目的:短暂性妊娠引起的库欣综合征是一种罕见的疾病,其特征是仅在怀孕期间表现出症状。通常在分娩或流产后自发解决。虽然已经确定GNAS与肾上腺肿瘤有关,其在妊娠性库欣综合征发病机制中的具体作用尚不明确。这项工作旨在研究GNAS突变与妊娠诱导的库欣综合征之间的关联。
方法:从患者外周血和肿瘤组织中提取DNA进行全外显子组测序(WES)和Sanger测序。我们使用AlphaFold预测野生型和突变型GNAS的蛋白质结构,并进行功能预测。和免疫组织化学用于检测疾病相关蛋白的表达。对报道的短暂性妊娠诱发库欣综合征的病例进行了回顾和总结。
结果:使用WES,我们在GNAS中鉴定了一个体细胞突变(NM_000516,c.C601T,p.R201C)使用计算方法预测会产生有害影响,例如AlphaFold。人绒毛膜促性腺激素(hCG)刺激试验有弱阳性结果,肾上腺腺瘤组织的免疫组织化学染色也显示黄体生成素/绒毛膜促性腺激素受体(LHCGR)和细胞色素P450家族11亚家族B成员1(CYP11B1)阳性。我们回顾了15例妊娠引起的短暂性库欣综合征。在这些案例中,在3例报告中,肾上腺的免疫组织化学染色显示LHCGR阳性表达,与我们的发现相似。
结论:短暂性妊娠诱导的库欣综合征可能与体细胞GNAS突变和由于LHCGR异常激活引起的肾上腺病理改变有关。
OBJECTIVE: Transient pregnancy-induced Cushing\'s syndrome is a rare condition characterized by the manifestation of symptoms solely during pregnancy, which typically resolve spontaneously following delivery or miscarriage. While it has been established that GNAS is associated with adrenal tumors, its specific role in the pathogenesis of pregnancy-induced Cushing\'s syndrome remains uncertain.This work aims to examine the association between GNAS mutation and pregnancy-induced Cushing\'s syndrome.
METHODS: DNA was extracted from patients\' peripheral blood and tumor tissues for whole-exome sequencing (WES) and Sanger sequencing. We used AlphaFold to predict the protein structure of wild-type and mutant GNAS and to make functional predictions, and immunohistochemistry was used to detect disease-associated protein expression. A review and summary of reported cases of transient pregnancy-induced Cushing\'s syndrome induced by pregnancy was conducted.
RESULTS: Using WES, we identified a somatic mutation in GNAS (NM_000516, c.C601T, p.R201C) that was predicted to have a deleterious effect using computational methods, such as AlphaFold. Human chorionic gonadotropin (hCG) stimulation tests had weakly positive results, and immunohistochemical staining of adrenal adenoma tissue also revealed positivity for luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and cytochrome P450 family 11 subfamily B member 1 (CYP11B1). We reviewed 15 published cases of transient Cushing\'s syndrome induced by pregnancy. Among these cases, immunohistochemical staining of the adrenal gland showed positive LHCGR expression in 3
case reports, similar to our findings.
CONCLUSIONS: Transient pregnancy-induced Cushing\'s syndrome may be associated with somatic GNAS mutations and altered adrenal pathology due to abnormal activation of LHCGR.