小狗阅读会员会员
医学顶刊SCI精读工具

扫码登录小狗阅读

阅读SCI医学文献
Document
订阅泛读方向 订阅泛读期刊
  • 我的关注
  • 我的关注
  • {{item.title}}

    按需关注领域/方向,精准获取前沿热点

  • {{item.title}}

    {{item.follow}}人关注

  • {{item.subscribe_count}}人订阅

    IF:{{item.impact_factor}}

    {{item.title}}

Germline CDKN1B loss-of-function variants cause pediatric Cushing's disease with or without an MEN4 phenotype.

生殖系 CDKN1B 功能缺失变异引起小儿库欣病伴或不伴 MEN4 表型。

  • 影响因子:5.19
  • DOI:10.1210/clinem/dgaa160
  • 作者列表:"Chasseloup F","Pankratz N","Lane J","Faucz FR","Keil MF","Chittiboina P","Kay DM","Hussein Tayeb T","Stratakis CA","Mills JL","Hernández-Ramírez LC
  • 发表时间:2020-03-31
Abstract

CONTEXT:Germline loss-of-function CDKN1B gene variants cause the autosomal dominant syndrome of multiple endocrine neoplasia type 4 (MEN4). Even though pituitary neuroendocrine tumors are a well-known component of the syndrome, only two cases of Cushing's disease (CD) have so far been described in this setting. AIM:To screen a large cohort of CD patients for CDKN1B gene defects and to determine their functional effects. PATIENTS:We screened 211 CD patients (94.3% pediatric) by germline whole-exome sequencing (WES) only (n=157), germline and tumor WES (n=27), Sanger sequencing (n=6) and/or germline copy number variant (CNV) analysis (n=194). Sixty cases were previously unpublished. Variant segregation was investigated in the patients' families and putative pathogenic variants were functionally characterized. RESULTS:Five variants of interest were found in one patient each: one truncating (p.Q107Rfs*12) and four non-truncating variants, including three missense changes affecting the CDKN1B protein scatter domain (p.I119T, p.E126Q, and p.D136G) and one 5'UTR deletion (c.-29_-26delAGAG). No CNVs were found. All cases presented early (10.5±1.3 years) and apparently sporadically. Aside from colon adenocarcinoma in one carrier, no additional neoplasms were detected in the probands or their families. In vitro assays demonstrated protein instability and disruption of the scatter domain of CDKN1B for all variants tested. CONCLUSIONS:Five patients with CD and germline CDKN1B variants of uncertain significance (n=2) or pathogenic/likely pathogenic (n=3) were identified, accounting for 2.6% of the patients screened. Our finding that germline CDKN1B loss-of-function may present as apparently sporadic, isolated pediatric CD has important implications for clinical screening and genetic counselling.

摘要

背景: 生殖系功能缺失 CDKN1B 基因变异引起多发性内分泌腺瘤 4 型 (MEN4) 的常染色体显性遗传综合征。尽管垂体神经内分泌肿瘤是该综合征的一个众所周知的组成部分,但迄今为止仅描述了两例库欣病 (CD)。 目的: 筛选 CDKN1B 基因缺陷的大型 CD 患者队列,并确定其功能效应。 患者: 我们仅通过生殖系全外显子组测序 (WES) (n = 211) 、生殖系和肿瘤 WES (n = 27) 筛查了 94.3% 例 CD 患者 (157 例儿科),sanger 测序 (n = 6) 和/或生殖系拷贝数变异 (CNV) 分析 (n = 194)。60 例以前未发表。在患者家庭中调查了变异分离,并对推定的致病变异进行了功能表征。 结果: 在每例患者中发现 5 个感兴趣的变异: 1 个截断 (p。q107Rfs * 12) 和 4 个非截断变异体,包括 3 个影响 CDKN1B 蛋白分散域的错义变化 (p。i119T,p。e126Q 和 p。d136G) 和一个 5 'utr 缺失 (c.-29 _-26delAGAG)。未发现 CNVs。所有病例均出现早期 (10.5 ± 1.3 年),且明显偶发。除了一个携带者的结肠腺癌,在先证者或其家族中未检测到额外的肿瘤。体外试验证明了所有检测变异体的蛋白不稳定性和 CDKN1B 散射域的破坏。 结论: 确定了 5 例意义不明确的 CD 和生殖系 CDKN1B 变异患者 (n = 2) 或致病性/可能致病性 (n = 3),占筛查患者的 2.6%。我们的发现生殖系 CDKN1B 功能丧失可能表现为明显散发、孤立的儿科 CD,对临床筛查和遗传咨询具有重要意义。

下载该文献
小狗阅读

帮助医生、学生、科研工作者解决SCI文献找不到、看不懂、阅读效率低的问题。提供领域精准的SCI文献,通过多角度解析提高文献阅读效率,从而使用户获得有价值研究思路。

相关文献
影响因子:3.03
发表时间:2020-01-02
来源期刊:Pituitary
DOI:10.1007/s11102-019-01023-0
作者列表:["Galm, Brandon P.","Buckless, Colleen","Swearingen, Brooke","Torriani, Martin","Klibanski, Anne","Bredella, Miriam A.","Tritos, Nicholas A."]

METHODS:Purpose Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). Methods We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. Results Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33–26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. Conclusion Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:4.48
发表时间:2020-01-01
DOI:10.1016/j.trsl.2019.07.013
作者列表:["Xiong Y","Tang Y","Fan F","Zeng Y","Li C","Zhou G","Hu Z","Zhang L","Liu Z"]

METHODS::Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:5.19
发表时间:2020-01-01
DOI:10.1210/clinem/dgz033
作者列表:["Arlien-Søborg MC","Grøndahl C","Bæk A","Dal J","Madsen M","Høgild ML","Pedersen SB","Bjerre M","Jørgensen JOL"]

METHODS:BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.

方向

复制标题
发送后即可在该邮箱或我的下载查看该文献
发送
该文献默认存储到我的下载

报名咨询

建议反馈
问题标题:
联系方式:
电子邮件:
您的需求: