A novel mutation in the NR0B1 gene in a family with monozygotic twin sisters and congenital adrenal hypoplasia affected children.

OBJECTIVE: Congenital adrenal hypoplasia (CAH) is a rare disorder that can be inherited in an X-linked or autosomal recessive pattern. CAH is frequently associated with hypogonadotropic hypogonadism (HHG) with absent or arrested puberty and impaired fertility caused by abnormalities in spermatogenesis. It is estimated that more than 50% of boys with idiopathic adrenal insufficiency have mutations in the NR0B1 gene product, DAX1. CASE REPORT: The proband is a young boy born after an uneventful pregnancy and delivery to non-consanguineous parents. At age 4 years and 4 months he came to our attention because of severe vomiting, abdominal pain, dehydration, and asthenia. The proband underwent a detailed clinical investigation including genetic testing. Sequencing analysis of the NR0B1 gene coding region from the affected child revealed a novel hemizygous deletion [c.385delC; p.(Leu129Cysfs*135)]. This mutation was also present in the heterozygous healthy mother and in her twin sister and in the first cousin of the proband. Monozygosity of the twin sisters was demonstrated. This suggests a de novo mutation and gonadal mosaicism for the deletion. CONCLUSIONS: Adrenal hypoplasia typically presents as adrenal insufficiency during the first few months of life, however, not necessarily as shown by our index case. HHG is thought to affect all NR0B1 mutated patients who reach puberty and, as understanding of the disease has improved, more of these patients survive while presenting different features of the disease, this emphasizing the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked CAH.

Ghrelin inhibits steroid biosynthesis by cultured granulosa-lutein cells.

CONTEXT: Growing evidence indicates that ghrelin may participate in the regulation of different aspects of reproductive function. The genes encoding for this peptide and its receptor are expressed in the human ovary, but their functional role is still unknown. OBJECTIVE: The aim of our study was to assess whether ghrelin has any effect on steroid synthesis by human granulosa-lutein cells and to identify the receptor isoform through which this potential effect is exerted. DESIGN, PATIENTS, AND METHODS: Thirty-five women with spontaneous ovulatory cycles undergoing in vitro fertilization for infertility due to uni- or bilateral tubal impatency or male factor were studied. Granulosa-lutein cells obtained from follicular fluid were incubated with increasing amounts of human acylated ghrelin (10(-11) to 10(-7) mol/liter) either alone or together with a 1:500 concentration of a specific anti-ghrelin receptor antibody [GH secretagogue receptor 1a (GHS-R1a)]. Culture media were tested for estradiol (E(2)) and progesterone (P(4)). The expression of GHS-R1a and GHS-R1b in human granulosa-lutein cells was also studied by real-time quantitative PCR. RESULTS: E(2) and P(4) concentrations in the culture media were significantly reduced by ghrelin in a dose-dependent fashion. The maximal decrease in E(2) (25%) and P(4) (20%) media concentrations was obtained with the 10(-7) and 10(-8) mol/liter ghrelin concentrations, respectively. The inhibitory effect of all ghrelin concentrations used was antagonized by the specific anti-ghrelin receptor-1a antibody added to the culture media and not by the specific anti-ghrelin receptor-1b antibody. Both 1a and 1b isoforms of the GHS-R were expressed in human granulosa-lutein cells, with the latter exceeding the former's expression (GHS-R1b/GHS-R1a ratio, 143.23 +/- 28.15). CONCLUSIONS: Ghrelin exerts an inhibitory effect on granulosa-lutein cells steroidogenesis by acting through its functional GHS-R1a. This suggests that ghrelin may serve an autocrine-paracrine role in the control of gonadal function and be part of a network of molecular signals responsible for the coordinated control of energy homeostasis and reproduction.