Impaired Mineralocorticoid Hormone Responses to Adrenocorticotropin Stimulation: Additional Characterization of Heterozygosity for the 21-Hydroxylase Deficiency Type of Congenital Adrenal Hyperplasia*

The urinary excretion of two Δ5-3β-OH, 16α-hydnoxysteroids, 16-OH-pregnenolone (16-OH-PG), and 16-OH-dehydroepiandrosterone (16-OH-DHA), has been determined in 18 patients with the C-21 hydroxylase deficiency type of congenital adrenal hyperplasia (CAH). The excretion of 16-OH-PG was generally above the normal range in young infants, fell over the first 4 months and was present in only one of eight control urine samples from patients with CAH over 5 months of age. The excretion of 16-OH-DHA was generally within the normal range in the young infants, fell over the first 4 months, and was not found in urine samples from CAH patients over 5 months of age. ACTH was administered to eight of the CAH patients and caused an increased excretion of both steroids when they were present in control urine samples. Of the five patients receiving ACTH who had neither steroid present in control urine, 16-OH-PG appeared in the two youngest but 16-OH-DHA appeared in none. The ratio of urinary 16-OH-PG/16-OH-DHA was significantly greater in the CAH patients than in the endocninologically normal patients. It was concluded that the pattern of excretion of 16-OH-PG and i6-OH-DHA in patients with CAH is an exaggeration of the normal infant pattern caused by the endogenous ACTH stimulation. The possible role of the fetal zone of the adrenal cortex in the secretion of these steroids was considered but the available evidence indicated that the permanent cartical zone was the site of origin.

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Mutation of IVS2 –12A/C>G in Combination with 707–714delGAGACTAC in the CYP21 Gene Is Caused by Deletion of the C4-CYP21 Repeat Module with Steroid 21-Hydroxylase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030047 ◽

2003 ◽

Vol 88 (6) ◽

pp. 2726-2729 ◽

Cited By ~ 12

Author(s):

Hsien-Hsiung Lee ◽

Shwu-Fen Chang ◽

Fuu-Jen Tsai ◽

Li-Ping Tsai ◽

Ching-Yu Lin

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Donor Site ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Aberrant Splicing ◽

Cyp21 Gene ◽

Pcr Product ◽

Intergenic Recombination ◽

21 Hydroxylase Deficiency

More than 90% of the cases of congenital adrenal hyperplasia are caused by mutations of the CYP21 gene. Approximately 75% of the defective CYP21 genes are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, mutation of the aberrant splicing donor site of IVS2 –12A/C>G at nucleotide (nt) 655 is believed to be a result derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707–714delGAGACTAC rarely exists alone, although this locus is a distance of 53 nt away from IVS2 –12A/C>G. From the molecular characterization of the mutation of IVS2 –12A/C>G combined with 707–714delGAGACTAC in patients with congenital adrenal hyperplasia, we found that it appeared to be in a 3.2-rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5′ end region of such a CYP21 haplotype had CYP21P-specific sequences. Our results indicate that the coexistence of these two mutations is caused by deletion of the CYP21P, XA, RP2, and C4B genes and intergenic recombination in the C4-CYP21 repeat module. Surprisingly, this kind of the haplotype of the mutated CYP21 gene has not been reported as a gene deletion.

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