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Molecular causes of congenital anomalies of the kidney and urinary tract (CAKUT). 先天性肾和尿路异常(CAKUT)的分子原因。
Q1 PEDIATRICS Pub Date : 2021-02-24 DOI: 10.1186/s40348-021-00112-0
Stefan Kohl, Sandra Habbig, Lutz T Weber, Max C Liebau

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 0.5-1/100 newborns and as a group they represent the most frequent cause for chronic kidney failure in children. CAKUT comprise clinically heterogeneous conditions, ranging from mild vesicoureteral reflux to kidney aplasia. Most forms of CAKUT share the pathophysiology of an impaired developmental interaction of the ureteric bud (UB) and the metanephric mesenchyme (MM). In most cases, CAKUT present as an isolated condition. They also may occur as a component in rare multi-organ syndromes. Many CAKUT probably have a multifactorial etiology. However, up to 20% of human patients and > 200 transgenic mouse models have a monogenic form of CAKUT, which has fueled our efforts to unravel molecular kidney (mal-)development. To date, genetic variants in more than 50 genes have been associated with (isolated) CAKUT in humans. In this short review, we will summarize typical imaging findings in patients with CAKUT and highlight recent mechanistic insight in the molecular pathogenesis of monogenic forms of CAKUT.

先天性肾和尿路异常(先天性肾和尿路异常)发生率为0.5-1/100新生儿,作为一个群体,它们是儿童慢性肾衰竭的最常见原因。ckut包括临床异质性疾病,从轻度膀胱输尿管反流到肾发育不全。大多数形式的CAKUT具有输尿管芽(UB)和后肾间质(MM)发育相互作用受损的病理生理特征。在大多数情况下,CAKUT表现为孤立状态。它们也可能作为罕见的多器官综合征的组成部分出现。许多CAKUT可能有多因素病因。然而,高达20%的人类患者和超过200只转基因小鼠模型具有单基因形式的CAKUT,这推动了我们解开分子肾(不良)发育的努力。迄今为止,已有超过50个基因的遗传变异与人类(分离的)CAKUT相关。在这篇简短的综述中,我们将总结CAKUT患者的典型影像学表现,并强调单基因形式的CAKUT分子发病机制的最新见解。
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引用次数: 17
Targeted deletion of Ruvbl1 results in severe defects of epidermal development and perinatal mortality. Ruvbl1的靶向缺失会导致严重的表皮发育缺陷和围产期死亡率。
Q1 PEDIATRICS Pub Date : 2021-02-12 DOI: 10.1186/s40348-021-00111-1
Claudia Dafinger, Thomas Benzing, Jörg Dötsch, Bernhard Schermer, Max C Liebau

Epidermal development is a complex process of regulated cellular proliferation, differentiation, and tightly controlled cell death involving multiple cellular signaling networks. Here, we report a first description linking the AAA+ (ATPases associated with various cellular activities) superfamily protein Ruvbl1 to mammalian epidermal development. Keratinocyte-specific Ruvbl1 knockout mice (Ruvbl1fl/flK14:Cretg) show a severe phenotype including dramatic structural epidermal defects resulting in the loss of the functional skin barrier and perinatal death. Thus, Ruvbl1 is a newly identified essential player for the development of differentiated epidermis in mice.

表皮发育是一个复杂的调控细胞增殖、分化和严格控制细胞死亡的过程,涉及多个细胞信号网络。在这里,我们首次报道了AAA+(与各种细胞活动相关的atp酶)超家族蛋白Ruvbl1与哺乳动物表皮发育的联系。角化细胞特异性Ruvbl1敲除小鼠(Ruvbl1fl/flK14:Cretg)表现出严重的表型,包括显著的结构性表皮缺陷,导致功能性皮肤屏障的丧失和围产期死亡。因此,Ruvbl1是新发现的小鼠表皮分化发育的重要参与者。
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引用次数: 0
Asprosin in pregnancy and childhood. 妊娠期和儿童期的阿司匹林。
Q1 PEDIATRICS Pub Date : 2020-12-23 DOI: 10.1186/s40348-020-00110-8
Ruth Janoschek, Thorben Hoffmann, Yousef Ashraf Tawfik Morcos, Gerhard Sengle, Jörg Dötsch, Eva Hucklenbruch-Rother
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引用次数: 10
Impact of early-life diet on long-term renal health. 早期饮食对长期肾脏健康的影响。
Q1 PEDIATRICS Pub Date : 2020-12-03 DOI: 10.1186/s40348-020-00109-1
Eva Nüsken, Jenny Voggel, Gregor Fink, Jörg Dötsch, Kai-Dietrich Nüsken

