HNF1B Mutations Are Associated With a Gitelman-like Tubulopathy That Develops During Childhood.

BACKGROUND: Mutations in the transcription factor hepatocyte nuclear factor 1B (HNF1B) are the most common inherited cause of renal malformations, yet also associated with renal tubular dysfunction, most prominently magnesium wasting with hypomagnesemia. The presence of hypomagnesemia has been proposed to help select appropriate patients for genetic testing. Yet, in a large cohort, hypomagnesemia was discriminatory only in adult, but not in pediatric patients. We therefore investigated whether hypomagnesemia and other biochemical changes develop with age. METHODS: We performed a retrospective analysis of clinical, biochemical, and genetic results of pediatric patients with renal malformations tested for HNF1B mutations, separated into 4 age groups. Values were excluded if concurrent estimated glomerular filtration rate (eGFR) was <30 ml/min per 1.73 m2, or after transplantation. RESULTS: A total of 199 patients underwent HNF1B genetic testing and mutations were identified in 52 (mut+). The eGFRs were comparable between mut+ and mut- in any age group. Although median plasma magnesium concentrations differed significantly between mut+ and mut- patients in all age groups, overt hypomagnesemia was not present until the second half of childhood in the mut+ group. There was also a significant difference in median potassium concentrations in late childhood with lower values in the mut+ cohort. CONCLUSIONS: The abnormal tubular electrolyte handling associated with HNF1B mutations develops with age and is not restricted to magnesium, but consistent with a more generalized dysfunction of the distal convoluted tubule, reminiscent of Gitelman syndrome. The absence of these abnormalities in early childhood should not preclude HNF1B mutations from diagnostic considerations.

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty.

CONTEXT: Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet. PATIENTS AND METHODS: We carried out a cross-sectional study in 30 males with STSD (age 6-27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing. RESULTS: Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage. CONCLUSIONS: In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.

No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies.

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS inter-convert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependent conversion of DHEA (0.1-2 mum) to DHEAS but no conversion of DHEAS (0.1-2 mum). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.