Bone Marrow Failure Disorders

骨髓衰竭疾病
  • 文章类型: Case Reports
    Diamond-Blackfan贫血(DBA)是一种罕见的,遗传性骨髓衰竭综合征是遗传和临床异质性的。随着时间的推移,DBA的诊断发生了变化,随着我们对疾病的各种遗传病因和表型表现的理解的进步。我们介绍了一个罕见的病例,该患者从未出现红系前体发育不全,增加了对DBA非典型表现的理解。我们的患者自发缓解,随后复发,DBA中的非典型和鲜为人知的过程。我们强调了诊断挑战性病例的重要考虑因素,并回顾了围绕DBA的主要悬而未决的问题。
    Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome that is both genetically and clinically heterogeneous. The diagnosis of DBA has changed over time, with advancements in our understanding of the varied genetic etiologies and phenotypic manifestations of the disease. We present a rare case of a patient who never developed erythroid precursor hypoplasia, adding to the understanding of atypical manifestations of DBA. Our patient had spontaneous remission followed by subsequent relapse, both atypical and poorly understood processes in DBA. We highlight important considerations in diagnostically challenging cases and review major outstanding questions surrounding DBA.
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  • 文章类型: Journal Article
    先天性角化症是一种罕见的遗传性疾病,具有经典的皮肤症状,有时伴有更严重的皮外表现,如骨髓衰竭,这可能是致命的。Eltrombopag是一种口服血小板生成素受体激动剂,在临床上用于增加免疫性血小板减少症和再生障碍性贫血患者的血小板水平。这里,3名患有先天性角化障碍的儿科患者表现出不同的疾病严重程度,其中标签外艾曲波帕治疗对骨髓衰竭无临床影响。这个,除了以前的病例报告中的阴性结果,支持在先天性角化障碍中排除使用eltrombopag。
    Dyskeratosis congenita is a rare inherited disease with classic cutaneous symptoms, sometimes accompanied with more severe extracutaneous manifestations such as bone marrow failure, which can be lethal. Eltrombopag is an orally available thrombopoietin receptor agonist in clinical use for increasing platelet levels in patients with immune thrombocytopenia and aplastic anemia. Here, 3 pediatric patients with dyskeratosis congenita are presented with varying disease severity, in which off-label eltrombopag treatment had no clinical effect on bone marrow failure. This, in addition to the negative results in a previous case report, supports the preclusion of eltrombopag use in dyskeratosis congenita.
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  • 文章类型: Case Reports
    目的:分析1例遗传性骨髓衰竭综合征患儿的临床及遗传特点,并对病因和机制进行了探索,结合临床实践。方法:分别收集先证者及其亲生父母的血液样本和临床资料。致病性变异采用下一代测序技术筛选,通过使用Sanger测序在该家族的所有成员中确认候选可变位点。结果:KAT6A(NM_006766)第17外显子发生杂合无义突变,c.4177G>T(p。E1393*)预测在蛋白质的酸性结构域内引起截短。谱系分析未显示先证者父亲和母亲之间该基因座的任何差异。在国内外数据库的文献检索中没有发现这种致病变异的报道,表明这是一种新发现的突变。根据美国医学遗传学学院的指导方针,初步确定该变异是致病的。KAT6A中新发现的杂合突变可能是该儿童疾病的原因。此外,遗传性骨髓衰竭综合征是一个突出的表现。结论:本研究不仅为我们提供了对这种罕见综合征的深入了解,而且加深了我们对KAT6A功能的理解。
    Objective: The clinical and genetic characteristics of a child with inherited bone marrow failure syndrome as prominent clinical manifestations and special facial features were analyzed, and the etiology and mechanism were explored in, combination with clinical practice. Methods: Blood samples and clinical information were collected separately from the proband and their biological parents. The pathogenic variant was verified using next-generation sequencing technology screening, and the candidate variable sites were confirmed by using Sanger sequencing among all members of the family. Results: A heterozygous nonsense mutation in exon 17 of KAT6A (NM_006766), c.4177G > T (p.E1393*) predicted to cause truncation within the acidic domain of the protein was identified. Pedigree analysis did not reveal any variation in this locus between the proband\'s father and mother. No report of this pathogenic variant was found in a literature search of domestic and foreign databases, indicating that it is a newly discovered mutation. According to the guidelines of the American College of Medical Genetics, the variation was preliminarily determined to be a pathogenic. The newly discovered heterozygous mutation in KAT6A may be the cause of the disease in this child. Additionally, inherited bone marrow failure syndrome is a prominent manifestation. Conclusion: This study not only provides us with an in-depth understanding of this rare syndrome but also deepens our understanding of the function of KAT6A.