In the last years, great advances have been made in the effort to understand how nutritional influences can affect long-term renal health. Evidence has accumulated that maternal nutrition before and during pregnancy and lactation as well as early postnatal nutrition is of special significance. In this review, we summarize epidemiologic and experimental data on the renal effects of perinatal exposure to energy restriction, low-protein diet, high-fat diet, high-fructose diet, and high- and low-salt diet as well as micronutrient deficiencies. Interestingly, different modifications during early-life diet may end up with similar sequelae for the offspring. On the other hand, molecular pathways can be influenced in opposite directions by different dietary interventions during early life. Importantly, postnatal nutrition significantly modifies the phenotype induced by maternal diet. Sequelae of altered macro- or micronutrient intakes include altered nephron count, blood pressure dysregulation, altered sodium handling, endothelial dysfunction, inflammation, mitochondrial dysfunction, and oxidative stress. In addition, renal prostaglandin metabolism as well as renal AMPK, mTOR, and PPAR signaling can be affected and the renin-angiotensin-aldosterone system may be dysregulated. Lately, the influence of early-life diet on gut microbiota leading to altered short chain fatty acid profiles has been discussed in the etiology of arterial hypertension. Against this background, the preventive and therapeutic potential of perinatal nutritional interventions regarding kidney disease is an emerging field of research. Especially individuals at risk (e.g., newborns from mothers who suffered from malnutrition during gestation) could disproportionately benefit from well-targeted dietary interventions.

在过去的几年中,在了解营养影响如何影响长期肾脏健康方面取得了巨大进展。越来越多的证据表明,孕前和哺乳期的孕产妇营养以及产后早期的营养具有特殊的意义。本文综述了围产期能量限制、低蛋白饮食、高脂肪饮食、高果糖饮食、高盐饮食和低盐饮食以及微量营养素缺乏对肾脏影响的流行病学和实验数据。有趣的是,早期饮食的不同改变可能会给后代带来类似的后遗症。另一方面,在生命早期,不同的饮食干预可能会对分子途径产生相反的影响。重要的是,产后营养显著改变母体饮食诱导的表型。宏量或微量营养素摄入改变的后遗症包括肾单位计数改变、血压失调、钠处理改变、内皮功能障碍、炎症、线粒体功能障碍和氧化应激。此外,肾脏前列腺素代谢以及肾脏AMPK、mTOR和PPAR信号传导可能受到影响,肾素-血管紧张素-醛固酮系统可能失调。最近,早期饮食对肠道微生物群的影响导致短链脂肪酸谱的改变在动脉高血压的病因学中得到了讨论。在此背景下,围产期营养干预对肾脏疾病的预防和治疗潜力是一个新兴的研究领域。特别是有风险的个体(例如,在妊娠期间患有营养不良的母亲所生的新生儿)可以从针对性良好的饮食干预中获得不成比例的好处。
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引用次数: 9
Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency. 两名复合杂合子瘦素受体缺乏症患者的诊断和治疗奥德赛。
Q1 PEDIATRICS Pub Date : 2020-11-03 DOI: 10.1186/s40348-020-00107-3
Stefanie Zorn, Julia von Schnurbein, Katja Kohlsdorf, Christian Denzer, Martin Wabitsch

Background: Rare genetic variations in the leptin-melanocortin signalling pathway can severely impair appetite regulation and cause extreme obesity in early childhood.

Case presentation: Our case reports describe the diagnostic and therapeutic procedures in a girl as well as in a non-related boy of non-consanguineous, German parents with severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour. Excessive weight gain within the first year of life initiated extensive diagnostics without finding a causal diagnosis. Furthermore, a wide range of intensive, interdisciplinary, and behavioural therapies for weight control were unsuccessful. Prior to bariatric surgery, the 18-year-old girl and the 14-year-old boy reached a BMI of 67.7 kg/m2 and 55.2 kg/m2, respectively. However, even surgical outcomes were unsatisfactory. A subsequently initiated genetic analysis including sequencing of the leptin receptor gene revealed compound heterozygous variants as a cause of the severe early-onset obesity in both patients (c.2598-3_2607delTAGAATGAAAAAG and c.2227 T>C; c.1874G>A and c.2051A>C). Both patients were enrolled in the clinical study RM-493-015 and treated with melanocortin receptor agonist setmelanotide. Currently, they are still on setmelanotide treatment in the extension trial RM-493-022.

