First trimester prenatal diagnosis of 21-hydroxylase deficiency by linkage analysis to HLA-DNA probes and by 17-hydroxyprogesterone determination

Mornet, Étienne; Boué, J; Raux-Demay, Marie Charles; Couillin, P.; Oury, Jean‐François; Dumez, Yves; Dausset, J; Cohen, Daniel; Boué, A

doi:10.1007/bf00279101

Cited by 61 publications

(23 citation statements)

References 21 publications

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“…At present, prenatal diagnosis is based on HLA typing of fibroblasts and measurement of hormone levels in amniotic fluid obtained by amniocentesis at about the 16th wk ofgestation (35), or HLA typing can be performed by Southern blot hybridization using DNA prepared from a chorionic villus sample (36). Prenatal diagnosis using oligonucleotide probes has two potential advantages over HLA typing: it obviates the need for a DNA sample from the index case and it excludes possible misdiagnosis due to recombinations within the HLA complex.…”

Section: Resultsmentioning

confidence: 99%

Nonsense mutation causing steroid 21-hydroxylase deficiency.

Globerman¹,

Amor²,

Parker³

et al. 1988

J. Clin. Invest.

118

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We determined the sequence of a mutant CYP21B gene isolated from a patient with the severe, "salt-wasting" form of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. Codon 318 in this gene is changed from CAG, encoding glutamine, to TAG, a nonsense codon. This is predicted to result in a completely nonfunctional enzyme due to premature termination of translation. In addition, when the cloned mutant gene was transfected into mouse VI adrenal cells, the resulting mRNA levels were decreased compared with transfected normal CYP21B genes. This mutation was carried by 3 of 20 unrelated patients with 21-hydroxylase deficiency alleles as determined by hybridization with a specific oligonucleotide probe. This mutation is also seen in the normal CYP21A pseudogone, so that its presence in the abnormal CYP21B gene may be the result of a gene conversion event.

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Section: Resultsmentioning

confidence: 99%

Nonsense mutation causing steroid 21-hydroxylase deficiency.

Globerman¹,

Amor²,

Parker³

et al. 1988

J. Clin. Invest.

118

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“…Intrauterine screening in at risk families is important and should consist of 17 hydroxy-progesterone assay and HLA typing in amniotic cells [16][17][18][19][20]. Hydrocortisone therapy should also be instituted in the mother in the hopes that it will prevent the genital ambiguity [21,22].…”

Section: Discussionmentioning

confidence: 99%

Congenital Adrenal Hyperplasia

Salman¹,

Abanamy²,

Basset³

et al. 1991

Ann Saudi Med

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The incidence of congenital adrenal hyperplasia in Saudi Arabia and the frequency of the carrier rate are not well known. Both figures should be high, considering the commonness of first-degree consanguinity in this part of the world. We present 25 cases of congenital adrenal hyperplasia, most of them due to a defect of the 21 hydroxylase enzyme, diagnosed and followed over three years at Suleimania Children's Hospital in Riyadh. There were ten boys and 15 girls exhibiting all degrees of masculinization, mostly Grade III (53%) and Grade IV and V (13.3% each). The degree of masculinization of the external genitalia in the girls (46XX) was sufficiently pronounced in seven patients to lead to sex identity errors at birth. This aggravated the psychological reactions in the families, particularly before the surgical correction. The frequency of neonatal deaths in the patients' families related to a similar disorder was high (12%). The mean age at onset of the salt-losing crises in affected infants was 9 days in females and 25 days in males and this was the most common clinical presentation of the disorder (80%). Systematic neonatal screening and intrauterine diagnosis in at risk families must be done to provide hormonal intervention and thus prevent the formation of ambiguous genitalia and avoid the resulting plastic surgery that must be performed in female patients. Congenital adrenal hyperplasia is common in Riyadh, where marriages between first-degree relatives are frequent. As everywhere, and particularly under the local sociocultural conditions, discussion is focused on the genetic sex which isnot always easy to determine, depending on the degree of masculinization of otherwise genetically defined females. The surgical correction and the psychological consequences in the affected families also contribute to the problems. Intrauterine and neonatal screening are therefore important. Likewise, intrauterine treatment may prevent genital abnormalities and the neonatal deaths caused by salt-losing crises. The etiology, medical and surgical treatment, and follow-up of clinical, radiological, and biological features are discussed, along with the problems of neonatal and intrauterine screening. Patients and MethodsCongenital adrenal hyperplasia was diagnosed in 25 patients who were followed up at the Suleimania Children's Hospital in Riyadh over a period of three years. Nationality and supposed sex as well as family history were recorded. The age of onset and clinical presentation, particularly the presence or absence of a salt-losing syndrome,

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“…When human leukocyte antigen (HLA) was found to be linked with CAH due to 21-OHD, diagnoses were made by using HLA genetic linkage marker analysis [Levine et al, 1978;Mornet et al, 1987;Strachan et al, 1987;Speiser et al, 1990]. This method resulted in many diagnostic errors due to recombination or haplotype sharing between parents.…”

Section: Introductionmentioning

confidence: 99%

Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) in Croatia

et al. 1997

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We report on the prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase in 20 at-risk pregnancies (16 salt-wasting and 4 simple virilizing families). We have diagnosed 3 affected fetuses (2 males and 1 female), 3 healthy homozygotes (2 males and 1 female), and 14 healthy heterozygotes (7 females and 7 males). These data were collected over 4 years. In 16 fetuses, the diagnosis was made with measurements of 17-hydroxyprogesterone (17-OHP) and delta-4-androstenedione (delta) in amniotic fluid (AF), human leukocyte antigen (HLA) typing of amniotic cells, as well as karyotypes between the 16th and 18th weeks of gestation. In 4 fetuses, DNA analysis of amniotic cells was also performed. In 3 pregnancies in which affected fetuses were suspected (on the basis of HLA typing and measurements of 17-OHP and delta concentrations in AF), the fetuses were electively aborted between the 17th to 19th weeks of gestation by parental decision. In all aborted fetuses, diagnosis was confirmed with HLA typing, autopsy findings of hyperplastic adrenal glands, and ambiguous genitalia in female fetuses. Postnatal diagnosis was confirmed in healthy fetuses with HLA typing and serum measurements of 17-OHP concentrations, and in 4 of them with DNA analysis. In 3 of the 4 families, DNA analyses revealed the following mutations: in Family 1, the index case mutation was Intron 2, Exon 3/Exon 6, and the fetus was Normal/Exon 6; in Family 2, the index case mutation was Ex1 Int2 Ex3/ Int2, and the fetus was Ex1 Int2 Ex3/Normal; and in Family 3, the index case mutation was Ex8(356)/Ex8(356), and the fetus was Ex8(356)/ Normal. We also report one case of prenatal diagnosis and treatment. Dexamethasone 0.5 mg BID (20 micrograms/kg/d) was given starting at 6th week of gestation. Prenatal diagnosis suggested, but did not prove, that the female fetus was a heterozygote as the fetus lacked the paternal mutation Ex8(318). No mutation was found in the mother. The fetus, the mother, and the affected sib shared a haplotype, further suggesting heterozygosity. The unaffected status was confirmed postnatally.

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First trimester prenatal diagnosis of 21-hydroxylase deficiency by linkage analysis to HLA-DNA probes and by 17-hydroxyprogesterone determination

Cited by 61 publications

References 21 publications

Nonsense mutation causing steroid 21-hydroxylase deficiency.

Nonsense mutation causing steroid 21-hydroxylase deficiency.

Congenital Adrenal Hyperplasia

Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) in Croatia

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