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  • 文章类型: Case Reports
    红细胞减少症和原发性骨髓纤维化的组合非常罕见。我们在这里报告了一名76岁的摩洛哥患者自2018年以来因特发性红细胞减少症进行随访的不寻常病例。最初用皮质治疗,然后用环孢素治疗。两年后,患者报告骨痛伴脾肿大。评估包括脊髓造影,骨髓活检和分子生物学显示骨髓纤维化。骨髓纤维化的病因评估为阴性,证实了其原始性质。患者接受ruxolitinib和输血支持。患者的预后良好,并以一般状况的改善为标志,脾肿大和输血率。红细胞减少症与骨髓增殖性疾病之间的关联是特殊的,文献中仅报道了少数病例。
    The combination of erythroblastopenia and primary myelofibrosis is very rare. We here report the unusual case of a 76-year-old Moroccan patient followed up since 2018 for idiopathic erythroblastopenia, initially treated with corticotherapy and then with ciclosporin. Two years later, the patient reported bone pain with splenomegaly. Assessment including myelogram, bone marrow biopsy and molecular biology showed myelofibrosis. Etiological assessment of myelofibrosis was negative confirming its primitive nature. The patient received ruxolitinib with transfusion support. Patient´s outcome was favorable and marked by improvement of general condition, splenomegaly and transfusion rate. The association between erythroblastopenia and myeloproliferative disorder is exceptional and only a few cases have been reported in the literature.
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  • 文章类型: Case Reports
    软骨-毛发发育不全(CHH)是一种综合征性免疫缺陷,其特征是干phy端发育不良,癌症易感性,和不同程度的贫血。在婴儿期可能表现为严重的联合免疫缺陷,或缓慢进展,直到在青春期后期/成年期完全显现。目前没有针对性的治疗,患者通常通过支持性措施来管理,或提供骨髓移植,如果临床表型是严重的,一个合适的供体是可用的。我们报告了一个年轻女孩的病例,该女孩表现为输血依赖性红细胞生成衰竭和类似自身免疫性淋巴增生综合征的免疫学特征,对经验性西罗莫司反应良好。她后来出现了明显的生长延迟,这最终归因于干phy端发育不良。通过全基因组测序(WGS)诊断为CHH,在不太敏感的基因诊断策略失败后。由于表现为隐球菌性脑膜脑炎的进行性联合免疫缺陷,患者最终接受了单倍体相同的骨髓移植。这个案例说明了西罗莫司在纠正贫血和部分控制与CHH相关的免疫畸变中的潜在作用。并提醒人们WGS在诊断具有复杂和非典型表现的患者中的宝贵作用。
    Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.
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  • 文章类型: Case Reports
    DNA连接酶IV缺乏是一种罕见的常染色体隐性遗传疾病,与受损的DNA修复机制有关。大多数DNA修复缺陷患者表现为神经功能缺损,联合免疫缺陷,骨髓衰竭,和/或血液肿瘤。我们介绍了3例具有不同临床表现的连接酶IV缺乏症的无关病例。患者1在5岁时出现骨髓衰竭,变形特征,T和B淋巴细胞减少。鉴定了LIG4基因中的复合杂合变体L19W/K635fs。患者2在16岁时出现复发性感染。他患有丙种球蛋白血症和B细胞缺失。鉴定了LIG4基因中的纯合R278H。患者3因白癜风和B细胞淋巴细胞减少(低类别转换B细胞)和低丙种球蛋白血症而转诊。还鉴定了LIG4中的纯合R278H。在过去的几年里,由连接酶IV缺乏引起的临床表现范围已经扩大,这使得很难建立准确的临床诊断。使用NGS可以进行正确的诊断,并提供更好的预后和足够的家庭咨询。
    DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling.
