Abstract
Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion.Case Presentation: We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP.Conclusions: A novel heterozygous nonsense mutation in the STS gene and a known heterozygous missense variant in the BCRP gene were found. The heterozygous nonsense mutation in the STS gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids.
Highlights
An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia
Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEA sulfate (DHEAS), are prohormones secreted in large amounts by the adrenal zona reticularis
Up to 74% of the daily production of DHEAS is hydrolyzed to DHEA (Figure 1) by the steroid sulfatase (STS) [1], and the latter steroid is converted into biologically active androgens and estrogens
Summary
An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. Up to 74% of the daily production of DHEAS is hydrolyzed to DHEA (Figure 1) by the steroid sulfatase (STS) [1], and the latter steroid is converted into biologically active androgens and estrogens. Females are carriers and with few exceptions do not manifest the disease in the heterozygous state [10, 11]
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