Prenatal Diagnosis of Congenital Adrenal Hyperplasia

Yau, Mabel; Khattab, Ahmed; New, Maria I.

doi:10.1016/j.ecl.2016.01.001

Cited by 21 publications

(22 citation statements)

References 88 publications

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“…HFA steroidogenesis is tightly regulated throughout the first and second trimesters, which is crucial because the adrenal steroid hormones affect the overall intrauterine endocrine environment from early fetal development. Elevated levels of HFA androgens can be a consequence of dysregulated adrenal steroid pathways, in which imbalanced steroidogenesis can cause masculinization of the external genitals in female fetuses with congenital adrenal hyperplasia (CAH) (17). However, HFA steroidogenesis is not well characterized during fetal development, as previous studies investigating the steroidogenic function have focused on either the first or the second/third trimester only, characterizing selected adrenal steroidogenic enzymes.…”

mentioning

confidence: 99%

Characterization of Human Adrenal Steroidogenesis During Fetal Development

Melau

Nielsen

Frederiksen

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context The endocrine function of human fetal adrenals (HFAs) is activated already during first trimester, but adrenal steroidogenesis during fetal life is not well characterized. Objective This study aimed to investigate HFA steroidogenesis by analyzing adrenal glands from first and second trimesters. Design and Setting Male and female HFA from gestational weeks (GWs) 8 to 19 were examined, including a total of 101 samples from 83 fetuses. Main Outcome Measure(s) Expression level of steroidogenic genes and protein expression/localization were determined by quantitative PCR and immunohistochemistry, respectively, and intra-adrenal steroid levels were quantified by LC-MS/MS. Results Transcriptional levels of StAR, CYP11A1, CYP17A1, CYP21A2, CYP11B1/2, and SULT2A1 were significantly higher in second trimester compared to first trimester (P < 0.05), whereas expression levels of 3β-HSD2 and ARK1C3 were unaltered between GWs 8 and 19. All investigated steroidogenic proteins were expressed in a distinct pattern throughout the investigated period, with most enzymes expressed primarily in the fetal zone, except 3β-HSD1/2, which was expressed mainly in the definitive zone. Abundant steroidogenic enzyme expression was reflected in overall high intra-adrenal tissue concentrations of mineralocorticoids, glucocorticoids, and androgens; cortisol was the most abundant (1071 to 2723 ng/g tissue), and testosterone levels were the lowest (2 to 14 ng/g tissue). Conclusions The expression profiles of HFA steroidogenic enzymes are distinct from first to second trimester, with no major differences between male and female samples. Intra-adrenal steroid hormone concentrations confirm that cortisol is produced throughout first and second trimesters, suggesting continued regulation of the hypothalamus-pituitary-adrenal axis during this entire period.

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mentioning

confidence: 99%

Characterization of Human Adrenal Steroidogenesis During Fetal Development

Melau

Nielsen

Frederiksen

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…In this situation, a false‐negative YSP result must be avoided as a conclusive, albeit invasive, and necessary test such as amniocentesis might not be undertaken despite a 50% risk of the newborn having the X‐linked disease. YSP is useful in possible cases of congenital adrenal hyperplasia, even when the sensitivity is not optimal, to avoid unnecessary maternal steroid treatment for male fetuses as this therapy is only required to prevent virilization in a female fetus . In such circumstances, the detection of fetal DNA might not be required for sex determination since the positive predictive value of YSP is extremely high.…”

Section: Discussionmentioning

confidence: 99%

Potentially effective method for fetal gender determination by noninvasive prenatal testing for X‐linked disease

Noda

Kato

et al. 2018

Congenital Anomalies

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Examination of maternal plasma cell-free DNA (cfDNA) for noninvasive prenatal testing for fetal trisomy is a highly effective method for pregnant women at high risk. This can be also applied to fetal gender determination in female carriers of severe X-linked disease. Polymerase chain reaction (PCR) analysis is a relatively simpler and less expensive method of detecting Y chromosome-specific repeats (Y-specific PCR; YSP), but is limited by the risk of false-negative results. To address this, we have developed a combined strategy incorporating YSP and an estimation of the fetal DNA fraction. Multiplex PCR for 30 single nucleotide polymorphism (SNP) loci selected by high heterozygosity enables the robust detection of the fetal DNA fraction in cfDNA. The cfDNA sample is first subjected to YSP. When the YSP result is positive, the fetus is male and invasive testing for an X-linked mutation is then required. When the YSP result is negative, the cfDNA sample is analyzed using multiplex PCR. If fetal DNA is then found in the cfDNA, invasive testing is not then required. If the multiplex PCR analysis of cfDNA is negative for fetal DNA, the fetal gender cannot be determined and invasive testing is still required. Our technique provides a potentially effective procedure that can help to avoid unnecessary invasive prenatal testing in some female carriers of severe X-linked disease.

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“…Due to the good genotype/phenotype correlation [ 1 , 2 , 22 , 23 ] CYP21A2 genotyping of the fetus is predictive for his/her clinical outcome. Therefore, several institutions offer CYP21A2 genotyping in the course of prenatal diagnosis and dexamethasone therapy [ 50 – 52 ]. It is, however, important to mention that prenatal therapy is still considered to be an experimental one [ 3 ] due to controversial data particularly concerning treatment outcome and maternal as well as fetal safety [ 53 – 55 ].…”

Section: Significance/scope Of Cyp21a2 Genotypingmentioning

confidence: 99%

EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency

2020

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Molecular genetic testing for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is offered worldwide and is of importance for differential diagnosis, carrier detection and adequate genetic counseling, particularly for family planning. In 2008 the European Molecular Genetics Quality Network (EMQN) for the first time offered a European-wide external quality assessment scheme for CAH (due to 21-OH deficiency). The interest was great and over the last years at about 60 laboratories from Europe, USA and Australia regularly participated in that scheme. These best practice guidelines were drafted on the basis of the extensive knowledge and experience got from those annually organized CAH-schemes. In order to obtain the widest possible consultation with practicing laboratories the draft was therefore circulated twice by EMQN to all laboratories participating in the EQA-scheme for CAH genotyping and was updated by that input. The present guidelines address quality requirements for diagnostic molecular genetic laboratories, as well as criteria for CYP21A2 genotyping (including carrier-testing and prenatal diagnosis). A key aspect of that article is the use of appropriate methodologies (e.g., sequencing methods, MLPA (multiplex ligation dependent probe amplification), mutation specific assays) and respective limitations and analytical accuracy. Moreover, these guidelines focus on classification of variants, and the interpretation and standardization of the reporting of CYP21A2 genotyping results. In addition, the article provides a comprehensive list of common as well as so far unreported CYP21A2-variants.

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Prenatal Diagnosis of Congenital Adrenal Hyperplasia

Cited by 21 publications

References 88 publications

Characterization of Human Adrenal Steroidogenesis During Fetal Development

Characterization of Human Adrenal Steroidogenesis During Fetal Development

Potentially effective method for fetal gender determination by noninvasive prenatal testing for X‐linked disease

EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency

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