A 4-hour Profile of 17-hydroxyprogesterone in Salt-wasting Congenital Adrenal Hyperplasia: Is the Serial Monitoring Strategy Worth the Effort?

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.

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Congenital Adrenal Hyperplasia with Salt Wasting Crisis: A Case Report

Journal of Nepal Medical Association ◽

10.31729/jnma.4811 ◽

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.

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Reverse circadian glucocorticoid treatment in prepubertal children with congenital adrenal hyperplasia

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0540 ◽

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.

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

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0166 ◽

2017 ◽

Vol 30 (12) ◽

Cited By ~ 2

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.

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Late-diagnosed salt-wasting congenital adrenal hyperplasia in adult patient

Problems of Endocrinology ◽

10.14341/probl8813 ◽

2018 ◽

Vol 64 (2) ◽

pp. 105-110

Author(s):

Liudmila Ya. Rozhinskaya ◽

Natalia Yu. Kalinchenko ◽

Zhanna E. Belaya ◽

Tatiana S. Zenkova ◽

Alexander S. Lutsenko ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Molecular Genetic ◽

Gas Chromatography Mass Spectrometry ◽

Adrenal Hyperplasia ◽

Molecular Genetic Study ◽

Hydroxylase Deficiency ◽

Salt Wasting ◽

Adrenal Cortical Adenoma ◽

17 Hydroxyprogesterone ◽

21 Hydroxylase Deficiency

We describe a unique case of diagnosing salt-wasting congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency in a 32-year-old male patient. Before establishing the diagnosis, the main patient complaint was infertility. In childhood, the patient suffered from developmental delay, often illness, overconsumption of salt, and often vomiting; he stopped growing at the age of 12 years. In the adolescent period, his physical condition improved. Later, the patient got married, but was infertile. Plasma steroid profiling by gas chromatography-mass spectrometry (GC-MS) revealed markedly increased levels of 17-hydroxyprogesterone and 21-deoxycortisol and a decreased cortisol level, which enabled the diagnosis of CAH and 21-hydroxylase deficiency. The diagnosis was confirmed by a molecular genetic study that detected a CYP21 gene mutation — l2 splice in the homo(hemi)zygotic state, which was characteristic of the salt-wasting form of CAH. Also, the patient had secondary adrenal cortical adenoma caused by prolonged ACTH hyperstimulation and secondary hypogonadism associated with excessive production of adrenal androgens, which led to elevated levels of estrogens inhibiting production of LH and FSH. Treatment of the patient with glucocorticoids and mineralocorticoids and then with androgens improved his clinical condition and hormonal parameters.

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Analysis of the Screening Results for Congenital Adrenal Hyperplasia Involving 7.85 Million Newborns in China: A Systematic Review and Meta-Analysis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.624507 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhuoguang Li ◽

Lianjing Huang ◽

Caiqi Du ◽

Cai Zhang ◽

Mini Zhang ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Data Extraction ◽

Meta Analysis ◽

Genetic Diseases ◽

Recall Rate ◽

Cochrane Library ◽

Adrenal Hyperplasia ◽

Salt Wasting ◽

Significant Difference ◽

17 Hydroxyprogesterone

BackgroundCongenital adrenal hyperplasia (CAH) is a group of congenital genetic diseases caused by defective steroidogenesis. Our study aims to systematically analyze the screening results for CAH in Chinese newborns.MethodsStudies were searched from PubMed, Web of Science, Cochrane library and some Chinese databases up to September, 2020. Meta-analysis was performed after quality assessment and data extraction.ResultsAfter a review of 2 694 articles, we included 41 studies enrolling 7 853 756 newborns. In our study, we found that the incidence of CAH in China was 0.43‱ [95% confidence intervals(CI), (0.39‱, 0.48‱)], or 1/23 024 [95%CI, (1/25 757,1/20 815)]. 27 studies were included for analysis of the screening positive rate, which gave a rate of 0.66% [95%CI, (0.54%, 0.78%)]. As for the recall rate of positive cases, 17 studies were included and showed that the recall rate reached 86.17% [95%CI, (82.70%, 89.64%)]. Among the CAH patients, the ratio of males to females was 1.92:1 (119:62), and the ratio of salt wasting (SW) to simple virilization (SV) type was 3.25:1 (104:32). The average 17-hydroxyprogesterone (17-OHP) value of CAH was 393.40 ± 291.85 nmol/L (Range 33-1 300 nmol/L); there was no significant difference between male and female patients (437.17 ± 297.27 nmol/L v.s. 322.25 ± 293.04 nmol/L, P=0.16), but a significant difference was found between SW and SV patients (483.29 ± 330.07 nmol/L v.s. 73.80 ± 7.83nmol/L, P=0.04).ConclusionWe systematically analyzed the current situation of neonatal CAH screening in China, which will deepen our understanding for future CAH screening and early diagnosis.

