Superior discriminating value of ACTH‐stimulated serum 21‐deoxycortisol in identifying heterozygote carriers for 21‐hydroxylase deficiency

Costa-Barbosa, Flávia A.; Tonetto-Fernandes, Vânia F.; Carvalho, Valdemir Melechco; Nakamura, Odete H.; Moura, Vivian de Oliveira; Bachega, Tânia A. S. S.; Vieira, José Gilberto H.; Kater, Cláudio E.

doi:10.1111/j.1365-2265.2010.03871.x

Cited by 42 publications

(40 citation statements)

References 37 publications

(55 reference statements)

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“…The high diagnostic value of 21-deoxycortisol has previously been observed by others [41] and by us [42], confirming our conclusion. In contrast, the 17-hydroxyprogesterone MoM cutoff alone – although sensitive – is not specific for 21OHD, since it can be elevated in ACC and in obesity as well.…”

Section: Discussionsupporting

confidence: 82%

Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units

et al. 2018

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Background/Aims: The high complexity of pediatric reference ranges across age, sex, and units impairs clinical application and comparability of steroid hormone data, e.g., in congenital adrenal hyperplasia (CAH). We developed a multiples-of-median (MoM) normalization tool to overcome this major drawback in pediatric endocrinology. Methods: Liquid chromatography tandem mass spectrometry data comprising 10 steroid hormones representing 905 controls (555 males, 350 females, 0 to > 16 years) from 2 previous datasets were MoM transformed across age and sex. Twenty-three genetically proven CAH patients were included (21-hydroxylase deficiency [21OHD], n = 19; 11β-hydroxylase deficiency [11OHD], n = 4). MoM cutoffs for single steroids predicting 21OHD and 11OHD were computed and validated through new, independent patients (21OHD, n = 8; adrenal cortical carcinoma, n = 6; obesity, n = 40). Results: 21OHD and 11OHD patients showed disease-typical, easily recognizable MoM patterns independent of age, sex, and concentration units. Two single-steroid cutoffs indicated 21OHD: 3.87 MoM for 17-hydroxyprogesterone (100% sensitivity and 98.83% specificity) and 12.28 MoM for 21-deoxycortisol (94.74% sensitivity and 100% specificity). A cutoff of 13.18 MoM for 11-deoxycortisol indicated 11OHD (100% sensitivity and 100% specificity). Conclusions: Age- and sex-independent MoMs are straightforward for a clinically relevant display of multi-steroid patterns. In addition, defined single-steroid MoMs can serve alone as predictors of 21OHD and 11OHD. Finally, MoM transformation offers substantial enhancement of routine and scientific steroid hormone data exchange due to improved comparability.

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Section: Discussionsupporting

confidence: 82%

Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units

et al. 2018

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“…The Janzen et al (21) study thus supports our present strategy of including 21S and cortisol rather than 17OHP/DOC for sensitive and specific detection of the carrier status. We also did not find the significant correlation between 17OHP and 21S published by Costa-Barbosa et al (23). This is possibly due to the fact that we only studied asymptomatic heterozygous carriers instead of non-classic CAH patients.…”

Section: Discussionmentioning

confidence: 37%

LC–MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers

Kulle

Riepe

Hedderich

et al. 2015

European Journal of Endocrinology

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Objective: Heterozygosity in 21-hydroxylase deficiency (21OHD) has been associated with hyperandrogenemic symptoms in children and adults. Moreover, the carrier status is mandatory for genetic counseling. We aimed at defining a hormonal parameter for carrier detection by mass spectrometry. Design: Eleven basal and ACTH-stimulated steroid hormones of heterozygous carriers of CYP21A2 mutations and control individuals were compared. Method: Hormones were determined in plasma samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 58 carriers (35 males, 23 females, age range 6-78 years) and 44 random controls (25 males, 19 females, age range 8-58 years). Results: Heterozygotes could be identified best applying the 17-hydroxyprogesteroneC21-deoxycortisol/cortisol!1000 ((17OHPC21S)/F!1000) equation 30 min after ACTH injection. An optimal cut-off value of 8.4 provided 89% sensitivity and specificity. Considering this data and a published frequency of heterozygotes of 1/50 to 1/61, the positive predictive value (PPV) of this cut-off is 12%. Of note, the negative predictive value (NPV) excluding heterozygosity in a given patient is 99.8%. Conclusion: Considering only marginal biochemical effects anticipated from heterozygosity, the stimulated ((17OHPC21S)/ F!1000) identifies and excludes heterozygotes remarkably well. Nevertheless, LC-MS/MS cannot replace genetic testing, since sensitivity and specificity did not reach 100%. However, due to the considerably high NPV of the optimal cut-off and to a specificity of even 100% applying a cut-off higher than 14.7, hormonal assessment of heterozygosity can be of significant aid in conditions with limited access to genetic testing, as in some health care systems. The ((17OHPC21S)/F!1000) equation can guide diagnostic considerations in the differential diagnosis of hyperandrogenism.

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“…Besides the usefulness of 21-Deox determination in differential diagnostics, the results of an earlier study suggested that 21-Deox might be superior to 17-OHP in the identification of heterozygote carriers for a 21-OH deficiency following an adrenocorticotropic hormone stimulation test [25]. The true value of this latter observation is yet to be elucidated.…”

Section: Discussionmentioning

confidence: 94%

Concurrent Confirmation and Differential Diagnosis of Congenital Adrenal Hyperplasia from Dried Blood Spots: Application of a Second-Tier LC-MS/MS Assay in a Cross-Border Cooperation for Newborn Screening

et al. 2015

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Background/Aims: Newborn screening for congenital adrenal hyperplasia (CAH) is generally performed using 17- hydroxyprogesterone dissociation-enhanced, lanthanide fluorescence immunoassay (DELFIA®). The primary screening results must be confirmed due to high false-positive rates; however, the need to obtain a separate specimen can hamper early recognition, differential diagnosis and treatment. We aimed to develop a single liquid chromatography-tandem mass spectrometry (LC-MS/MS) method that allows both the confirmation and differential diagnosis of CAH using the same dried blood spot (DBS) as in primary screening. Methods: An LC-MS/MS assay for cortisol, 21-deoxycortisol, 11-deoxycortisol, 4-androstenedione and 17-hydroxyprogesterone was developed, validated and applied to a total of 163 DBS samples tested positive in primary newborn screening in a cross-border cooperation. Results: Excellent baseline resolution and reliable determination of all analytes were achieved in DBS samples following simple sample preparation without derivatization. Of a total of 163 DBS samples tested positive in primary screening, the 21-hydroxylase-deficient form of CAH was confirmed in 1 sample. Conclusions: The present LC-MS/MS assay was successfully applied as a second-tier test in a cross-border cooperation for newborn screening. The assay allows concurrent confirmation and differential diagnosis of CAH and can be performed on the same DBS samples as in primary screening, enabling early diagnosis and treatment.

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Superior discriminating value of ACTH‐stimulated serum 21‐deoxycortisol in identifying heterozygote carriers for 21‐hydroxylase deficiency

Cited by 42 publications

References 37 publications

Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units

Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units

LC–MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers

Concurrent Confirmation and Differential Diagnosis of Congenital Adrenal Hyperplasia from Dried Blood Spots: Application of a Second-Tier LC-MS/MS Assay in a Cross-Border Cooperation for Newborn Screening

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