No evidence of mutations in the genes for type I and type II 3β-hydroxysteroid dehydrogenase (3βHSD) in nonclassical 3βHSD deficiency

Nonclassical 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴-isomerase deficiency (NC3βHSDD) has been diagnosed in hyperandrogenic women with an increasing frequency during the last 14 yr. Fifteen menarcheal women with androgen excess syndrome, diagnosed with NC3βHSDD previously were restudied, in 12 after discontinuation of glucocorticoid treatment, in 2 patients never treated with glucocorticoids, and in 1 both before and after glucocorticoid therapy. Each of the 15 patients underwent ACTH stimulation testing, in some cases on multiple occasions. Although some (very few) patients seem to have improved with time, others remained the same or got worse. Molecular DNA analysis was also performed in 6 of the patients, using the strategy successfully used to detect point mutations in the type II 3β-hydroxysteroid dehydrogenase (3βHSD) gene, which are responsible for classical 3βHSD deficiency. This strategy consists of the direct sequencing of polymerase chain reaction-amplified DNA fragments corresponding to the complete coding sequence and all intron-exon junctions and to the 5′- and 3′-noncoding region of this gene. We were unable to demonstrate any mutation of the type II 3βHSD gene in these 6 patients. To gain additional information about potential mutations, direct sequencing of the type I 3βHSD gene was also performed using this same strategy, and no mutations were found. The present study strongly suggests that unlike the salt-losing and nonsalt-losing forms of classical 3βHSD deficiency, NC3βHSDD is not due to a mutant type II 3βHSD enzyme. However, the possibility remains of a mutation(s) in the unsequenced regions of the type II 3βHSD gene or elsewhere, such as in a gene for modulatory protein, playing a specific role in the expression of the type II 3βHSD gene. On the other hand, knowing the multiple hormonal controls to which 3βHSD activity is subject, it cannot be excluded that at least in some cases, NC3βHSDD may be an acquired defect, the result of endogenous or environmental factors.