Nonclassic steroid 21-hydroxylase deficiency is an attenuated adrenal enzyme defect that is commonly the basis of hyperandrogenic syndromes. Inherited as an autosomal recessive trait, it is known to occur with high frequency in the general population and with increased frequency in a number of ethnic groups, including the Yugoslav population. Following expansion of the original data on 21 families in Croatia to a total of 49 Croatian and Serbian families, we establish that this enzymatic disorder is increased in this Slavic population and provide an updated estimate for the gene frequency of 0.092 (0.035\x=req-\ 0.149). Also in keeping with earlier reports, we continue to note the absence of association between nonclassic 21\ x=r eq-\ hydroxylase deficiency occurring among Yugoslavs and HLA-B14;DR1.Nonclassic steroid 21-hydroxylase deficiency is an autosomal recessive disorder that is known to occur with very high frequency generally, and which in addition shows increased prevalence in certain ethnic populations (1). This partial adrenal enzyme defect may or may not be clinically manifest in af¬ fected individuals, but can be identified by hor¬ mone criteria. Mild to moderate elevations of serum androgens result from increased secretion by the adrenal of androgens and of androgenic precursors which undergo peripheral conversion to active hormones. Biochemical indices of reduced adrenal 21-hydroxylation are serum elevations of the steroid intermediates 17a-hydroxyprogesterone (17-OHP), the principal substrate of 21-hy-droxylase, which fails to be converted to 11-deoxycortisol (compound S), the direct precursor of Cor¬ tisol, and also of A4-androstenedione (A4-A), im¬ mediately distal to 17-OHP in the androgenic pathway. Clinical effects arising from 21-hydroxy¬ lase deficiency vary between individuals and the different ages within the same individual.The first population genetic study on nonclassic 21-hydroxylase deficiency (1) identified an in¬ creased incidence among Yugoslavs, estimating the gene frequency among this population to be 0.125 (0.042-0.268 (95% confidence limits)) based on data from 21 families in Zagreb, SR Croatia, Yu¬ goslavia (1). This study observed that positive link¬ age disequilibrium between nonclassic 21-hydroxy¬ lase deficiency and HLA-B14;DR1 existing in other ethnic groups at increased risk, Ashkenazic Jews, Hispanics, and Italians, was absent in the Yu¬ goslav patient group.The population genetic analysis of the original study in 167 families was based on inference of genotype and gene counting as follows: Obligate hétérozygotes (the parents of affected offspring) in each pedigree were genotyped by HLA association and ACTH stimulation hormone testing. Occur¬ rence of the nonclassic deficiency trait in a tested parent identified the presence of a nonclassic de¬ ficiency alíele also on the second haplotype. Con¬ sidering that the second (nontransmitted) haplotypes of known hétérozygotes still represent a Klinika za djecje bolesti REBRO1 and Centar za tipizaciju tkiva REBRO2,
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is the most common inherited defect of adrenal steroid biosynthesis. At least 36 mutations in the CYP21 gene, which is mapped to chromosome 6p21.3, have been described. We performed genetic analysis of the CYP21 gene in a patient with classic 21-OHD CAH and her family. The entire exonic coding regions and intronic regions, as well as the -1 kb 5' upstream promoter region, were thoroughly sequenced and analyzed. Despite extensive sequencing, no mutation was found in this 3.7 kb area. The 11beta-hydroxylase defect, closely mimicking the clinical and biochemical phenotype of classic 21-OHD, was excluded by directly sequencing 2.6 kb covering the entire coding of the CYP11B1 gene. Herein we describe a phenotypically and hormonally affected patient with classic simple virilizing 21-OHD CAH who lacks a mutation in the entire CYP21 gene and coding region of the CYP11B1 gene.
Five individuals with the asymptomatic, 'nonclassical', 'cryptic' form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OH) deficiency from 5 unrelated families were discovered during hormonal studies and HLA-typing performed in a series of 24 families with CAH due to 21-OH deficiency. Four of the 5 individuals with the 'cryptic' form of CAH belong to families where the index case was a patient with the classical form of CAH due to 21-OH deficiency. The fifth one originated from a family where the index case was a girl with the 'non-classical', 'late-onset' form of the disease. All the 5 individuals had no clinical symptoms in spite of clearcut biochemical signs of 21-OH deficiency: increased 17-OH-progesterone (17-OHP), dehydroepiandrosterone and androstenedione levels, particularly after ACTH-stimulation. The 17-OHP response upon ACTH stimulation of heterozygotes for this 'non-classical' form of 21-OH deficiency did not differ from the response of heterozygous individuals for the classical form of the disease. The results of this study confirm the hypothesis that individuals with the 'cryptic' form of CAH due to 21-OH deficiency are genetic compounds bearing one allele for the severe, classical form, and on the homologous locus, another one for the mild 'nonclassical' form of CAH due to 21-OH deficiency. Their genotype was 21-OHsevere/21-OHmild, The gene for 'cryptic' 21-OH deficiency, as well as the gene for the classical form of the disease is linked to the HLA system, but in our population apparently it is not in genetic disequilibrium with the antigens B 14 DR 1, as it was shown for other populations studied up to now.
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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