic Disorder ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of the adrenal cortex characterized by impairment of cortisol biosynthesis (with possible impairment of aldosterone biosynthesis) and excessive pituitary ACTH release, which promotes oversecretion of intact pathways products: 17-hydroxyprogesterone (17OHP), progesterone, and adrenal androgens androstendione and testosterone. 21-hydroxylase deficiency, being the most common cause of congenital adrenal hyperplasia is a chronic disorder, that requires life-long glucocorticoid treatment, that aims both to replace cortisol and prevent ACTH-driven androgen excess. Nevertheless, reaching the optimal glucocorticoid dose is challenging because currently available glucocorticoid formulations cannot replicate the physiological circadian rhythm of cortisol secretion. The difficulties in striking the balance between uneffective normalizing of ACTH-level and excess glucocorticoid exposure leads to different abnormalities, that starts to develop at first months of life and progress, frequently gaining especial clinical meaning in adult age. In the present clinical case we introduce 35 years old male patient with salt-wasting form of 21-hydroxylase deficiency, which had either complications considered to progress due to insufficient glucocorticoid therapy, and some metabolic abnormalities, associated with supraphysiological doses of glucocorticoids.

scholarly journals Graves’ Thyrotoxicosis Leading to Adrenal Decompensation and Hyperandrogenemia in a Pediatric Patient with Salt-Wasting Congenital Adrenal Hyperplasia

2018 ◽  
Vol 2018 ◽  
pp. 1-3
Author(s):  
Meghan E. Fredette ◽  
Lisa Swartz Topor
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Crisis ◽  
Adrenal Hyperplasia ◽  
Free T4 ◽  
Adrenal Androgens ◽  
Case Presentation ◽  
Adrenal Hormones ◽  
Salt Wasting ◽  
Glucocorticoid Deficiency ◽  
Stress Dose

Introduction. Thyroid hormone is known to accelerate glucocorticoid turnover. In a thyrotoxic state, individuals with adrenal insufficiency are unable to increase endogenous cortisol production to compensate for increased turnover, placing them at risk for symptoms of glucocorticoid deficiency and adrenal crisis. In patients with salt-wasting congenital adrenal hyperplasia (SW-CAH), hyperandrogenemia is a measurable reflection of relative glucocorticoid insufficiency. Case Presentation. A 12-year-old girl with SW-CAH reported 3 recent episodes of vomiting without diarrhea, and accompanying tachycardia, responsive to stress dose steroids. In the previous 9 months, she unintentionally lost 2.6 kg. She had tachycardia and new thyromegaly. Labs showed suppressed TSH, elevated free T4 and total T3, and elevated thyroid stimulating immunoglobulin (TSI) consistent with Graves’ disease. Adrenal androgens were markedly elevated. Maintenance hydrocortisone dose was 25 mg/m2/day and was not changed. Methimazole was initiated. Four weeks later, free T4 and adrenal androgens normalized. She had no further vomiting episodes. Conclusions. Thyrotoxicosis must be included in the differential diagnosis of individuals with SW-CAH who present with episodes concerning for adrenal crises, escalating hydrocortisone requirements, and/or inadequate suppression of adrenal hormones.

scholarly journals Sodium Chloride Supplementation Is Not Routinely Performed in the Majority of German and Austrian Infants with Classic Salt-Wasting Congenital Adrenal Hyperplasia and Has No Effect on Linear Growth and Hydrocortisone or Fludrocortisone Dose

2017 ◽  
Vol 89 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Walter Bonfig ◽  
Friedhelm Roehl ◽  
Stefan Riedl ◽  
Jürgen Brämswig ◽  
Annette Richter-Unruh ◽  
...  
Keyword(s):  
Sodium Chloride ◽  
Congenital Adrenal Hyperplasia ◽  
Routine Care ◽  
Sodium Content ◽  
Adrenal Crisis ◽  
First Year ◽  
Adrenal Hyperplasia ◽  
Salt Wasting ◽  
First Year Of Life ◽  
Oral Sodium

Introduction: Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous. Objective: To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database. Results: Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999–2004 to 37.5% in children born 2011–2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life. Conclusion: In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis.

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.

scholarly journals Congenital Adrenal Hyperplasia with Salt Wasting Crisis: A Case Report

2020 ◽  
Vol 58 (221) ◽  
Author(s):  
Deependra Mandal ◽  
Deepa Khanal ◽  
Rajan Phuyal ◽  
Uttara Adhikari
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Elevated Level ◽  
Autosomal Recessive ◽  
Oral Prednisolone ◽  
Severe Form ◽  
Adrenal Hyperplasia ◽  
Autosomal Recessive Disorders ◽  
Salt Wasting ◽  
17 Hydroxyprogesterone ◽  
Recessive Disorders

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders due to deficienciesof enzymes involved in steroidogenesis. The most common form is a 21-hydroxylase deficiencywhich can be classical or non-classical. The severe form also called Classical Congenital AdrenalHyperplasia is usually detected after birth to infant period. If Congenital Adrenal Hyperplasia is notdiagnosed and treated early, neonates are susceptible to sudden death in the early weeks of life. Wereport a case of thirty-five days male with a salt-wasting variant of congenital adrenal hyperplasia.The diagnosis was based on an elevated level of 17-hydroxyprogesterone. He was managed and lifelong oral Prednisolone and Fludrocortisone were prescribed.

