Background: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR and characterized by defect in adrenal and gonadal steroidogenesis and lipid droplet accumulation in steroidogenic cells. 46,XY patients with classic LCAH typically present with female-type external genitalia, while those with nonclassic LCAH have masculinized external genitalia. The rarity of the nonclassic form precludes the clarification of pubertal and reproductive functions in this condition.
Objective: The aim of this study was to define long-term outcome of testicular function in nonclassic LCAH.
Methods: We retrospectively reviewed medical charts of three Japanese males with nonclassic LCAH in our institution. We also performed genetic analysis of STAR and functional assay of a novel sequence variation of STAR.
Results: Our patients were diagnosed with primary adrenal insufficiency (PAI) at 5 days, 4 years, or 5 years of age. All exhibited complete male external genitalia and completed pubertal development without androgen replacement. Endocrinological data showed preserved testosterone synthesis, despite increased gonadotropin levels in Patients 2 and 3. Semen analyses showed normozoospermia in Patient 1 and mild oligozoospermia in Patient 2. Electron microscopic analysis of testicular biopsy from Patient 2 at 13 years of age revealed prominent lipid accumulation in the cytosol of Leydig cells.Sanger sequencing identified the same compound heterozygous mutations in STAR (p.Glu258* and p.Arg272Cys) in Patients 1 and 2 and a heterozygous dominant-negative mutation in STAR (p.Gly22_Leu59del) in Patient 3. Functional assay of STAR-Arg272Cys with COS-1 cells determined the residual activity as 35% of the wild-type STAR.
Conclusion: These results indicate that testosterone synthesis in nonclassic LCAH can be preserved to complete pubertal development and to induce germ cell maturation despite lipid accumulation of the Leydig cells.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology