A new compound heterozygous frameshift mutation in the type II 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) gene causes salt-wasting 3 beta-HSD deficiency congenital adrenal hyperplasia.

We report a new compound heterozygous frameshift mutation in the type II 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) gene in a Pakistanian female child with the salt-wasting form of 3 beta-HSD deficiency congenital adrenal hyperplasia. The child, born with clitoral enlargement, manifesting salt-wasting adrenal crisis, and public hair growth during infancy, was treated with hormonal replacement therapy. The etiology of her congenital adrenal hyperplasia, however, was not defined. Two of her siblings, as well as one paternal cousin with ambiguous genitalia and palpable gonads and another paternal cousin with normal female genitalia, had symptoms of adrenal crisis and died during early infancy. Thus, although the family history suggested possible 3 beta-HSD deficiency disorder, suppressed adrenal function caused by excess glucocorticoid therapy in this child at 7 yr of age did not allow hormonal diagnosis. To confirm 3 beta-HSD deficiency, we sequenced the type II 3 beta-HSD gene in the patient, her family, and the parents of her decreased paternal cousins. The type II 3 beta-HSD gene region of a putative promoter, exons I, II, III, and IV, and exon-intron boundaries were amplified by PCR and sequenced in all subjects. The DNA sequence of the child revealed a single nucleotide deletion at codon 318 [ACA (Thr)-->AA] in exon IV in one allele, and two nucleotide deletions at codon 273 [AAA(Lys)-->A] in exon IV in the other allele. The remaining gene sequences were normal. The codon 318 mutation was found in one allele from the father, brother, and parents of the deceased paternal cousins. The codon 273 mutation was found in one allele of the mother and a sister. These findings confirmed inherited 3 beta-HSD deficiency in the child caused by the compound heterozygous type II 3 beta-HSD gene mutation. Both codon 273 and 318 mutations yielding frameshift and premature stop codons at codons 279 and 367, respectively, are predicted to result in an altered and truncated type II 3 beta-HSD protein, thereby causing salt-wasting 3 beta-HSD deficiency in the patient. The type II 3 beta-HSD gene findings and clinical history of her family members suggest that the patient's deceased siblings were likely affected males with the same compound heterozygous mutations of the gene as in the proband, whereas the deceased cousins were likely affected with the homozygous codon 318 mutation in the gene.