Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls.

Objective: 17beta-hydroxysteroid dehydrogenase type 3 isoenzyme (17beta-HSD3) is required to produce testosterone for male sex differentiation. Mutations in the HSD17B3 gene cause 17betaHSD3 deficiency and result in XY sex reversal of varying degree. We report the phenotypes of 14 subjects with 17betaHSD3 deficiency in relation to sex of rearing, androgen production, and HSD17B3 mutations.

Design: Cases were identified through the Cambridge Disorders of Sex Development Database where detailed clinical information was recorded, results of hCG stimulation tests were available, and HSD17B3 mutation was identified.

Results: Fourteen subjects from seven pedigrees (four consanguineous) had the following seven mutations: A56T, N130S, E215D, S232L, C268Y, V205E, and a novel mutation M197K. XY sex reversal was classified as complete in 10 infants at birth. Inguinal masses suggestive of androgen insensitivity syndrome (AIS) occurred in five infants. Contrasexual virilization reminiscent of 5alpha-reductase deficiency occurred in four subjects at puberty. The median (range) testosterone : androstenedione (T/A) ratio after a short hCG stimulation test was 0.32 (0.12-3.4). The S232L mutation identified in three affected family members caused isolated, severe hypospadias in one member who was raised male; virilization occurred despite in vitro studies showing an inactive mutant enzyme. Ratios of T/A in this pedigree were more than 0.8.

Conclusion: XY sex reversal is sufficiently variable in 17betaHSD3 deficiency to cause problems in accurate diagnosis, particularly in distinguishing it from AIS. It should be considered in undervirilized male infants with normal Wolffian duct structures, absent Müllerian ducts, and normal adrenal steroid biosynthesis; or when an assigned female subject virilizes at puberty. Elevated hCG-stimulated T/A ratio may occur, and sex of rearing may not be concordant within affected families with the same HSD17B3 mutation. The T/A ratio, mutation analysis and functional analysis of the mutant enzyme taken in isolation, respectively, may not conclusively establish a diagnosis of 17betaHSD3 deficiency in undervirilized male subjects; the reasons for these discrepancies remain unknown.