[Gonadotropin-dependent precocious puberty: genetic and clinical characteristics].

BACKGROUND: In 90% cases of girls and 25-60% cases of boys the cause of gonadotropin-dependent precocious puberty (PP) is unclear. Up to 25-27.5% of gonadotropin-dependent PP cases are monogenic and suggest autosomal-dominant inheritance with incomplete sex-dependent penetrance. To date, mutations in genes KISS1, KISS1R, MKRN3, DLK1 have been described as causal variants leading to precocious hypothalamic-pituitary axis activation in childhood. Genetic testing in patients with hereditary forms of PP can expand our knowledge of underlying molecular mechanisms of the disease and it  is also necessary for genetic counselling. AIM: To study clinical features and genetic characteristics of patients with idiopathic gonadotropin-dependent precocious puberty. MATERIALS AND METHODS: A group of patients with idiopathic gonadotropin-dependent precocious puberty and positive family history (early or precocious puberty) was examined. Laboratory and instrumental diagnostic tests, full-exome sequencing (NGS, next-generation sequencing) were provided for all patients. RESULTS: The study included 30 patients (29 girls, 1 boy) with idiopathic gonadotropin-dependent precocious puberty. The median of patients age at the time of the examination was 7,2 years [6,5; 7,7]. Positive family history presented in all cases: in 40% of patients on father's side, in 37% - on mother's side, in 23% of patients PP was diagnosed in siblings. The fullexome sequencing was conducted to 21 patients: in 61,9% of cases (95% CI [40;79]) nucleotide variants were identified   in genes, associated with gonadotropin-dependent precocious puberty. MKRN3 gene defect was detected in most cases (77% cases (95% CI [49; 92]), which consistent with international data on its highest prevalence in the monogenic forms of PP. In 23% of cases (95% CI [7; 50]) nucleotide variants were identified in other candidate genes associated with neuroontogenesis and neuroendocrine regulation mechanisms of hypothalamic-pituitary axis. CONCLUSION: Our study confirms that detailed family history data in children with PP provides a rational approach to molecular-genetic testing. Data of inheritance pattern and clinical manifestations will simplify the diagnosis of hereditary forms of disease and enhance genetic counselling of families, followed by timely examination and administration of pathogenetic therapy.

[Familial case of hypogonadotropic hypogonadism as the CHARGE syndrome manifestation].

CHARGE syndrome is a rare autosomal dominant disease caused by CHD7 gene mutations. Individuals with CHARGE display a wide spectrum of clinical features. It might be presented only as a delay puberty, which does not require any hormone replacement therapy to severe CHARGE phenotype, requiring a multidisciplinary therapeutic approach. Wild spectrum of clinical presentation can be seen even among the patients with identical mutation. Diagnosis might be suspected by a combination of major and minor clinical criteria of this disorder, but molecular genetic analysis is mandatory for final verification. Accurate diagnosis is essential to informing patients about all possible clinical features, reproductive status and choosing the correct treatment approach. The most common endocrine abnormality in patients with CHARGE syndrome is the disturbance in gonadotropins function ranged from delay puberty to persistent hypogonadotropic hypogonadism with different olfactory phenotypes, resulted by specific role of CHD7 in GnRH neuronal embryogenesis.We describe a familial case of CHARGE syndrome with significant intrafamilial clinical heterogeneity due to CHD7 gene mutation.