Here, we report on a female adolescent with overweight and a very high DHEAS serum level. The hypothesis that the origin of DHEAS excess was the presence of either an ovarian or a suprarenal DHEAS-producing tumor was not confirmed. Sonographic and MRT investigations did not support its presence. In addition, effective dexamethasone suppression of DHEA and DHEAS excluded this diagnosis. Steroid sulfatase (STS) hydrolyses alkyl and aryl steroid sulfates to their unconjugated forms. STS deficiency was suspected although ichthyosis was absent. Sequence analysis revealed a heterozygote single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification. The detected nonsense mutation in the STS gene, however, was in the heterozygote state, therefore it was not supposed to be responsible for STS deficiency. In line with the genetic data, the bioassay revealed normal enzyme activity in patients leukocyte. A potential defect of one or more transporter proteins was suggested. Prominent candidate efflux transporter for the present study were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs but also some endogenous substrates such as sulfated steroids. On the uptake site several OATP and OAT carriers were on the list. Using exon-spanning PCR, all exons of the above mentioned membrane transporters were sequenced. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity. In conclusion, a novel heterozygous nonsense mutation in the steroid sulfatase gene and a known heterozygous missense variant of the steroid sulfate efflux transporter were found in this patient. The combination of the two heterozygous mutations could possibly together explain the observed high levels of DHEAS and some other sulfated steroids.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology