A rational, non-radioactive strategy for the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Coeli-Lacchini, Fernanda Borchers; Turatti, Wendy; Elias, Paula Condé Lamparelli; Elias, Lucila Leico Kagohara; Martinelli, Carlos Eduardo; Moreira, Ayrton Custódio; Antonini, Sonir Roberto Rauber; Castro, Margaret de

doi:10.1016/j.gene.2013.03.082

Cited by 15 publications

(18 citation statements)

References 34 publications

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“… 18 The frequency of the p.Pro30Leu mutation is very low in parts of the world other than Eastern Asia: 3.6% in France, 19 2.0% in Spain, 20 2.2% in Israel, 21 and 1.7% in Brazil. 22 Japanese patients with NC21-OHD were similar to Chinese patients in that the most common mutation was also p.Pro30Leu with a reported allele frequency of 50.0% (7/14 alleles) in one study 23 and 37.5% (6/16 alleles) in another investigation of Japanese patients. 24 This suggests that the characteristics of CYP21A2 mutations might differ between eastern Asian populations and others.…”

Section: Discussionmentioning

confidence: 56%

Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype–phenotype correlations

Zhang

Lü

2017

J Int Med Res

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ObjectiveThe spectrum of molecular defects in Chinese patients with 21-hydroxylase deficiency (21-OHD), and genotype–phenotype relationships are unknown.MethodsWe screened eight patients with non-classical (NC) 21-OHD and 35 with classical 21-OHD, and detected nine known mutations.ResultsThe most frequent mutation among the 43 21-OHD cases was p.Ile172Asn (allele frequency, 36.0%), followed by c.290-13A/C > G (20.9%), Del (8.6%), p.Pro30Leu (7.0%), p.Gln318Ter (7.0%), p.Val281Leu (4.7%), p.Arg356Trp (2.3%), p.[Ile236Asn; Val237Glu; Met239Lys] (2.3%), and E3Δ8 bp (1.2%). The frequency spectrum of CYP21A2 mutations in the Chinese population was similar to that in the Japanese population, except that p.Val281Leu was identified in Chinese NC21-OHD patients at a frequency of 25.0%, whereas it was absent in Japanese patients. We found that genotype could predict phenotype in 88.3% of patients.ConclusionSome characteristics appear to be unique to the Chinese population, but genotype was strongly predictive of phenotype.

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Section: Discussionmentioning

confidence: 56%

Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype–phenotype correlations

Zhang

Lü

2017

J Int Med Res

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“…In Brazil, there is no national database of CAH cases diagnosed in the country, which makes a population-wide study difficult. All patients with CAH in Brazil are referred to tertiary centers, and we know that unscreened cohorts from other CAH centers in São Paulo share similar characteristics with ours, ' such as unbalanced female-to-male and SW-to-SV ratios (55)(56)(57)(58)(59). The burden in some poorer regions of the country is even worse (60).…”

Section: Discussionmentioning

confidence: 52%

The Cost-Effectiveness of Congenital Adrenal Hyperplasia Newborn Screening in Brazil: A Comparison Between Screened and Unscreened Cohorts

Miranda

Haddad

Trindade³

et al. 2021

Front. Pediatr.

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Background: Newborn screening for congenital adrenal hyperplasia (CAH-NBS) is not yet a worldwide consensus, in part due to inconclusive evidence regarding cost-effectiveness because the analysis requires an understanding of the short- and long-term costs of care associated with delayed diagnosis.Objective: The present study aimed to conduct a cost-effectiveness analysis (CEA) to compare the costs associated with CAH-NBS and clinical diagnosis.Methods: A decision model comparing the two strategies was tested by sensitivity analysis. The cost analysis perspective was the public health system. Unscreened patients' data were extracted from medical records of Hospital das Clinicas, Saõ Paulo, and screened data were extracted from the NBS Referral Center of São Paulo. The population comprised 195 classical patients with CAH, clinically diagnosed and confirmed by hormonal/CYP21A2 analysis, and 378,790 newborns screened during 2017. Adverse outcomes related to late diagnosis were measured in both cohorts, and the incremental cost-effectiveness ratio (ICER) was calculated. We hypothesized that CAH-NBS would be cost-effective.Results: Twenty-five screened infants were confirmed with CAH (incidence: 1:15,135). The mortality rate was estimated to be 11% in unscreened infants, and no deaths were reported in the screened cohort. Comparing the unscreened and screened cohorts, mean serum sodium levels were 121.2 mEq/L (118.3–124.1) and 131.8 mEq/L (129.3–134.5), mean ages at diagnosis were 38.8 and 17 days, and hospitalization occurred in 76% and 58% of the salt-wasting patients with the in the two cohorts, respectively. The NBS incremental cost was US$ 771,185.82 per death averted, which yielded an ICER of US$ 25,535.95 per discounted life-year saved.Conclusions: CAH-NBS is important in preventing CAH mortality/morbidity, can reduce costs associated with adverse outcomes, and appears cost-effective.

