Abstract
BackgroundBoys carrying mutations in the NR0B1 gene develop adrenal hypoplasia congenita (AHC) and impaired sexual development due to the combination of hypogonadotropic hypogonadism (HH) and primary defects in spermatogenesis.MethodsWe analysed the evolution of hypothalamic-pituitary-testicular function of 8 boys with AHC due to NR0B1 mutations. Our objective was to characterize and monitor the progressive deterioration of this function.ResultsThe first symptoms appeared in the neonatal period (n = 5) or between 6 months and 8.7 years (n = 3). Basal plasma adrenocorticotrophic hormone (ACTH) concentrations increased in all boys, whilst cortisol levels decreased in one case. The natremia was equal or below 134 mmol/L and kaliemia was over 5 mmol/L. All had increased plasma renin. In 3 of 4 patients diagnosed in the neonatal period and evaluated during the first year, the basal plasma gonadotropins concentrations, and their response to gonadotropin releasing hormone (GnRH) test (n = 2), and those of testosterone were normal. The plasma inhibin B levels were normal in the first year of life. With the exception of two cases these concentrations decreased to below the normal for age. Anti-Müllerian hormone concentrations were normal for age in all except one case, which had low concentrations before the initiation of testosterone treatment. In 3 of the 8 cases the gene was deleted and the remaining 5 cases carried frameshift mutations that are predicted to introduce a downstream nonsense mutation resulting in a truncated protein.ConclusionsThe decreases in testosterone and inhibin B levels indicated a progressive loss of testicular function in boys carrying NR0B1 mutations. These non-invasive examinations can help to estimate the age of the testicular degradation and cryopreservation of semen may be considered in these cases as investigational procedure with the aim of restoring fertility.
Highlights
The DAX-1 protein is an orphan member of the nuclear receptor superfamily
Boys carrying mutations in the NR0B1 gene develop adrenal failure and showed impaired sexual development at puberty, followed by infertility. This impairment is due to the combination of hypogonadotropic hypogonadism (HH) [2,3,4] and a primary defect in spermatogenesis [5]
This study shows that the plasma inhibin B, testosterone, luteinising hormone (LH), follicle stimulating hormone (FSH) and antiMullerian hormone (AMH) concentrations are normal in the first year of life, and interestingly there is a normal increase in inhibin B concentration that occurred at 6 months
Summary
The DAX-1 (dosage sensitive sex reversal, adrenal hypoplasia congenita, critical region of the human chromosome, gene 1) protein is an orphan member of the nuclear receptor superfamily. It is encoded by the NR0B1 gene, which is expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary [1]. Boys carrying mutations in the NR0B1 gene develop adrenal failure (adrenal hypoplasia congenital, AHC) and showed impaired sexual development at puberty, followed by infertility This impairment is due to the combination of hypogonadotropic hypogonadism (HH) [2,3,4] and a primary defect in spermatogenesis [5]. Boys carrying mutations in the NR0B1 gene develop adrenal hypoplasia congenita (AHC) and impaired sexual development due to the combination of hypogonadotropic hypogonadism (HH) and primary defects in spermatogenesis
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