ESPE Abstracts

Introduction: 3-beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency causes a rare form of Congenital Adrenal Hyperplasia (CAH) characterised by varying degrees of mineralocorticoid and glucocorticoid deficiencies with undermasculinisation in genetic males. The biochemical hallmarks are elevated androgen precursors in the delta5 pathway (dehydroepiandrosterone (DHEA) and 17-pregnenolone), with low mineralocorticoids and low (stimulated) cortisol levels. Immunoassays are widely used to measure serum cortisol and some are reported to be associated with cross-reactivity in 21-hydroxylase deficiency, 11-beta hydroxylase deficiency and some drugs, but not previously reported in HSD3B2deficiency. Herein, we describe a case with HSD3B2deficiency where the establishment of the diagnosis was delayed due to cross-reactivity of cortisol immunoassays.

Case: The baby was born after an uneventful pregnancy at term with a normal birth weight. The genitalia appeared atypical and undermasculinsed (external masculinisation score [EMS] = 6). The karyotype was 46,XY. No hypoglycaemia or jaundice was noted. At three days after birth, the hormonal evaluation showed a satisfactory stimulated peak cortisol of 504 nmol/l (>500 nmol/L) [Siemens Atellica® immunoassay], but a raised baseline 17OHP of 22.5nmol/l (< 6nmol/L) [liquid chromatography/ tandem mass spectrometry; LC/MSMS]. The urinary steroid profile (USP), performed in a service laboratory, was inconclusive. Following the exclusion of glucocorticoid deficiency and the baby being well, he was discharged home with appropriate follow-up arrangements. At the age of 14 days, infant developed salt wasting (Na:125 mmol/l; K:5.4nmol/l); a repeat hormonal profile revealed further increase of 17OHP (149 nmol/l) but with normal random cortisol (740 nmol/l; Siemens Atellica®). The baby received antibiotics for a suspected urinary tract infection and sodium supplementation. In view of the rising 17OHP levels, suggestive of CAH, we questioned the accuracy of the cortisol assay and cross-evaluated the sample on a different platform. From a fresh early morning sample, we obtained significantly different results on different cortisol assay platforms: Siemens Atellica®:722 nmol/L; Abbott Architect®:190 nmol/L; LC/MSMS:18 nmol/L. A repeat urinary steroid profile was consistent with HSD3B2 deficiency which was subsequently confirmed genetically with a frameshift variant in HSD3B2: c.818_819delAA p.(Lys273Argfs*7). The baby was started on hydrocortisone, fludrocortisone and salt supplements and is thriving well on steroid replacement.

Conclusion: Immunoassays for steroid quantification can have clinically significant interferences, in CAH, where there is an unusually high accumulation of steroid precursors. This may result in diagnostic dilemmas and delayed treatment. We advise employing u mass-spectrometry-based assays for the initial hormonal assessment in CAH.