Khabibullina D A, Kolodkina A A, Vizerov T V, Zubkova N A, Bezlepkina O B
Endocrinology Research Center.
Probl Endokrinol (Mosk). 2023 May 11;69(2):58-66. doi: 10.14341/probl13215.
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.
To study clinical features and genetic characteristics of patients with idiopathic gonadotropin-dependent precocious puberty.
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.
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.
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.
在90%的女孩和25 - 60%的男孩中，促性腺激素依赖性性早熟（PP）的病因尚不清楚。高达25 - 27.5%的促性腺激素依赖性PP病例是单基因的，提示常染色体显性遗传且具有不完全性别的外显率。迄今为止，KISS1、KISS1R、MKRN3、DLK1基因的突变已被描述为导致儿童期下丘脑 - 垂体轴过早激活的致病变异。对遗传性PP患者进行基因检测可以扩展我们对该疾病潜在分子机制的认识，这对于遗传咨询也是必要的。
研究特发性促性腺激素依赖性性早熟患者的临床特征和遗传特征。
对一组患有特发性促性腺激素依赖性性早熟且有阳性家族史（早发或性早熟）的患者进行检查。为所有患者提供了实验室和仪器诊断测试以及全外显子测序（NGS，下一代测序）。
该研究纳入了30例特发性促性腺激素依赖性性早熟患者（29名女孩，1名男孩）。检查时患者年龄中位数为7.2岁[6.5；7.7]。所有病例均有阳性家族史：40%的患者父亲一方有，37%母亲一方有，23%的患者兄弟姐妹中被诊断为PP。对21例患者进行了全外显子测序：61.9%的病例（95%可信区间[40；79]）在与促性腺激素依赖性性早熟相关的基因中鉴定出核苷酸变异。大多数病例（77%的病例（95%可信区间[49；92]）检测到MKRN3基因缺陷，这与该基因在单基因形式的PP中患病率最高的国际数据一致。23%的病例（95%可信区间[7；50]）在与下丘脑 - 垂体轴神经发生和神经内分泌调节机制相关的其他候选基因中鉴定出核苷酸变异。
我们的研究证实，PP患儿详细的家族史数据为分子遗传学检测提供了合理的方法。遗传模式和临床表现的数据将简化遗传性疾病的诊断，并加强对家庭的遗传咨询，随后及时进行检查和给予病因治疗。
