Heterozygote detection in congenital adrenal hyperplasia.

Handelsman, D J; Howe, Christopher J.; Conway, Ann J.; Turtle, J. R.

doi:10.1093/clinchem/29.1.48

Cited by 6 publications

(4 citation statements)

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“…The prevalence of classic 21-OH deficiency is high, affecting about 1 in 10,000 individuals (1, 4), whereas heterozygocity for this disorder varies considerably, ranging from 1 in 20 to 1 in 60 in large populations and ethnic groups (5,6). Following ACTH stimulation, carriers of 21-OH deficiency display increased secretion of cortisol precursors, including 17-hydroxyprogesterone (17-OHP), and lower concentrations of 11-deoxycorticosterone and aldosterone, compared with normal subjects (7)(8)(9)(10). In 50 -80% of 21-OH deficiency carriers, 17-OHP responses to ACTH stimulation fall above the 95th percentile for the control population (7)(8)(9)(10), indicating that the majority of these subjects may have mild impairment in cortisol biosynthesis and, consequently, compensatory increases of hypothalamic CRH secretion.…”

Section: -2236 2004)mentioning

confidence: 99%

Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Charmandari¹,

Merke

Negro

et al. 2004

The Journal of Clinical Endocrinology & Metabolism

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Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 +/- 3.4 vs. 42.7 +/- 6.4 microg/d, P = 0.03) and higher peak ACTH (75.7 +/- 8.1 vs. 54.2 +/- 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 +/- 28.1 vs. 107.1 +/- 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.

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Section: -2236 2004)mentioning

confidence: 99%

Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Charmandari¹,

Merke

Negro

et al. 2004

The Journal of Clinical Endocrinology & Metabolism

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“…Several studies from various groups have conveyed that between 50 and 80% of carriers exhibit a 17-OHP level after ACTH stimulation and that is above the 95th percentile of the control value [ 37 , 39 , 42 , 45 ]. The purpose of this study was to determine the frequency of identified defects of the CYP21A2 gene and also to weigh the regulatory 3′UTR region of the gene in a clinically symptomatic cohort of 169 females, characterized by hyperandrogenaemia.…”

Section: Introductionmentioning

confidence: 99%

Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia

Neocleous

Fanis

Toumba

et al. 2017

International Journal of Endocrinology

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Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the ∗52C>T, ∗440C>T, and ∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the ∗12C>T and ∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.

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“…Compared to normal female individuals, female carriers of 21-OHD frequently demonstrate an exaggerated secretion of the 21-OH precursor 17-OHP after ACTH administration ( 51 ). It has been reported that 50-80% of carriers exhibit 17-OHP levels above the 95 th percentile of the control level after ACTH stimulation ( 51 , 52 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

17-Hydroxyprogesterone Response to Standard Dose Synacthen Stimulation Test in CYP21A2 Heterozygous Carriers and Non-carriers in Symptomatic and Asymptomatic Groups: Meta-analyses

Polat¹,

Arslan²

2022

Jcrpe

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Objective: Standard dose synacthen stimulation test (SDSST) is a gold standard screening test for evaluating adrenal gland function. Despite studies using SDSST to identify heterozygosity in CYP21A2 , the reliability of the test for this purpose is still controversial. Therefore, the meta-analyses were performed to determine the differences in 17-hydroxyprogesterone (17-OHP) responses to standard dose (0.25 mg) SDSST in the diagnosis of CYP21A2 heterozygous individuals, with or without clinical signs of androgen excess disorders. Methods: PubMed and MEDLINE databases were searched. A total of 1215 subjects (heterozygous carriers n=669, mutation-free controls n=546) were included in the meta-analyses. Results: Basal 17-OHP median/mean levels were 4.156 (3.05-10.5)/5.241 (±2.59) nmol/L and 3.90 (2.20-9.74)/4.67 (±2.62) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Stimulated 17-OHP median/mean levels were 17.29 (14.22-37.2)/19.51 (±7.63) nmol/L and 9.27 (7.32-15.9)/10.77 (±3.48) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Basal 17-OHP median/mean levels were 3.21 (2.64-4.78)/3.33 (±0.84) nmol/L and 3.12 (1.82-3.6)/2.83 (±0.71) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. Stimulated 17-OHP median/mean levels were 14.16 (12.73-16.37)/14.16 (±1.37) nmol/L and 6.26 (4.9-8.23)/6.48 (±1.2) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. The cut-off levels for stimulated 17-OHP were 10.48 nmol/L and 13.48 nmol/L for asymptomatic heterozygous and symptomatic heterozygous, respectively. Conclusion: The meta-analyses support the idea that stimulated 17-OHP level has potential for use in identifying CYP21A2 carriers. Besides, considering differences in the basal and stimulated 17-OHP levels in symptomatic heterozygous individuals compared to those who were asymptomatic heterozygous could increase the accuracy of the test.

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Heterozygote detection in congenital adrenal hyperplasia.

Cited by 6 publications

References 0 publications

Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia

17-Hydroxyprogesterone Response to Standard Dose Synacthen Stimulation Test in CYP21A2 Heterozygous Carriers and Non-carriers in Symptomatic and Asymptomatic Groups: Meta-analyses

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