Conclusion: Our case report illustrates the urgent necessity of early genetic diagnostics in children with severe early-onset obesity to avoid frustrating and potentially damaging therapies. Thus, genetic examination should precede bariatric surgery. In the future, several pharmacological therapies will be available for some forms of monogenetic obesity.

背景:瘦素-黑色素皮质素信号通路中的罕见基因变异会严重影响食欲调节,导致幼儿期极度肥胖:我们的病例报告描述了一个女孩和一个非亲缘关系男孩的诊断和治疗过程,他们的父母都是德国人,非近亲结婚,患有严重的早发性肥胖症、明显的多食和永久性觅食行为。出生后第一年体重增长过快,医生对其进行了广泛的诊断,但没有找到病因。此外,为控制体重而采取的各种强化、跨学科和行为疗法均未奏效。在接受减肥手术之前,18 岁女孩和 14 岁男孩的体重指数分别为 67.7 kg/m2 和 55.2 kg/m2。然而,即使是手术结果也不尽如人意。随后启动的基因分析(包括瘦素受体基因测序)发现,复合杂合变体是导致这两名患者早发严重肥胖症的原因(c.2598-3_2607delTAGAATGAAAAAG 和 c.2227T>C;c.1874G>A 和 c.2051A>C)。这两名患者都参加了 RM-493-015 临床研究,并接受了黑色素皮质素受体激动剂 Setmelanotide 的治疗。目前,他们仍在 RM-493-022 扩展试验中接受塞美拉诺肽治疗:我们的病例报告说明,对于早发重度肥胖症患儿,迫切需要尽早进行基因诊断,以避免令人沮丧且可能造成损害的治疗。因此,在进行减肥手术前应先进行遗传学检查。未来,将有多种药物疗法可用于治疗某些形式的单基因肥胖症。
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引用次数: 0
Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts' consensus. 主要孤立性GHD中不断发展的垂体激素缺陷:综述和专家共识。
Q1 PEDIATRICS Pub Date : 2020-11-03 DOI: 10.1186/s40348-020-00108-2
Gerhard Binder, Dirk Schnabel, Thomas Reinehr, Roland Pfäffle, Helmuth-Günther Dörr, Markus Bettendorf, Berthold Hauffa, Joachim Woelfle

Isolated growth hormone deficiency (GHD) is defined by growth failure in combination with retarded bone age, low serum insulin-like growth factor-1, and insufficient GH peaks in two independent GH stimulation tests. Congenital GHD can present at any age and can be associated with significant malformations of the pituitary-hypothalamic region or the midline of the brain. In rare instances, genetic analysis reveals germline mutations of transcription factors involved in embryogenesis of the pituitary gland and the hypothalamus. Acquired GHD is caused by radiation, inflammation, or tumor growth. In contrast to organic GHD, idiopathic forms are more frequent and remain unexplained.There is a risk of progression from isolated GHD to combined pituitary hormone deficiency (> 5% for the total group), which is clearly increased in children with organic GHD, especially with significant malformation of the pituitary gland. Therefore, it is prudent to exclude additional pituitary hormone deficiencies in the follow-up of children with isolated GHD by clinical and radiological observations and endocrine baseline tests. In contrast to primary disorders of endocrine glands, secondary deficiency is frequently milder in its clinical manifestation. The pituitary hormone deficiencies can develop over time from mild insufficiency to severe deficiency. This review summarizes the current knowledge on diagnostics and therapy of additional pituitary hormone deficits occurring during rhGH treatment in children initially diagnosed with isolated GHD. Although risk factors are known, there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency. Lifelong monitoring of the endocrine function of the pituitary gland is recommended in humans with organic GHD. This paper is the essence of a workshop of pediatric endocrinologists who screened the literature for evidence with respect to evolving pituitary deficits in initially isolated GHD, their diagnosis and treatment.

