Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

BACKGROUND: Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome characterized by erythroid aplasia, physical malformation, and cancer predisposition. Twenty ribosomal protein genes and three non-ribosomal protein genes have been identified associated with DBA.
METHODS: To investigate the presence of novel mutations and gain a deeper understanding of the molecular mechanisms of disease, targeted next-generation sequencing was performed in 12 patients with clinically suspected DBA. Literatures were retrieved with complete clinical information published in English by November 2022. The clinical features, treatment, and RPS10/RPS26 mutations were analyzed.
RESULTS: Among the 12 patients, 11 mutations were identified and 5 of them were novel (RPS19, p.W52S; RPS10, p.P106Qfs*11; RPS26, p.R28*; RPL5, p.R35*; RPL11, p.T44Lfs*40). Including 2 patients in this study, 13 patients with RPS10 mutations and 38 patients with RPS26 mutations were reported from 4 and 6 countries, respectively. The incidences of physical malformation in patients with RPS10 and RPS26 mutations (22% and 36%, respectively) were lower than the overall incidence in DBA patients (~50%). Patients with RPS26 mutations had a worse response rate of steroid therapy than RPS10 (47% vs. 87.5%), but preferred RBC transfusions (67% vs. 44%, p = 0.0253).
CONCLUSIONS: Our findings add to the DBA pathogenic variant database and demonstrate the clinical presentations of the DBA patients with RPS10/RPS26 mutations. It shows that next-generation sequencing is a powerful tool for the diagnosis of genetic diseases such as DBA.

暂无摘要。

OBJECTIVE: To investigate the distribution of body mass index (BMI) and risk factors for obesity in children with Diamond-Blackfan Anemia (DBA).
METHODS: The children with DBA who attended National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, from January 2003 to December 2020 were enrolled as subjects. The related clinical data and treatment regimens were recorded. The height and weight data measured within 1 week before or after follow-up time points were collected to calculate BMI. The risk factors for obesity were determined by multivariate regression analysis in children with DBA.
RESULTS: A total of 129 children with DBA were enrolled, among whom there were 80 boys (62.0%) and 49 girls (38.0%), with a median age of 49 months (range 3-189 months). The prevalence rate of obesity was 14.7% (19/129). The multivariate logistic regression analysis showed that the absence of ribosomal protein gene mutation was closely associated with obesity in children with DBA (adjusted OR=3.63, 95%CI: 1.16-11.38, adjusted P=0.027). In children with glucocorticoid-dependent DBA, obesity was not associated with age of initiation of glucocorticoid therapy, duration of glucocorticoid therapy, and maintenance dose of glucocorticoids (P>0.05).
CONCLUSIONS: There is a high prevalence rate of obesity in children with DBA, and the absence of ribosomal protein gene mutation is closely associated with obesity in children with DBA.
目的: 探讨先天性纯红细胞再生障碍性贫血（Diamond-Blackfan anemia，DBA）患儿的体重指数分布情况，并分析DBA患儿肥胖发生的相关因素。方法: 选取2003年1月至2020年12月于中国医学科学院北京协和医学院血液病医院儿童血液病诊疗中心就诊的DBA患儿为研究对象，收集患儿的临床资料、治疗方案，以及于随访时间点前后1周内测量的身高、体重并计算体重指数，分析DBA患儿肥胖发生的影响因素。结果: 129例DBA患儿中，男性80例（62.0%），女性49例（38.0%），中位测量年龄为49（范围：3~189）个月，肥胖发生率为14.7%（19/129）。多因素logistic回归分析发现，无核糖体蛋白基因突变与DBA患儿肥胖发生关系密切（调整后OR=3.63，95%CI：1.16~11.38，调整后P=0.027）。在激素依赖DBA患儿中，肥胖发生与激素开始治疗年龄、激素治疗时间、激素维持剂量无关（P>0.05）。结论: DBA患儿肥胖发生率较高，无核糖体蛋白基因突变与DBA患儿肥胖的发生密切相关。.

由机体核糖体合成或功能障碍所导致的一组疾病称为核糖体病，多数为遗传性罕见病。其中，以造血衰竭为主要表现的核糖体病主要包括先天性纯红细胞再生障碍性贫血（Diamond-Blackfan anemia，DBA）、舒-戴综合征（Shwachma-Diamond syndrome，SDS）以及部分先天性角化不良（congenital dyskeratosis，DC）。由于该类疾病发病率低，临床异质性大，我国医师对其认识不够充分，此类疾病常被误诊、漏诊。本文从发病机制、临床特点及诊疗手段的角度，对核糖体异常相关造血衰竭疾病进行综述。.

