Aldosterone Synthesis in Salt-Wasting Congenital Adrenal Hyperplasia with Complete Absence of Adrenal 21-Hydroxylase

Speiser, Phyllis; Agdere, Levon; Ueshiba, Hajime; White, Perrin C.; New, Maria I.

doi:10.1056/nejm199101173240302

Cited by 92 publications

(25 citation statements)

References 34 publications

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“…Nor did separate examination of aldosterone alone allow improved distinction between mutation groups A and B, representing severely and moderately defective CYP2 1 genotype combinations, respectively. Based on data included in this and earlier reports (37) Figure 4. Relationship ofphenotype score to mutation group.…”

Section: Discussionmentioning

confidence: 99%

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Speiser¹,

Dupont²,

Zhu³

et al. 1992

J. Clin. Invest.

532

401

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Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172 --Asn (16%), and Val-281 --Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy. (J. Clin. Invest. 1992. 90:584-595.) Key words: steroid 21-hydroxylase deficiency-CYP21

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Section: Discussionmentioning

confidence: 99%

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Speiser¹,

Dupont²,

Zhu³

et al. 1992

J. Clin. Invest.

532

401

View full text Add to dashboard Cite

show abstract

“…Phenotypic variance may even be present in siblings (29), which suggests a role for modifiers of 21-hydroxylase transcription, translation, and action. As cases have been described with spontaneous partial recovery from CAH (30), factors apart from the CYP21 gene effect must play a role. The observed discordance between genotype and phenotype may be the result of either postulated extraadrenal hydroxylase activity or other factors that modify steroid synthesis or steroid action.…”

Section: Discussionmentioning

confidence: 99%

Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

Krone

Braun

Roscher

et al. 2000

The Journal of Clinical Endocrinology &Amp; Metabolism

295

107

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Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppv null ) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppv A to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppv B was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppv C was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression. (J Clin Endocrinol Metab 85: 1059 -1065, 2000)

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“…Since the clinical severity of CAH patients reflects the degree of residual activity of the mutant CYP21A2 [1], a mild increase in enzymatic activity in extra-adrenal tissues may benefit patients with severe enzymatic defects. Indeed maintenance of minimal cortisol production may help to prevent life-threatening adrenal crisis in these patients [13].…”

Section: Cyp21a1 Induction By An Ex Vivo Protocol Using An Rv Vectormentioning

confidence: 99%

Extra-adrenal induction of <i>Cyp21a1</i> ameliorates systemic steroid metabolism in a mouse model of congenital adrenal hyperplasia

et al. 2016

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Aldosterone Synthesis in Salt-Wasting Congenital Adrenal Hyperplasia with Complete Absence of Adrenal 21-Hydroxylase

Cited by 92 publications

References 34 publications

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

Extra-adrenal induction of <i>Cyp21a1</i> ameliorates systemic steroid metabolism in a mouse model of congenital adrenal hyperplasia

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