Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency

Abstract

Steroid 17β-hydroxysteroid dehydrogenase III (17β-HSD3) deficiency is a rare autosomal recessive disorder that usually presents in patients with a 46,XY karyotype with ambiguous genitalia at birth. The 17β-HSD3 enzyme, which is encoded by the HSD17B3 gene, converts gonadal delta-4 androstenedione (Δ4) to testosterone (T). Such 17β-HSD3 enzyme deficiency is expected to lead to an increased ratio of D4 to T when the patient undergoes a human chorionic gonadotropin stimulation (hCG) test. Two patients with 46,XY disorders of sexual differentiation were studied. Serum D4 and T levels were measured by HPLC tandem mass spectrometry. As one of the patients was born to consanguineous parents, we performed single nucleotide polymorphism (SNP) microarray to analyze regions of homozygosity (ROH). The HSD17B3 gene was sequenced using the Sanger method. Contrary to expectations, both patients demonstrated decreased D4/T ratio after hCG stimulation. Initial sequencing results for the androgen receptor or 5α-reductase were negative for mutations. ROH analysis identified HSD17B3 as a candidate gene that might cause the disease. Sanger sequencing of the HSD17B3 gene confirmed 17β-HSD3 deficiency in both patients. Serum D4/T ratios are not reliable parameters for the diagnosis of 17β-HSD3 deficiency. Molecular genetic analysis provides accurate diagnosis.

A novel HSD17B3 gene mutation in a 46,XY female‐phenotype newborn identified by whole‐exome sequencing

“…In our patient, the basal T/Δ4A ratio was 0.39 at the age of 3 months, suggesting 17β‐HSD3 enzyme deficiency, but the post‐hCG T/Δ4A ratio was 0.99, above the cut‐off value of 0.8. Khattab et al . have shown the unreliability of T/Δ4A ratios for the diagnosis of 17β‐HSD3 enzyme deficiency based on their experience with two patients.…”

Rapid Molecular Genetic Diagnosis with Next-Generation Sequencing in 46,XY Disorders of Sex Development Cases: Efficiency and Cost Assessment

“…In 17β-HSD3 deficiency, the diagnosis could be established using specific hormonal tests, but a molecular analysis for responsible genes must be performed for a definitive diagnosis [16,21]. In 2 children with 17β-HSD3 deficiency-related atypical genitalia, Khattab et al [22] found the testosterone/Δ4-androstenedione ratio to be normal using chorionic gonadotropin stimulation, but then proved the diagnosis with Sanger sequencing. Thus, even though hormonal analyses can provide guidance, sometimes they may cause delays in diagnosis.…”

Mutational Profile of 10 Afflicted Egyptian Families with 17-β-HSD-3 Deficiency

“…Two Egyptian patients (5 and 7) showed a borderline decrease in T/Δ4 ratio values. In a recent study, although measuring hormone levels by a sensitive method, it was found that serum T/Δ4 ratios were increased after hCG stimulation in 2 patients with 17-β-HSD-3 deficiency 72 [Khattab et al, 2015]. This reconfirms the importance of molecular genetic analysis for reaching an accurate and definitive diagnosis.…”

“…A diagnostic hallmark of the disease is a decreased serum T/Δ4 ratio (<0.8-0.9) after human chorionic gonadotrophin (hCG) stimulation in prepubertal patients [Faisal Ahmed et al, 2000]. The reliability of hormonal investigations is questionable, and the definitive diagnosis mainly rests on molecular analysis [Khattab et al, 2015].…”