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  • 文章类型: Case Reports
    UDP-半乳糖-4'-差向异构酶(GALE)缺乏的广义形式导致张力减退,未能茁壮成长,白内障,和肝功能衰竭。非广泛性形式的个体可能保持无症状,长期结果不确定。我们报告了GALEp.R51W/p的2岁儿童复合杂合。G237D,从未出现经典半乳糖血症的症状,但有先天性二尖瓣和三尖瓣畸形和幽门狭窄的病史,并出现全血细胞减少症.预测计算工具和红细胞中测量的降低的GALE活性支持变异的致病性。GALE功能通过UDP-N-乙酰基-半乳糖胺和-葡糖胺的差向异构化延伸到聚糖的生物合成。对基因本体论联盟数据库的询问显示了几种与正常造血和房室瓣形态发生有关的推定蛋白质,需要N-糖基化以获得足够的功能性。我们假设通过限制由于GALE缺乏而导致的底物供应,N-连接蛋白糖基化的改变可以解释患者的表型。
    The generalized form of UDP-galactose-4\'-epimerase (GALE) deficiency causes hypotonia, failure to thrive, cataracts, and liver failure. Individuals with non-generalized forms may remain asymptomatic with uncertain long-term outcomes. We report a 2-year-old child compound heterozygous for GALE p.R51W/p.G237D who never developed symptoms of classic galactosemia but has a history of congenital combined mitral and tricuspid valve malformation and pyloric stenosis, and presented with pancytopenia. Variant pathogenicity was supported by predictive computational tools and decreased GALE activity measured in erythrocytes. GALE function extends to the biosynthesis of glycans by epimerization of UDP-N-acetyl-galactosamine and -glucosamine. Interrogation of the Gene Ontology consortium database revealed several putative proteins involved in normal hematopoiesis and atrioventricular valve morphogenesis, requiring N-glycosylation for adequate functionality. We hypothesize that by limiting substrate supply due to GALE deficiency, alterations in N-linked protein glycosylation can explain the patient\'s phenotype.
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  • 文章类型: Case Reports
    2019-2020年SARS-CoV-2大流行期间报告的COVID-19症状主要是呼吸道和胃肠道,关于神经系统表现的报道很少。我们描述了一个17岁的女性,患有CorneliadeLange综合征和控制良好的癫痫,他们在COVID-19相关的多炎症综合征期间遭受了严重的皮质损伤。
    Symptoms of COVID-19, as reported during the SARS-CoV-2 pandemic in 2019-2020, are primarily respiratory and gastrointestinal, with sparse reports on neurological manifestations. We describe the case of a 17-year old female with Cornelia de Lange syndrome and well controlled epilepsy, who sustained significant cortical injury during a COVID-19 associated multi-inflammatory syndrome.
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  • 文章类型: Case Reports
    COVID-19现在已经在全球传播,10-20%的病例被认为病情严重。然而,免疫缺陷患者中有关COVID-19的信息仍然有限.我们治疗了一名56岁的男子,他在接受套细胞淋巴瘤化疗后患上了COVID-19。长时间发烧1个月后,病人的呼吸状况迅速恶化,他死了.化疗后免疫功能低下患者的COVID-19,即使症状轻微,可引起快速免疫重建和呼吸恶化。因此,建议谨慎,直到确认SARS-CoV-2的PCR测试结果为阴性。
    COVID-19 has now spread globally, and 10-20% of the cases are thought to proceed to a severe condition. However, information on COVID-19 in immunodeficient patients remains limited. We treated a 56-year-old man who developed COVID-19 after chemotherapy for mantle cell lymphoma. After 1 month of prolonged fever, the patient\'s respiratory condition deteriorated rapidly, and he died. COVID-19 in immunocompromised patients after chemotherapy, even with mild symptoms, can cause rapid immune reconstitution and respiratory deterioration. Therefore, caution is advised until negative PCR test results for SARS-CoV-2 are confirmed.
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  • 文章类型: Case Reports
    The occurrences of hyperuricemia and acute kidney injury after antithymocyte globulin treatment are unusual in kidney transplant recipients. Here, we report a unique case of acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia.
    A 40-year-old woman with aplastic anemia who received a kidney transplant 5 years 6 months before presented to our emergency department with complaints of oliguria, generalized edema, and general weakness 6 days after receiving antithymocyte globulin treatment for acute T-cell-mediated rejection. Urinalysis revealed 100 uric acid crystal particles. The blood chemistry test results showed rapid increases in serum creatinine (from 2.86 mg/dL to 5.58 mg/dL) and uric acid levels (from 10.2 mg/dL to 32.7 mg/dL), which suggested acute uric acid nephropathy. Tumor lysis syndrome was suspected to be the cause of the acute uric acid nephropathy; hence, the patient was reevaluated for aplastic anemia. Human leukocyte antigen-DR15 was positive, and flow cytometry revealed a low percentage of glycophosphatidyl inositol-deficient granulocytes (2.9%), which suggested paroxysmal nocturnal hemoglobinuria clones. These findings indicate that the previously diagnosed aplastic anemia had either originally been hypocellular myelodysplastic syndrome (MDS) or later transformed into hypocellular MDS, which is a type of bone marrow failure syndrome.
    Clinicians should consider unexpected tumor lysis syndrome to be the cause of complications after antithymocyte globulin treatment in kidney transplant recipients with underlying bone marrow failure syndrome.
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