Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency through molecular genetic analysis of the CYP21A2 gene
3
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Purpose: Deficiency of 21-hydroxylase (21-OHD) is an autosomal recessively inherited disorder that is characterized by adrenal insufficiency and androgen excess. This study was performed to investigate the clinical utility of prenatal diagnosis of 21-OHD using molecular genetic testing in families at risk.Methods: This study included 27 pregnant women who had previously borne a child with 21-OHD. Fetal tissues were obtained using chorionic villus sampling (CVS) or amniocentesis. After the genomic DNA was isolated, Sanger sequencing of <i>CYP21A2</i> and multiplex ligation-dependent probe amplification were performed. The clinical and endocrinological findings were reviewed retrospectively.Results: A total of 39 prenatal genetic tests was performed on 27 pregnant women and their fetal tissues. The mean gestational age at the time of testing was 11.7 weeks for CVS and 17.5 weeks for amniocentesis. Eleven fetuses (28.2%) were diagnosed with 21-OHD. Among them, 10 fetuses (90.9%) harbored the same mutation as siblings who were previously diagnosed with 21-OHD. Among these, 4 fetuses (3 males and 1 female) identified as affected were born alive. All 4 patients have been treated with hydrocortisone, 9α-fludrocortisone, and sodium chloride since a mean of 3.7 days of life. The male patients did not show hyponatremia and dehydration, although they harbored pathogenic variants associated with the salt-wasting type of 21-OHD.Conclusion: This study demonstrated the diagnostic efficacy and clinical consequences of diagnosis by prenatal genetic testing in families at risk for 21-OHD. All patients identified as affected were treated with hydrocortisone and 9α-fludrocortisone early after birth, which can prevent a life-threatening adrenal crisis.
Abstract
Purpose: Deficiency of 21-hydroxylase (21-OHD) is an autosomal recessively inherited disorder that is characterized by adrenal insufficiency and androgen excess. This study was performed to investigate the clinical utility of prenatal diagnosis of 21-OHD using molecular genetic testing in families at risk.Methods: This study included 27 pregnant women who had previously borne a child with 21-OHD. Fetal tissues were obtained using chorionic villus sampling (CVS) or amniocentesis. After the genomic DNA was isolated, Sanger sequencing of <i>CYP21A2</i> and multiplex ligation-dependent probe amplification were performed. The clinical and endocrinological findings were reviewed retrospectively.Results: A total of 39 prenatal genetic tests was performed on 27 pregnant women and their fetal tissues. The mean gestational age at the time of testing was 11.7 weeks for CVS and 17.5 weeks for amniocentesis. Eleven fetuses (28.2%) were diagnosed with 21-OHD. Among them, 10 fetuses (90.9%) harbored the same mutation as siblings who were previously diagnosed with 21-OHD. Among these, 4 fetuses (3 males and 1 female) identified as affected were born alive. All 4 patients have been treated with hydrocortisone, 9α-fludrocortisone, and sodium chloride since a mean of 3.7 days of life. The male patients did not show hyponatremia and dehydration, although they harbored pathogenic variants associated with the salt-wasting type of 21-OHD.Conclusion: This study demonstrated the diagnostic efficacy and clinical consequences of diagnosis by prenatal genetic testing in families at risk for 21-OHD. All patients identified as affected were treated with hydrocortisone and 9α-fludrocortisone early after birth, which can prevent a life-threatening adrenal crisis.
