The case described herein corroborates the strong genotype-phenotype correlation associated with the HSD3B2p.P222Q mutation, which leads to a classic salt-wasting 3β-HSD deficiency.
Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping.
To date a total of 34 mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing, and 23 missense mutations) have been identified in the HSD3B2 gene in 56 individuals from 44 families suffering from classical 3beta-HSD deficiency.
A novel A10E homozygous mutation in the HSD3B2 gene causing severe salt-wasting 3beta-hydroxysteroid dehydrogenase deficiency in 46,XX and 46,XY French-Canadians: evaluation of gonadal function after puberty.
In conclusion, a structurally lengthy MT II 3beta-HSD enzyme due to a nonstop mutation was relatively detrimental in intact cells causing the nonclassic phenotype of 3beta-HSD deficiency.
Thus, the elucidation of the molecular basis of 3beta-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3beta-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3beta-HSD superfamily.
In hyperandrogenic children and women, the pathogenic mechanism of a subtle abnormality in adrenal 3 beta-HSD activity, determined by modestly elevated ACTH stimulated delta-5 steroid levels, which led to the diagnosis of mild nonclassic 3 beta-HSD deficiency in the past, is outside of the type II 3 beta-HSD gene which encodes adrenals and gonads in humans and remains to be further explored.
These findings suggest that the degree of ACTH-stimulated delta 5 precursor steroid abnormality, such as delta 5-17P levels up to 10 SD above the normal mean level found in our PP patients, is not caused by a mild variant of 3 beta HSD deficiency CAH resulting from type II or type I 3 beta HSD gene mutation.
Both codon 273 and 318 mutations yielding frameshift and premature stop codons at codons 279 and 367, respectively, are predicted to result in an altered and truncated type II 3 beta-HSD protein, thereby causing salt-wasting 3 beta-HSD deficiency in the patient.
Molecular DNA analysis was also performed in 6 of the patients, using the strategy successfully used to detect point mutations in the type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene, which are responsible for classical 3 beta HSD deficiency.
We report mutations of the type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene in two siblings, male and female, with congenital adrenal hyperplasia caused by classical nonsalt-losing 3 beta HSD deficiency.
To better understand the molecular basis of the phenotypic heterogeneity found in 3 beta HSD deficiency, we analyzed the structure of type I and II 3 beta HSD genes in a female patient with nonsalt-losing 3 beta HSD deficiency diagnosed at puberty.
The structures of the highly homologous type I and II 3 beta-HSD genes have been analyzed in three male pseudohermaphrodite 3 beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3 beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing.
These data indicate a homozygous combined missense/frameshift mutation in exon IV of the type II 3 beta-HSD gene resulting in severe salt-wasting adrenal and gonadal 3 beta-HSD deficiency in the patient.
Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3beta-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated Delta5-17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 SD above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 SD above the normal female mean level [28 +/- 10 (SD) nmol/liter]; and ACTH-stimulated Delta5-17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 SD above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 SD above the normal mean ratio [32 +/- 12 (SD)].
In hyperandrogenic children and women, the pathogenic mechanism of a subtle abnormality in adrenal 3 beta-HSD activity, determined by modestly elevated ACTH stimulated delta-5 steroid levels, which led to the diagnosis of mild nonclassic 3 beta-HSD deficiency in the past, is outside of the type II 3 beta-HSD gene which encodes adrenals and gonads in humans and remains to be further explored.
These findings suggest that the degree of ACTH-stimulated delta 5 precursor steroid abnormality, such as delta 5-17P levels up to 10 SD above the normal mean level found in our PP patients, is not caused by a mild variant of 3 beta HSD deficiency CAH resulting from type II or type I 3 beta HSD gene mutation.
Three female patients heterozygotic for severe 3 beta-HSD deficiency CAH with one allele mutation of the gene demonstrated normal ACTH-stimulated hormone profiles.
In conclusion, despite partial gonadal 3 beta HSD deficiency, the dynamics of gonadotropin and gonadal hormone secretion in these siblings indicate the absence of increased LH secretion, in contrast to the markedly increased ACTH secretion resulting from adrenal 3 beta HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)
Three patients (13%) were diagnosed to have a mild form of 3 beta-hydroxysteroid dehydrogenase deficiency based upon the response of serum delta 5-17-hydroxypregnenolone (delta 5-17P) and dehydroepiandrosterone, and the ratio of delta 5-17P/17-OHP to ACTH stimulation (delta 5-17P: 1543 +/- 272 ng/dl vs. Tanner stage I control subjects, 350 +/- 197 ng/dl; dehydroepiandrosterone: 675 +/- 190 ng/dl vs. Tanner stage I control subjects, 82 +/- 79 ng/dl; delta 5-17P/17-OHP: 8.1 +/- 2.6 vs. Tanner stage I control subjects, 1.4 +/- 0.6).