孤立性生长激素缺乏症(GHD)的定义是生长衰竭合并骨龄延缓、血清胰岛素样生长因子-1低以及两次独立生长激素刺激试验中生长激素峰值不足。先天性GHD可以出现在任何年龄,并可能与垂体-下丘脑区域或大脑中线的显著畸形有关。在罕见的情况下,遗传分析揭示了参与脑垂体和下丘脑胚胎发生的转录因子的种系突变。获得性GHD是由辐射、炎症或肿瘤生长引起的。与有机GHD相比,特发性GHD更常见,但仍无法解释。存在从孤立性GHD发展为合并垂体激素缺乏症的风险(总组> 5%),这在患有有机GHD的儿童中明显增加,特别是垂体明显畸形的儿童。因此,在对孤立性GHD患儿的随访中,通过临床和放射学观察以及内分泌基线测试,排除额外的垂体激素缺乏是谨慎的。与原发性内分泌腺疾病相比,继发性内分泌腺缺乏的临床表现往往较轻。垂体激素缺乏可以随着时间的推移从轻度不足发展到严重不足。这篇综述总结了目前在诊断为孤立性GHD的儿童在rhGH治疗期间发生的额外垂体激素缺陷的诊断和治疗方面的知识。虽然危险因素是已知的,但没有绝对的标准可以排除没有进展为联合垂体激素缺乏症风险的儿童。建议对有机GHD患者终生监测脑垂体内分泌功能。这篇论文是儿科内分泌学家研讨会的精华,他们筛选了文献中关于最初孤立的GHD中发展的垂体缺陷及其诊断和治疗的证据。
{"title":"Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts' consensus.","authors":"Gerhard Binder,&nbsp;Dirk Schnabel,&nbsp;Thomas Reinehr,&nbsp;Roland Pfäffle,&nbsp;Helmuth-Günther Dörr,&nbsp;Markus Bettendorf,&nbsp;Berthold Hauffa,&nbsp;Joachim Woelfle","doi":"10.1186/s40348-020-00108-2","DOIUrl":"https://doi.org/10.1186/s40348-020-00108-2","url":null,"abstract":"<p><p>Isolated growth hormone deficiency (GHD) is defined by growth failure in combination with retarded bone age, low serum insulin-like growth factor-1, and insufficient GH peaks in two independent GH stimulation tests. Congenital GHD can present at any age and can be associated with significant malformations of the pituitary-hypothalamic region or the midline of the brain. In rare instances, genetic analysis reveals germline mutations of transcription factors involved in embryogenesis of the pituitary gland and the hypothalamus. Acquired GHD is caused by radiation, inflammation, or tumor growth. In contrast to organic GHD, idiopathic forms are more frequent and remain unexplained.There is a risk of progression from isolated GHD to combined pituitary hormone deficiency (> 5% for the total group), which is clearly increased in children with organic GHD, especially with significant malformation of the pituitary gland. Therefore, it is prudent to exclude additional pituitary hormone deficiencies in the follow-up of children with isolated GHD by clinical and radiological observations and endocrine baseline tests. In contrast to primary disorders of endocrine glands, secondary deficiency is frequently milder in its clinical manifestation. The pituitary hormone deficiencies can develop over time from mild insufficiency to severe deficiency. This review summarizes the current knowledge on diagnostics and therapy of additional pituitary hormone deficits occurring during rhGH treatment in children initially diagnosed with isolated GHD. Although risk factors are known, there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency. Lifelong monitoring of the endocrine function of the pituitary gland is recommended in humans with organic GHD. This paper is the essence of a workshop of pediatric endocrinologists who screened the literature for evidence with respect to evolving pituitary deficits in initially isolated GHD, their diagnosis and treatment.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"7 1","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2020-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-020-00108-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38663549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
A case of recurrent herpes simplex 2 encephalitis, VZV reactivations, and dominant partial interferon-gamma-receptor-1 deficiency supports relevance of IFNgamma for antiviral defense in humans. 一例复发性单纯疱疹2型脑炎、VZV再激活和显性部分干扰素- γ受体-1缺乏支持干扰素γ与人类抗病毒防御的相关性。
Q1 PEDIATRICS Pub Date : 2020-10-14 DOI: 10.1186/s40348-020-00106-4
Julia Körholz, Nicole Richter, Jochen Schäfer, Catharina Schuetz, Joachim Roesler

Background: Unlike infections with mycobacteria, reports of unusual viral infections in interferon-gamma-receptor (IFNγR) deficient patients are scarce. Therefore, discussion about increased susceptibility to viral infections in these patients is ongoing.

