Objectives: 17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency results in insufficient biosynthesis of testosterone and consequently dihydrotestosterone. This is important for the fetal development of male genitalia. Thus, most 46,XY patients with 17 beta-HSD3 deficiency have a female appearance at birth and present with virilization at puberty. This study presents the differences in the clinical and hormonal data and analyses of gonadal characteristics in two siblings with 17 beta-HSD3 deficiency.

Case presentation: Patient 1 presented with deepening of the voice and signs of virilization at puberty and increased serum levels of testosterone (T) of 10.9 nmol/L (2.9 SDS) and androstenedione (Delta 4) of 27 nmol/L (3.3 SDS) were observed. The T/Delta 4-ratio was 0.39. Patient 2 was clinically prepubertal at the time of diagnosis, but she also had increased levels of T at 1.97 nmol/L (2.9 SDS), Delta 4 at 5 nmol/L (3.3 SDS), and the T/Delta 4-ratio was 0.40, but without signs of virilization. Both siblings were diagnosed as homozygous for the splice-site mutation c.277+4A>T in intron 3 of HSD17B3. They were subsequently gonadectomized and treated with hormone replacement therapy. The gonadal histology was overall in accordance with pubertal status, although with a dysgenetic pattern in both patients, including Sertoli-cell-only tubules, few tubules containing germ cells, and presence of microliths.

Conclusions: Two siblings with 17 beta-HSD3 deficiency differed in pubertal development at the time of diagnosis and showed marked differences in their clinical presentation, hormonal profile, gonadal morphology and expression of cell lineage markers. Early diagnosis of 17 beta-HSD3 deficiency appears beneficial to ameliorate long-term consequences.