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

Obesity and metabolism ◽

10.14341/omet10032 ◽

2020 ◽

Vol 16 (4) ◽

pp. 90-102 ◽

Cited By ~ 1

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.

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Monozygotic twins discordant for congenital adrenal hyperplasia due to mosaicism

Acta Endocrinologica ◽

10.1530/eje-19-0249 ◽

2020 ◽

Vol 182 (2) ◽

pp. K7-K13 ◽

Cited By ~ 1

Author(s):

Michelle L Kluge ◽

Evan Graber ◽

Kathryn Foley ◽

Lynnette V Hansen ◽

Heidi L Sellers ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Cell Line ◽

Gene Deletion ◽

Molecular Genetic ◽

Monozygotic Twins ◽

Adrenal Hyperplasia ◽

Differential Distribution ◽

Salt Wasting ◽

Show Evidence ◽

17 Hydroxyprogesterone

Introduction Genotype-phenotype discordance occurs occasionally in congenital adrenal hyperplasia (CAH). Its causes are largely unknown. We describe a case of monochorionic, diamniotic twins with discordant clinical presentations of CAH, and show evidence for this being due to mosaicism resulting from a postzygotic full gene deletion of CYP21A2 prior to twinning. Case description A 7-day-old 36-week gestation female infant (Twin A) presented to the emergency department with elevated 17-hydroxyprogesterone (17-OHP). Her identical twin (Twin B) had normal 17-OHP on newborn screening. Both twins showed signs of virilization, more pronounced in Twin B. Molecular genetic testing of both twins and their parents showed a WT paternally-inherited CYP21A2 and a maternally-inherited copy containing the c.293-13C>G mutation. Both twins were also found to have a 5′-CYP21A1P/CYP21A2-3′ hybrid (product of the common 30-kb deletion), derived from the deletion of the paternally-inherited CYP21A2. Neither mother nor father carried the deletion. Conclusions The genetic findings are consistent with mosaicism for two CYP21A2 cell lines in both twins. The first cell line is expected, based on parental results, while the second line is due to a postzygotic full gene deletion of the paternally-inherited WT CYP21A2. The resultant genotype, compound heterozygosity for c.293-13C>G and a CYP21A2 full gene deletion, is consistent with a salt-wasting CAH phenotype. Differential distribution of the second cell line between the twins is most likely the cause for their discrepant phenotypes. We believe this is the first report of somatic CYP21A2 mosaicism, and represents a novel cause for discrepant CAH phenotypes in monozygotic twins.

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Abstract #810984: Discordant Serum 17-Hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-Oxygenated-Androgens Useful?

Endocrine Practice ◽

10.1016/s1530-891x(20)39842-6 ◽

2020 ◽

Vol 26 ◽

pp. 39-40

Author(s):

Smita Jha

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

17 Hydroxyprogesterone

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Concurrence of Meningomyelocele and Salt-Wasting Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Case Reports in Pediatrics ◽

10.1155/2015/196374 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4

Author(s):

Heves Kırmızıbekmez ◽

Rahime Gül Yesiltepe Mutlu ◽

Serdar Moralıoğlu ◽

Ahmet Tellioğlu ◽

Ayşenur Cerrah Celayir

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Growth Retardation ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Salt Wasting ◽

Significant Regression ◽

One Year ◽

The One ◽

21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) is a group of inherited defects of cortisol biosynthesis. A case of classical CAH due to 21-hydroxylase deficiency (21-OHD) with early onset of salt waste and concurrence of meningomyelocele (MMC) was presented here. The management of salt-wasting crisis which is complicated by a postrenal dysfunction due to neurogenic bladder was described. Possible reasons of growth retardation in the one-year follow-up period were discussed. A significant regression of the phallus with proper medical treatment was also mentioned.

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