37 NON-CLASSICAL 3-β-HSD DEFICIENCY DUE TO POINT MUTATION IN THE TYPE II 3-β-HSD GENE

Abstract

Congenital adrenal hyperplasia due to 3β-HSD deficiency may be classified in 2 clinical subtypes: the blassical form- with or without salt-loss and a non classical form described in pubertal hirsute females and in girls with premature pubarche. Recently the complete structure of the two human 3β-HSD genes (type I and type II) have been characterized. The type II gene encodes the 3β-HSD enzyme in the adrenal glands, ovary and testis whereas the type I gene encodes the 3β-HSD enzyme in the placenta and peripheral tissue. We describe here the first case with non classical 3β-HSD deficiency due to a point mutation in 3-β-HSD type II. The patient, a 5-year-old white girl presented, with pubic hair, acne and normal external genitalia. Her parents were not consanguineous and denied similar cases in the family. CA 5.3 yrs. Height 111 cm (+0.1 SD) Weight:23 kg; Bone age:5.75 ys; Breasts:Tanner I; Pubic hair: Tanner III. The ACTH test (25 IU iv) found normal cortisol levels and high levels of Δ5-steroids: DHEA.17PREG and 17PREG/17OHP ratio. The Δ4-steroids 17OHP, Δ4-A and T were also elevated, 24 hours basal urinary steroids were analyzed by gas chromatography and revealed elevated pregnenetriol(5PT)=715 μg/24hs (NL:80-352) and 5PT/THE+THF+5αTHF ratio=0.96 (NL:0.05) confirming the 3β-HSD deficiency. The treatment with DEX 0.2 mg reversed all the steroid abnormalities. The 4 exons of the type II 3β-HDS gene were amplified by PCR and screened for mutations by denaturing gradiente gel eletrophoresis (DGGE). DGGE detected a mutation in exon 3 of 3β-HSD type II. Sequencing showed the mutation to be a single missense mutation of GCC→ACC in codon 82 leading to the substitution in the affected patient of threonine for the normal alanine. The patient is homozygous for the mutation and her parents are both heterozygous. We conclude that non-classical form of 3β-HSD deficiency could also be caused by point mutation in 3β-HSD type II gene as in the classical form.