Identification of heterozygote carriers of congenital adrenal hyperplasia by radioimmunoassay of serum 17-OH progesterone

In a group of 18 unrelated Danish children with 21 -hydroxylase deficiency (21 -OH def), human leukocyte antigen (HLA) typing revealed a significant increase of Bw47 and a significant decrease of B8. HLA studies of the families of 14 probands predicted among the siblings 11 heterozygote carriers and 3 genetically unaffected. Glyoxalase studies showed a recombination fraction of 8%. ACTH-stimulated 17-OH progesterone is the only hormone value useful in the discrimination between heterozygotes and normals. Two families are described in detail. In one family, one of two HLA-identical brothers had classical virilizing congenital adrenal hyperplasia (CAH), while the other was a normal boy without 21 -OH def. In another family with 3 girls, one had classical, salt-wasting CAH, one had ‘late onset’ CAH, and the third sister and the father shared the HLA-B14 antigen and were shown to have ‘cryptic’21-OH def.

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“…3.2 pg/1 [27], The upper limit in non-affected siblings was 1.7 pg/1 -at the same level as found in other studies: 1.5 [22,27] and 2.0 pg/1 [25].…”

Section: Resultssupporting

confidence: 88%

Heterozygotes and Cryptic Patients in Families of Patients with Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Petersen¹,

Svejgaard²,

Nielsen³

et al. 1982

Horm Res

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“…At the hormone level, heterozygotes have normal or only slightly elevated basal plasma levels of 17-hydroxyprogesterone (17OHP) (3). Following corticotrophin (ACTH) injection, heterozygotes usually show an increased rise of 17OHP compared with controls, but it is not possible to identify heterozygosity based on stimulated 17OHP alone (11,12,13,14). A different approach to detect heterozygotes is the calculation of substrate-to-product ratios.…”

Section: Introductionmentioning

confidence: 99%

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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“…Once an index case has been identified, relatives are often eager to ascertain their carrier status and, hence, risk for affected offspring. [Krensky et al, 1977]. To determine the sensitivity of ACTH stimulation tests and to determine whether the magnitude of ACTH-stimulated steroid hormone responses correlated with molecular genotype, we compared the 21-hydroxylase molecular genotype with steroid hormone responses in 51 individuals.…”

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confidence: 99%

Identification of heterozygotic carriers of 21-hydroxylase deficiency: Sensitivity of ACTH stimulation tests

Witchel

Lee

1998

Am. J. Med. Genet.

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common autosomal-recessive disorder. To ascertain carrier status, adrenocorticotropin (ACTH) stimulation tests are often used. To determine the sensitivity of ACTH stimulation to detect heterozygotes and to correlate stimulated 17-hydroxyprogesterone responses with molecular genotype, we compared molecular genetic analysis of the 21-hydroxylase (CYP21) gene with 17-hydroxyprogesterone responses at 30 min in 51 individuals. Molecular genotype analysis and ACTH stimulation tests were performed in healthy volunteers (n = 20) and relatives of patients with congenital adrenal hyperplasia (n = 31). Polymerase chain reaction (PCR) amplification, single-strand conformational polymorphism (SSCP) analysis, allele-specific oligonucleotide hybridization (ASOH) analysis, and restriction fragment length polymorphism (RFLP) analysis were utilized to screen for 14 CYP21 mutations which account for >90% of the mutations associated with 21-hydroxylase deficiency. Molecular genotype analysis classified 28 individuals as heterozygotic carriers and 23 individuals as normal for all mutations tested. As a group, the heterozygotes had significantly greater stimulated 17-hydroxyprogesterone responses at 10 and 30 min (P < 0.0005). However, on an individual basis, 14/28 (50%) genotyped heterozygotic carriers had stimulated 17-hydroxyprogesterone concentrations, 17-hydroxyprogesterone/cortisol ratios, and 17-hydroxyprogesterone incremental elevations indistinguishable from the genotyped normal individuals. Thus, a normal 17-hydroxyprogesterone response to ACTH stimulation testing does not exclude carrier status for 21-hydroxylase deficiency. Molecular genotype analysis is a more reliable method to determine 21-hydroxylase heterozygotes.

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Identification of heterozygote carriers of congenital adrenal hyperplasia by radioimmunoassay of serum 17-OH progesterone

Cited by 56 publications

References 8 publications

Heterozygotes and Cryptic Patients in Families of Patients with Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Heterozygotes and Cryptic Patients in Families of Patients with Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

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

Identification of heterozygotic carriers of 21-hydroxylase deficiency: Sensitivity of ACTH stimulation tests

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