Congenital pure red cell aplasia, also known as Diamond-Blackfan anemia (DBA), is a hereditary disease characterized by pure red cell aplasia and congenital malformation. Its main clinical features are anemia, dysplasia, and tumor susceptibility. Ribosomal protein (RP) gene mutation is the main pathogenesis of DBA. The most common type of gene mutation is RPS19 gene mutation. Heterozygous mutations in as many as 19 RP genes and other non-RP genes mutations have been identified in DBA. This review summarized briedfly the latest research advances in the pathogenesis of DBA.
UNASSIGNED: 先天性纯红细胞再生障碍性贫血发病机制的研究进展.
UNASSIGNED: 先天性纯红细胞再生障碍又名Diamond-Blackfan贫血（DBA），是以单纯红系再生障碍和先天性畸形为特征的遗传性疾病，以贫血、身体发育异常和肿瘤易感性为主要临床特征。核糖体蛋白质（RP）基因突变是DBA的主要发病机制，最常见的基因突变类型为RPS19基因突变，目前已在DBA患者中发现了19个RP基因的杂合突变及其他非RP基因的突变。本文对基因突变引起DBA的最新研究进展进行综述。.

Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome, characterized by red blood cell aplasia, developmental abnormalities, and enhanced risk of malignancy. However, the underlying pathogenesis of DBA is yet to be understood. Recently, mutations in the gene encoding ribosomal protein (RP) L18 were identified in DBA patients. RPL18 is a crucial component of the ribosomal large subunit but its role in hematopoiesis remains unknown. To genetically model the ribosomal defect identified in DBA, we generated a rpl18 mutant line in zebrafish, using CRISPR/Cas9 system. Molecular characterization of this mutant line demonstrated that Rpl18 deficiency mirrored the erythroid defects of DBA, namely a lack of mature red blood cells. Rpl18 deficiency caused an increase in p53 activation and JAK2-STAT3 activity. Furthermore, we found inhibitors of JAK2 or STAT3 phosphorylation could rescue anemia in rpl18 mutants. Our research provides a new in vivo model of Rpl18 deficiency and suggests involvement of signal pathway of JAK2-STAT3 in the DBA pathogenesis.

Ribosome is a vital molecular machine for protein translation in the cell. Defects in several ribosomal proteins including RPS19, RPL11 and RPS14 have been observed in two types of anemia: Diamond Blackfan Anemia and 5q- syndrome. In zebrafish, deficiency of these ribosomal proteins shows similar anemic phenotype. It remains to be determined if any other ribosome proteins are similarly involved in regulating erythropoiesis. Here we generated mutations in zebrafish rps9, a rarely studied ribosomal protein gene, and investigated its function. Analysis of this mutant demonstrates that rps9 disruption leads to impairment of erythrocyte maturation, resulting in anemia. In addition, the overall phenotype including the anemic state is p53-dependent in rps9 mutants. Furthermore, this anemic state can be partially relieved by the treatment of L-leucine, and dexamethasone, which have been previously used in rescuing the phenotype of other ribosomal protein mutants. Finally, by comparing the phenotype, we show that there are considerable differences in morphology, cytomorphology, and hemoglobin levels for four ribosomal protein mutants in zebrafish. Based on the observed difference, we suggest that the level of anemic severity correlates with the delayed status of erythrocyte maturation in zebrafish models.

Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N terminus, are seen in patients with Diamond-Blackfan anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N terminus, including aberrant upregulation of Gata2 and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N terminus of GATA1. Chromatin-binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice provide novel insights into the role of the N terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.

Diamond-Blackfan anemia (DBA), a congenital pure red cell aplasia (PRCA), is characterized by normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. DBA10, a subset of DBA, is an autosomal dominant disease caused by a mutation in RPS26. So far, there are 30 disease-causing variants in RPS26 being reported, however, only three of them are small insert mutations.
Here we report a three-month Chinese boy who presents with anemia from postnatal day 2. He was suspected to have Diamond-Blackfan anemia, according to the clinical result. Thus, whole-exome sequencing was performed for precise diagnosis.
Here, a novel insert mutation c.96dupG in RPS26 was identified by whole-exome sequencing, which caused neonatal DBA in a Chinese boy. This is the first case report of a Chinese DBA10 patient who carries a small insertion in the RPS26 gene. These findings expand the mutation diversity of RPS26 and demonstrate the clinical presentations of the Chinese DBA10 patient.