Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR and characterized by a defect in steroidogenesis and lipid droplet accumulation in steroidogenic cells. Patients with 46,XY and classic LCAH will typically present with female-type external genitalia. However, those with nonclassic LCAH will have masculinized external genitalia. The rarity of the nonclassic form has precluded the clarification of the long-term outcomes of testicular function in nonclassic LCAH. We report the cases of three adult males with nonclassic LCAH in whom primary adrenal insufficiency had been diagnosed at 5 days, 4 years, and 5 years of age. All exhibited complete male external genitalia and had completed pubertal development without androgen replacement. The endocrinological data showed preserved gonadal function in patients 1 and 2 and hypergonadotropic hypogonadism in patient 3. Semen analyses showed normozoospermia in patient 1 and mild oligozoospermia in patient 2. Electron microscopic analysis of a testicular biopsy specimen from patient 2 at 13 years of age revealed prominent lipid accumulation in the cytosol of Leydig cells. Patients 1 and 2 shared the same compound heterozygous mutations in STAR (p.Glu258* and p.Arg272Cys). Patient 3 possessed a heterozygous dominant-negative mutation in STAR (p.Gly22_Leu59del). A functional assay of a variant STAR-Arg272Cys determined the residual activity as 35% of the wild-type STAR. The results from the present case series and a review of four previously reported adult cases indicate that testosterone synthesis can be preserved in most males with nonclassic LCAH to complete pubertal development and induce germ cell maturation despite lipid accumulation in the Leydig cells.

This paper describes the testicular histopathology in 2 male patients with congenital lipoid adrenal hyperplasia who underwent orchiectomy at age 7 (case 1) and 12 (case 2) years, respectively. In both cases, seminiferous tubules were normal in diameter (mean: case 1 88.7 μm; case 2 115.9 μm) and consisted of an age-appropriate number of type A spermatogonia (mean: case 1 1.7/tubule; case 2 4.0/tubule) and an increased number of Sertoli cells (mean: case 1 34.7/tubule; case 2 27.9/tubule). The interstitial space was abundant and contained normal to increased numbers of Leydig cells (mean: case 1 4.0/ tubule; case 2 6.1/tubule) that were filled with lipid droplets. We suspect that lipid accumulation in Leydig cells is consistent with defective conversion of cholesterol into pregnenolone and thus constitutes the characteristic feature of this disease, while the remaining findings appear to be common to disorders associated with hypergonadotropic hypogonadism.

No abstract

We report on two unrelated children, a girl and a boy, with regressive metaphyseal dysplasia. Both children had bow legs and a transient growth decline in early childhood. Metaphyseal modifications of the long bones in the children were most conspicuous at an early age and then subsided by age 2 to 3 years. The father of the boy may have had the same disorder, because he was shorter than his sibs and showed mild modifications of the vertebral end plates with mild narrowing of the interpediculate distance of the lumbar spine. The evolution of the metaphyseal dysplasia in the children closely resembled that of metaphyseal anadysplasia (MAD), which is X-linked recessive in inheritance. By contrast, the occurrence of an isolated, affected girl and possible father-to-son transmission reported here were consistent with autosomal dominant transmission, suggesting heterogeneity of MAD. Molecular studies of the type X collagen gene in the boy did not demonstrate any disease-causing mutation.