A novel HSD3B2 variant of uncertain significance (c.64_66del, p.Leu22del) in a female infant with 3β-hydroxysteroid dehydrogenase deficiency presenting with completely normal external genitalia: a case report

Abstract Background 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare form of congenital adrenal hyperplasia (CAH), typically presenting with salt-wasting and, in females, ambiguous genitalia, or undervirilization in males. Case presentation We report the case of a 10-day-old female infant who presented with feeding difficulties, generalized skin hyperpigmentation, and hyperkalemia, yet had completely normal external genitalia. Genetic analysis identified compound heterozygous variants in the HSD3B2 gene: a novel, maternally inherited in-frame deletion, c.64_66del (p.Leu22del), currently classified as a variant of uncertain significance (VUS) according to ACMG/AMP guidelines; and a paternally inherited, likely pathogenic missense variant, c.674 T>A (p.Val225Asp). The c.64_66del variant has not been previously reported; it forms compound heterozygosity with the paternal likely pathogenic variant, consistent with an autosomal recessive inheritance pattern. However, its independent pathogenicity remains to be confirmed by functional studies. Conclusions This case emphasizes that 3β-HSD deficiency should be suspected in neonates with salt-wasting manifestations, even with completely normal external genitalia (Prader stage 0). The identification of this novel c.64_66del VUS adds to the allelic repertoire of the HSD3B2 gene and underscores the importance of early genetic testing, which strongly supports the diagnosis while also emphasizing the need for functional studies to clarify the pathogenicity of uncertain variants.