Gonadotropin- and Adrenocorticotropic Hormone-Independent Precocious Puberty of Gonadal Origin in a Patient with Adrenal Hypoplasia Congenita Due to DAX1 Gene Mutation - A Case Report and Review of the Literature: Implications for the Pathomechanism.

BACKGROUND/AIMS: Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) classically associated with hypogonadotropic hypogonadism. Unexpectedly, precocious puberty (PP) has been reported in some cases, its mechanism remaining unclear. METHODS: We longitudinally studied a boy with AHC due to DAX1 gene mutation who developed peripheral PP at age 4.5 years. Initially he presented pubic hair, penile enlargement, advanced bone age and elevated testosterone levels. PP progressed with acne, body odour and ejaculations. In addition, we summarized reported findings of patients with DAX1 mutations and PP in the literature in a structured manner providing a basis to discuss possible pathomechanisms of PP in DAX1 patients. RESULTS: In our patient, hydrocortisone treatment was increased to 20 mg/m2/day as suggested in similar published cases. However, despite the suppression of adrenocorticotropic hormone (ACTH), this remained without clinical effect or change in laboratory results. The progression of symptoms of pubertal development was well suppressed under cyproterone acetate treatment. Twenty-four-hour steroid urine excretion rate measurements excluded an effect of adrenal androgens and showed a prepubertal rise of excreted testosterone. Testes size remained small. GnRH testing showed peripheral PP. CONCLUSION: We hypothesize that an intrinsic, gonadotropin- and ACTH-independent activation of steroidogenesis in the DAX1 deficient testes leads to PP in AHC patients with DAX1 mutations.

Up-regulation of Bcl-2 during adipogenesis mediates apoptosis resistance in human adipocytes.

Targeting apoptotic pathways in adipocytes has been suggested as a pharmacological approach to treat obesity. However, adipocyte apoptosis was identified as a cause for macrophage infiltration into adipose tissue. Previous studies suggest that mature adipocytes are less sensitive to apoptotic stimuli as compared to preadipocytes. Here, we aimed to identify proteins mediating apoptosis resistance in adipocytes. Our data revealed that the anti-apoptotic protein Bcl-2 (B-cell lymphoma 2) is up-regulated during adipogenic differentiation. Bcl-2 overexpression in preadipocytes lowers their apoptosis sensitivity to the level of mature adipocytes. Vice versa Bcl-2 knockdown in adipocytes sensitizes these cells to CD95-induced apoptosis. Taken together, our findings suggest a shift in the balance of pro-apoptotic and anti-apoptotic molecules during adipogenesis resulting in a higher apoptosis resistance. This study sheds new light on the apoptotic process in human fat cells and may constitute a new possible target for the specific regulation of adipose tissue mass.