Case presentation: We describe a 51-year-old male with dominant partial interferon-gamma-receptor-1 (IFNγR1)-deficiency and recurrent Herpes simplex 2 meningoencephalitis as well as other viral reactivations since childhood.

Conclusions: This case further confirms an enhanced risk for viral disease in IFNγR-deficient patients and a role of interferon gamma for human antiviral defense.

背景:与分枝杆菌感染不同,干扰素γ受体(IFNγR)缺乏患者中异常病毒感染的报道很少。因此,关于这些患者对病毒感染易感性增加的讨论正在进行中。病例介绍:我们描述了一位51岁男性,患有显性部分干扰素- γ受体-1 (IFNγR1)缺乏和复发性单纯疱疹2型脑膜脑炎,以及自童年以来的其他病毒再激活。结论:该病例进一步证实了ifn γ r缺陷患者发生病毒性疾病的风险增加以及干扰素γ在人类抗病毒防御中的作用。
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引用次数: 1
A role for the alpha-8 integrin chain (itga8) in glomerular homeostasis of the kidney. α -8整合素链(itga8)在肾脏肾小球稳态中的作用。
Q1 PEDIATRICS Pub Date : 2020-10-01 DOI: 10.1186/s40348-020-00105-5
Ines Marek, Karl Friedrich Hilgers, Wolfgang Rascher, Joachim Woelfle, Andrea Hartner

Glomerulonephritis results in a dysregulation of glomerular cells and may end up in chronic alterations and subsequent loss of renal function. Therefore, understanding mechanisms, which contribute to maintain glomerular integrity, is a pivotal prerequisite for therapeutic interventions. The alpha-8 integrin chain seems to be an important player to maintain glomerular homeostasis by conferring mechanical stability and functional support for the renal capillary tuft.

肾小球肾炎导致肾小球细胞的失调,并可能以慢性改变和随后的肾功能丧失而告终。因此,了解维持肾小球完整性的机制是治疗干预的关键先决条件。α -8整合素链似乎通过赋予肾毛细血管丛的机械稳定性和功能支持,在维持肾小球稳态中起着重要作用。
{"title":"A role for the alpha-8 integrin chain (itga8) in glomerular homeostasis of the kidney.","authors":"Ines Marek,&nbsp;Karl Friedrich Hilgers,&nbsp;Wolfgang Rascher,&nbsp;Joachim Woelfle,&nbsp;Andrea Hartner","doi":"10.1186/s40348-020-00105-5","DOIUrl":"https://doi.org/10.1186/s40348-020-00105-5","url":null,"abstract":"<p><p>Glomerulonephritis results in a dysregulation of glomerular cells and may end up in chronic alterations and subsequent loss of renal function. Therefore, understanding mechanisms, which contribute to maintain glomerular integrity, is a pivotal prerequisite for therapeutic interventions. The alpha-8 integrin chain seems to be an important player to maintain glomerular homeostasis by conferring mechanical stability and functional support for the renal capillary tuft.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"7 1","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-020-00105-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38440651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 8
Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report. 杂合变异体中不确定意义的突变可能导致严重身材矮小:一份病例报告。
Q1 PEDIATRICS Pub Date : 2020-09-16 DOI: 10.1186/s40348-020-00104-6
Nami Mohammadian Khonsari, Sahar Mohammad Poor Nami, Benyamin Hakak-Zargar, Tessa Voth

Background: Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature.

Case presentation: We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature.