참고문헌 (35)
- Speiser PW, "Congenital adrenal hyperplasia", N Engl J Med, 349, pp.776~788 (2003)
- New MI, "Genetic disorders of steroid hormone synthesis and metabolism", Baillieres Clin Endocrinol Metab, 9, pp.525~554 (1995)
- New MI, "Steroid disorders in children : congenital adrenal hyperplasia and apparent mineralocorticoid excess", Proc Natl Acad Sci U S A, 96, pp.12790~12797 (1999)
- White PC, "Steroid 21-hydroxylase deficiency and the major histocompatibility complex", Hum Immunol, 15, pp.404~415 (1986)
- Higashi Y, "Evidence for frequent gene conversion in the steroid 21-hydroxylase P-450(C21)gene-implications for steroid 21-hydroxylase deficiency", Am J Hum Genet, 42, pp.17~25 (1988)
- White PC, "Mutations in steroid 21-hydroxylase(CYP21)", Hum Mutat, 3, pp.373~378 (1994)
- Concolino P, "Multiplex ligation-dependent probe amplification(MLPA)assay for the detection of CYP21A2 gene deletions", duplications in congenital adrenal hyperplasia : first technical report, 2009, pp.402, 164~170
- Tolba A, "Copy number variations in genetic diagnosis of congenital adrenal hyperplasia children", Front Genet, 13, pp.785570~ (2022)
- Tusie-Luna MT, "Gene conversions and unequal crossovers between CYP21(steroid 21-hydroxylase gene)and CYP21P involve different mechanisms", Proc Natl Acad Sci U S A, 92, pp.10796~10800 (1995)
- Speiser PW, "Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency", J Clin Invest, 90, pp.584~595 (1992)
- Joint LWPES, "ESPE CAH Working Group", Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology, 2002, pp.87, 4048~4053
- Honour JW, "Evaluation of neonatal screening for congenital adrenal hyperplasia", Hormone Res, 55, pp.206~211 (2001)
- Merke DP, "Congenital adrenal hyperplasia due to 21-hydroxylase deficiency", N Engl J Med, 383, pp.1248~1261 (2020)
- Speiser PW, "Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency : an endocrine society clinical practice guideline", J Clin Endocr Metab, 103, pp.4043~4088 (2018)
- Jeffcoate TN, "Diagnosis of the adrenogenital syndrome before birth", Lancet, 2, pp.553~555 (1965)
- Pang S, "Pitfalls of prenatal diagnosis of 21-hydroxylase deficiency congenital adrenal hyperplasia", J Clin Endocrinol Metab, 61, pp.89~97 (1985)
- Gueux B, "Prenatal-diagnosis of 21-hydroxylase deficiency congenital adrenal-hyperplasia by simultaneous radioimmunoassay of 21-deoxycortisol and 17-hydroxyprogesterone in amniotic-fluid", J Clin Endocr Metab, 66, pp.534~537 (1988)
- Forest MG, "Pitfalls in prenatal-diagnosis of 21-hydroxylase deficiency by amniotic-fluid steroid analysis-a 6 years experience in 102 pregnancies at risk", Ann Ny Acad Sci, 458, pp.130~147 (1985)
- Prado MJ, "Development of CYP21A2 genotyping assay for the diagnosis of congenital adrenal hyperplasia", Mol Diagn Ther, 21, pp.663~675 (2017)
- New MI, "Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies", J Clin Endocrinol Metab, 86, pp.5651~5657 (2001)
- Dubey S, "Prenatal diagnosis of steroid 21-hydroxylase-deficient congenital adrenal hyperplasia : experience from a tertiary care centre in India", Indian J Med Res, 145, pp.193~201 (2017)
- Ma DY, "Noninvasive prenatal diagnosis of 21-hydroxylase deficiency using target capture sequencing of maternal plasma DNA", Sci Rep, 7, pp.7427~ (2017)
- New MI, "Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma", J Clin Endocr Metab, 99, pp.E1022~E1030 (2014)
- Chorionic villus sampling, "centers for disease control and prevention", MMWR Recomm Rep, 44, pp.1~12 (1995)
- Choi JH, "Clinical phenotype and mutation spectrum of the CYP21A2 gene in patients with steroid 21-hydroxylase deficiency", Exp Clin Endocrinol Diabetes, 120, pp.23~27 (2012)
- Baumgartner-Parzer S, "EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency", Eur J Hum Genet, 28, pp.1341~1367 (2020)
- White PC, "Optimizing newborn screening for congenital adrenal hyperplasia", J Pediatr, 163, pp.10~12 (2013)
- Chan CL, "Congenital adrenal hyperplasia and the second newborn screen", J Pediatr, 163, pp.109~113 (2013)
- Swerdlow AJ, "Mortality in patients with congenital adrenal hyperplasia : a cohort study", J Pediatr, 133, pp.516~520 (1998)
- Bachelot A, "Management of endocrine disease : congenital adrenal hyperplasia due to 21-hydroxylase deficiency : update on the management of adult patients and prenatal treatment", Eur J Endocrinol, 176, pp.R167~R181 (2017)
- Fernandez-Balsells MM, "Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase(CYP21A2)deficiency : a systematic review and meta-analyses", Clin Endocrinol, 73, pp.436~444 (2010)
- Carmichael SL, "Maternal corticosteroid use and orofacial clefts", Am J Obstet Gynecol, 197, pp.585~ (2007)
- Damsted SK, "Exogenous glucocorticoids and adverse cerebral effects in children", Eur J Paediatr Neurol, 15, pp.465~477 (2011)
- Hirvikoski T, "Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone", J Clin Endocr Metab, 92, pp.542~548 (2007)
- Dalziel SR, "Cardiovascular risk factors after antenatal exposure to betamethasone : 30-year follow-up of a randomised controlled trial", Lancet, 365, pp.1856~1862 (2005)