Revisiting Classical 3β-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases

Abstract

Context The clinical effects of classical 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency are insufficiently defined due to a limited number of published cases. Objective To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3βHSD2 deficiency. Design Multicenter, cross-sectional study. Setting Nine tertiary pediatric endocrinology clinics across Turkey. Patients Children with clinical diagnosis of 3βHSD2 deficiency. Main Outcome Measures Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3βHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. Results Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ± 5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3βHSD2 activity in vitro had a non-salt–losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. Conclusions Genetically-documented 3βHSD2 deficiency includes salt-losing and non-salt–losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3βHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3βHSD2 deficiency.

Genotypic Sex and Severity of the Disease Determine the Time of Clinical Presentation in Steroid 17α-Hydroxylase/17,20-Lyase Deficiency

“…A panel of 15 adrenal steroids was measured by the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method using a commercial kit (Eureka Lab Division, Ancona, Italy). Analyses were performed on a Shimadzu LCMS 8050 tandem mass spectrometer equipped with a Shimadzu Nexera XR LC-20AD HPLC system (Shimadzu Corporation, Japan) [18]. Adrenal steroids measured in the patient group were compared to those of sex and age-matched controls ( n = 210; median age 11.5; IQR: 7.1–14 years).…”

Disorders of Sex Development of Adrenal Origin

“…Genotypic females are generally born mildly virilized, presenting with enlarged clitoris, incomplete labial fusion and genital hyperpigmentation due to the shift from DHEA to testosterone by HSD3B1 ( Table 1 ); however, they can present with normal external genitalia at birth. Preserved mineralocorticoid function and non-virilized genitalia may lead to underdiagnosis ( 55 ). Genotypic males are invariably undervirilized due to insufficient testicular conversion of DHEA to testosterone ( Table 2 ).…”

“…Diagnosis of the classic form of 3βHSD2D based on 17-hydroxypregnenolone levels above 100 nmol/L (3300 ng/dl) either basal or after ACTH stimulation is the best single biological criterion of 3βHSD2D. In addition, the baseline 1000-fold elevation of 17-hydroxypregnenolone to cortisol ratio and low 11-oxygenated androgens by liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides an unequivocal biochemical diagnostic parameter ( 53 , 55 ). Nonetheless, diagnosis at birth could be challenging due to HSD3B1 activity which can convert some of the elevated 17-hydroxypregnenolone to 17-hydroxyprogesterone, leading to false positives on neonatal screening for 21OHD ( 57 ).…”

Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant

“…Essential Biochemistry/Pathophysiology 3β-HSD2 enzyme converts 5-3β-hydroxysteroids into corresponding 4-3-keto isomers, Preg to Prog, 17αhydroxypregnenolone (17OHPreg) to 17α-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA) to 4androstenedione ( 4A), and androstenediol to T. In SW HSD3B2-D, glucocorticoid and mineralocorticoid are impaired causing hyponatremia, hyperkalemia, and elevated renin concentrations in both sexes. In females, 3β-HSD2 deficiency prevents the flooding of 17OHP and 4A to backdoor and 11-oxyandrogen production pathways (see CYP21A2-D) ( Figures 1A,B); in males, T production is impaired during the critical period of sexual differentiation and dihydrotestosterone (DHT) production is subsequently reduced by classical and backdoor pathways (30).…”

“…The principal diagnostic test for HSD3B2-D is the serum measurement of 17-OHpreg, cortisol, 4A, 17-OHP, and DHEA (basal or post-ACTH stimulation) (28) with a predominance of 5 steroids (i.e., Preg, 17OHPreg, and DHEA) over 4 steroids (Prog, 17OHP, and 4A). Guran et al (30) reported that high baseline 17OHpreg-to-cortisol ratio and low 11-oxyandrogen concentrations by LC/MSMS provide an unequivocal biochemical diagnosis of patients with HSD3B2-D. Although urinary steroid profiling is considered to be similarly accurate and less invasive for diagnosis (38), it can be notoriously difficult to diagnose HSD3B2-D on urine sample alone due to the naturally high levels of 3βOH5ene steroids in neonates.…”