Conclusion: We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

背景:线状骨生长是通过生长板软骨细胞的分裂来实现的,受生长激素等内分泌和旁分泌因素的调节。对软骨形成有负面影响的突变可能会导致身材矮小。一种这样的突变可能发生在ACAN基因上,导致身材矮小和骨质老化。同样,生长激素受体(GHR)的突变可导致Laron综合征(LS),这是统称为生长激素不敏感综合征(GHI)的几种疾病之一。另一个例子是浮港综合征(FHS),这是一种罕见的常染色体显性遗传病,由SRCAP基因突变引起,也会导致身材矮小。病例介绍:我们报告的情况下,6岁的女性伴随突变的三个基因上述。这里报道的突变是在基因研究中发现的,通常是良性的,引起一种意义不明的变异。然而,我们的患者的表型只能通过这些基因的致病性突变的复合作用来解释。在患者的父亲和祖父身上也发现了一些相同的突变。两人都表现出身材矮小,但程度不同于我们的病人。虽然这些突变通常被报道为无关紧要,但当它们一起出现时,会导致患者严重的身材矮小和特定的表型。我们认为,尽管GHI谱系是通过常染色体隐性模式遗传的,但这些杂合突变的总和导致了严重的身材矮小,尽管我们的患者,父亲和祖父通过罕见的ACAN和SRCAP突变看到了有限的GHI,据我们所知,以前在文献中没有报道过作为致病突变。结论:我们调查了这些变异对GHI症状和体征的加重或掩盖可能的协同作用,希望通过我们的罕见病例更好地了解这些基因及其功能。
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引用次数: 2
Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. 儿童偏色差性脑白质营养不良患者造血干细胞移植后的早期临床过程。
Q1 PEDIATRICS Pub Date : 2020-09-03 DOI: 10.1186/s40348-020-00103-7
Judith Beschle, Michaela Döring, Christiane Kehrer, Christa Raabe, Ute Bayha, Manuel Strölin, Judith Böhringer, Andrea Bevot, Nadja Kaiser, Benjamin Bender, Alexander Grimm, Peter Lang, Ingo Müller, Ingeborg Krägeloh-Mann, Samuel Groeschel

Background: Long-term outcomes of hematopoietic stem cell transplantation (HSCT) in children with juvenile metachromatic leukodystrophy (MLD) have been investigated systematically, while short-term effects of HSCT on the course of the disease remain to be elucidated.

Results: In this study, the clinical course was evaluated over the first 24 months following HSCT, conducted at our center in 12 children with juvenile MLD (mean follow-up 6.75 years, range 3-13.5) and compared with 35 non-transplanted children with juvenile MLD. Motor function (GMFM-88 and GMFC-MLD), cognitive function (FSIQ), peripheral neuropathy (tibial nerve conduction velocity), and cerebral changes (MLD-MR severity score) were tested prospectively. Seven children remained neurologically stable over a long period, five exhibited rapid disease progression over the first 12 to 18 months after transplantation. In the latter, time from first gross motor symptoms to loss of independent walking was significantly shorter compared with non-transplanted patients at the same stage of disease (p < 0.02). Positive prognostic factors were good motor function (GMFM = 100%, GMFC-MLD = 0) and a low MR severity score (≤ 17) at the time of HSCT.

Conclusions: Our results show that if disease progression occurs, this happens early on after HSCT and proceeds faster than in non-transplanted children with juvenile MLD, indicating that HSCT may trigger disease progression.

背景:造血干细胞移植(HSCT)治疗青少年色差性脑白质营养不良(MLD)的长期结果已经被系统地研究过,而HSCT对该疾病病程的短期影响仍有待阐明。结果:在本研究中,我们对12例青少年MLD儿童(平均随访6.75年,范围3-13.5年)进行了HSCT后的前24个月的临床病程进行了评估,并与35例未移植的青少年MLD儿童进行了比较。前瞻性检测运动功能(GMFM-88和GMFC-MLD)、认知功能(FSIQ)、周围神经病变(胫神经传导速度)和大脑变化(MLD-MR严重程度评分)。7名儿童长期保持神经系统稳定,5名儿童在移植后的前12至18个月内表现出疾病的快速进展。后者从出现大运动症状到丧失独立行走的时间明显短于同阶段未移植患者(p < 0.02)。阳性预后因素为HSCT时良好的运动功能(GMFM = 100%, GMFC-MLD = 0)和低MR严重程度评分(≤17)。结论:我们的研究结果表明,如果发生疾病进展,这种进展发生在HSCT后早期,并且比未移植的少年MLD儿童更快,这表明HSCT可能引发疾病进展。
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引用次数: 17
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Molecular and cellular pediatrics
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