Heterozygotes and Cryptic Patients in Families of Patients with Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Abstract

In a group of 18 unrelated Danish children with 21 -hydroxylase deficiency (21 -OH def), human leukocyte antigen (HLA) typing revealed a significant increase of Bw47 and a significant decrease of B8. HLA studies of the families of 14 probands predicted among the siblings 11 heterozygote carriers and 3 genetically unaffected. Glyoxalase studies showed a recombination fraction of 8%. ACTH-stimulated 17-OH progesterone is the only hormone value useful in the discrimination between heterozygotes and normals. Two families are described in detail. In one family, one of two HLA-identical brothers had classical virilizing congenital adrenal hyperplasia (CAH), while the other was a normal boy without 21 -OH def. In another family with 3 girls, one had classical, salt-wasting CAH, one had ‘late onset’ CAH, and the third sister and the father shared the HLA-B14 antigen and were shown to have ‘cryptic’21-OH def.

'Cryptic' form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the Yugoslav population

“…The results of the hor¬ monal studies of our patients with 'non-classical' 21-OH deficiency are in agreement with the results of other investigators (Levine et al , 1981Petersen et al 1982). Therefore, our hormonal studies combined with HLA typing were not able to differentiate if the father's genotype a/b and the daughter's geno¬ type a/c represent a combination of a gene for the severe with a gene for the mild form of the disease (21-OHsevere/21-OHmild), or a combination of two genes for the mild form of 21-OH deficiency (21-OHmild/21-OHmild).…”

“…Our results confirm the hypothesis that the in¬ dividuals with the 'non-classical', 'cryptic' form of 21-OH deficiency are genetic compounds, bearing one alíele for the severe, classical form and on the homologous locus, another alíele for the mild, 'non-classical' form of 21-OH deficiency (21-OH^vere/2l-OHmüd) (Levine et al , 1981Petersen et al 1982). Like the alíele for the severe, classical form which is genetically linked to the HLA-system (New et al 1983), there is strong evidence from other studies that the alíele for the mild, 'non-classical' form of 21-OH deficiency is as well linked to the HLA system, being in genetic disequilibrium with the 14 and DR 1 antigens (Laron et al 1980;Pollack et al 1981;Coullin et al 1982;O'Neil et al 1982).…”

“…There are several reports in the literature (Gutai et al 1977;Zachmann & Prader 1978;Levine et al 1980Levine et al , 1981Petersen et al 1982) on family mem¬ bers of patients with classical or 'late-onset' 21-OH deficiency who, in spite of elevated plasma 17-OHP and androgen levels, and in spite of increased urinary 17-KS and pregnanetriol excretion, were completely asymptomatic.…”

“…Clinically the 'late onset' (symptomatic) 21-OH deficiency is characterized by lack of signs of intra¬ uterine virilization at birth and with their late appearance in the form of hirsutism, clitoromegaly or amenorrhoea in prepubertal years or in puberty The 'cryptic' (asymptomatic) 21-OH deficiency has no signs of disease whatsoever, even not in adulthood, although its hormonal profile is similar to that of the 'late onset' form of 21-OH deficiency Lee et al 1982;Petersen et al 1982). …”

Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia

“…Several studies from various groups have conveyed that between 50 and 80% of carriers exhibit a 17-OHP level after ACTH stimulation and that is above the 95th percentile of the control value [37, 39, 42, 45]. The purpose of this study was to determine the frequency of identified defects of the CYP21A2 gene and also to weigh the regulatory 3′UTR region of the gene in a clinically symptomatic cohort of 169 females, characterized by hyperandrogenaemia.…”