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“…Exhaustive molecular protocols, including distal regulatory regions, 22 were performed in this peculiar family and nothing was found; nevertheless, we cannot ignore that molecular studies may have some pitfalls in identifying 21OHD phenotypes, 35,36 and that complex or cryptic causes may lead to possible false‐negative genotypic variation 37 . Moreover, we cannot exclude in our cohort any unintentional use of substances (e.g., steroid‐containing supplements or imidazole) that could have interfered with adrenal steroidogenesis leading to functional enzyme defects.…”

Section: Discussionmentioning

confidence: 99%

“…Individuals were finally deemed WT if no GPV, deletions, or duplications could be identified. However, complete sequencing—including a 600 base pair from the 5′‐untranslated region promoter region 22 —was performed in any WT disclosing suspicious values of pACTH 21DF and/or 17P. Following extensive molecular evaluation, study subjects were ultimately classified as NC, HZ and WT, according to their actual CYP21A2 genotype, and were subsequently analysed and compared with their preliminary hormonal profile.…”

Section: Introductionmentioning

confidence: 99%

Reassessment of predictive values of ACTH‐stimulated serum 21‐deoxycortisol and 17‐hydroxyprogesterone to identify CYP21A2 heterozygote carriers and nonclassic subjects

Costa-Barbosa

Carvalho

Oliveira

et al. 2021

Clinical Endocrinology

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Introduction Heterozygotes (HZs) for 21‐hydroxylase deficiency (21OHD) are highly prevalent, ranging from 1:60 to 1:11 for classic and nonclassic (NC) forms, respectively. Detection of HZ and asymptomatic NC by CYP21A2 genotyping is valuable for genetic counselling, but costly, complex and narrowly available. Adrenocorticotropic hormone (ACTH)‐stimulated serum 17‐hydroxyprogesterone (17P) and 21‐deoxycortisol (21DF) discriminate 21OHD phenotypes effectively, notably if measured simultaneously by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Objective This study was performed to reassess former LC‐MS/MS‐defined post‐ACTH 21DF, 17P and cortisol (F) cutoffs in family members at risk for 21OHD. Design and Patients Prospective study in which we screened 58 asymptomatic relatives from families with 21OHD patients and compared post‐ACTH steroid phenotypes with subsequent genotypes. Results Post‐ACTH 21DF, 17P, F and (21DF + 17P)/F ratio segregate NC, HZ and wild‐type (WT) phenotypes (subsequently genotyped) with some overlap. New receiver operating characteristic curve‐defined cutoffs for post‐ACTH 21DF, 17P and (21DF + 17P)/F ratio are 60 ng/dl, 310 ng/dl and 12 (unitless). Twenty‐six of 33 HZ and all 6 NC (82.1%) had post‐ACTH 21DF > 60 and 17P > 310 ng/dl, whereas 17/19 WT (89.5%) had values below cutoffs. Post‐ACTH 21DF and 17P had a strong positive correlation (r = .9558; p < .001). A (21DF + 17P)/F ratio > 12 correctly identified 36 of 39 HZ plus NC (92.3% sensitivity) with 84.2% specificity (16 of 19 WT). Given the high frequency of 21OHD HZ, the negative prediction of ratio values below 12 excludes heterozygosity in 99.8% and 99.1% for classic and NC mutations, respectively. Conclusions Reassessed ACTH‐stimulated 21DF and 17P cutoffs by LC‐MS/MS (60 and 310 ng/dl, respectively) correctly recognised 82.5% HZ plus NC, but combined precursor‐to‐product ratio ([21DF + 17P]/F) cutoff of 12 was superior, identifying 92.3% HZ plus NC. Since one WT subject is an outlier (potential HZ), these values would be somewhat better reinforcing their utility for screening asymptomatic relatives at risk for 21OHD.

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A rational, non-radioactive strategy for the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Cited by 15 publications

References 34 publications

Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype–phenotype correlations

Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype–phenotype correlations

The Cost-Effectiveness of Congenital Adrenal Hyperplasia Newborn Screening in Brazil: A Comparison Between Screened and Unscreened Cohorts

Reassessment of predictive values of ACTH‐stimulated serum 21‐deoxycortisol and 17‐hydroxyprogesterone to identify CYP21A2 heterozygote carriers and nonclassic subjects

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