Clinical, endocrine, and molecular findings in 17 beta-hydroxysteroid dehydrogenase type 3 deficiency

The 17 beta-hydroxysteroid dehydrogenases (17 beta HSD) gene family comprises different enzymes involved in the biosynthesis of active steroid hormones. The 17 beta HSD type 3 (17 beta HSD3) isoenzyme catalyzes the reductive conversion of the inactive C19-steroid, Delta(4)-androstenedione (Delta(4)-A), into the biologically active androgen, testosterone (T), in the Leydig cells of the testis. It is encoded by the 17 beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) gene, which maps to chromosome 9q22. Mutations in the HSD17B3 gene are associated with a rare form of 46,XY disorder of sex development referred to as 17 beta HSD3 deficiency (or as 17-ketosteroid reductase deficiency), due to impaired testicular conversion of Delta(4)-A into T. 46,XY patients with 17 beta HSD3 deficiency are usually classified as female at birth, raised as such, but develop secondary male features at puberty. Diagnosis, and consequently early treatment, is difficult because clinical signs from birth until puberty may be mild or absent. Biochemical diagnosis of 17 beta HSD3 deficiency requires measurement of serum T/Delta(4)-A ratio after hCG stimulation test in pre-pubertal subjects, while baseline values seem to be informative in early infancy and adolescence. However, low basal T/Delta(4)-A ratio is not specific for 17 beta HSD3 deficiency, being sometimes also found in patients with other defects in T synthesis or with Leydig cells hypoplasia. Mutational analysis of the 17HSDB3 gene is useful in confirming the clinical diagnosis of 17 beta HSD3 deficiency. This review describes clinical findings, diagnosis, and molecular basis of this rare disease.