scholarly journals Adverse Effects of Ramadan Fasting in a Girl with Salt-Losing Congenital Adrenal Hyperplasia

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Valeria Calcaterra ◽  
Francesco Bassanese ◽  
Andrea Martina Clemente ◽  
Rossella Amariti ◽  
Corrado Regalbuto ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Insufficiency ◽  
Treatment Plan ◽  
Management Plan ◽  
Hormonal Control ◽  
Adrenal Crisis ◽  
Adrenal Hyperplasia ◽  
Ramadan Fasting ◽  
Salt Wasting ◽  
Classic Form

Objective. Congenital adrenal hyperplasia (CAH) is the most common cause of adrenal insufficiency in pediatrics. Chronic glucocorticoid replacement is the mainstay of treatment in the classic forms of CAH, and mineralocorticoid replacement therapy is mandatory in the salt-wasting form. Fasting is a mild stressor, which can expose to dehydration, hypotension, hypoglycemia, and acute adrenal crisis in patients with adrenal insufficiency. Case. We report the case of an adolescent affected by the classic form with salt-losing CAH, who observed Ramadan for 30 days, without individualized therapeutic management plan. After Ramadan, a dramatic increase of ACTH level (1081 pg/ml, n.v. 6–57), reduced cortisolemia, tendency to hypotension, and weight loss were recorded. She experienced insomnia, intense thirst, asthenia, and headache. The symptoms disappeared restarting the previous therapy schedule and increasing the total hydrocortisone daily dose with progressive restoring of hormonal control. Conclusion. Our case confirms that patients with CAH are vulnerable, especially during fasting in Ramadan, with a higher risk of acute adrenal crisis. CAH patients should reform and individualize their treatment plan and be submitted to careful monitoring.

scholarly journals Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia

2019 ◽  
Author(s):  
Leif Karlsson ◽  
Michela Barbaro ◽  
Ewoud Ewing ◽  
David Gomez-Cabrero ◽  
Svetlana Lajic
Keyword(s):  
Dna Methylation ◽  
Congenital Adrenal Hyperplasia ◽  
Hdl Cholesterol ◽  
Adrenal Hyperplasia ◽  
Blood Lipid Profile ◽  
Glucocorticoid Treatment ◽  
C Peptide ◽  
Genome Wide ◽  
Metabolic Outcome

AbstractBackgroundPatients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome.MethodsWe analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 ±6.5 years [y]) and 37 population controls (mean age=17.0 ±6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, glucose homeostasis, blood lipid profile and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age=19.1, ±6.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment.ResultsWe identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p=0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p=0.044 and p=0.034) and genotype (p=0.044 and p=0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035).ConclusionIn conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH.

Scalp hair 17-hydroxyprogesterone and androstenedione as a long-term therapy monitoring tool in congenital adrenal hyperplasia

2016 ◽  
Vol 85 (4) ◽  
pp. 522-527 ◽  
Author(s):  
Gerard Noppe ◽  
Yolanda B. de Rijke ◽  
Jan W. Koper ◽  
Elisabeth F.C. van Rossum ◽  
Erica L.T. van den Akker
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Scalp Hair ◽  
Therapy Monitoring ◽  
Term Therapy ◽  
Adrenal Hyperplasia ◽  
Monitoring Tool ◽  
17 Hydroxyprogesterone ◽  
Long Term Therapy

The effects of long-term normalization of sodium balance on linear growth in disorders with aldosterone deficiency

1983 ◽  
Vol 102 (4) ◽  
pp. 577-582 ◽  
Author(s):  
Ursula Kuhnle ◽  
Ariel Rösler ◽  
Judith A. Pareira ◽  
Peter Gunzcler ◽  
Lenore S. Levine ◽  
...  
Keyword(s):  
Plasma Renin Activity ◽  
Linear Growth ◽  
Pubertal Development ◽  
Normal Growth ◽  
Plasma Renin ◽  
Sodium Balance ◽  
Adrenal Hyperplasia ◽  
Glucocorticoid Replacement Therapy ◽  
17 Hydroxyprogesterone

Abstract. The effect of normalization of sodium balance was evaluated in children with aldosterone deficiency of several etiologies. In salt-losing congenital adrenal hyperplasia (CAH), treatment with a mineralocorticoid in doses that normalized plasma renin activity (PRA) induced a marked increase in linear growth. Serum 17-hydroxyprogesterone (17-OHP) and androgens fell further when adequate sodium balance was achieved, allowing in some cases a reduction in glucocorticoid replacement dose. Together with PRA measurement they were the most sensitive indicators of adequate mineralocorticoid and glucocorticoid replacement therapy. In 2 teenage children with aldosterone deficiency due to Addison's and autoimmune polyglandular disease similar improvement in growth as well as onset of puberty occurred when sodium balance was normalized by increased mineralocorticoid therapy. These studies show that adequate sodium balance is essential for normal growth and pubertal development.

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