Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement.

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.

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Background: Anemia in children is common and finding the underlying cause is often uncomplicated. However, in some cases, the underlying diagnosis is rare and difficult to diagnose. Case presentation: A toddler presented with severe anemia with normal red cell indices and a low reticulocyte count. The remaining hematological parameters were normal, bar a slight thrombocytosis. At this point a diagnosis of transient erythroblastopenia of childhood (TEC) was made. The child continued to have slight anemia with intermittent macrocytosis and reticulocytopenia throughout childhood. Growth and development was normal, and there were no signs of congenital abnormalities in the heart or kidneys nor any craniofacial or phalangeal defects. Repeated bone marrow examinations showed no significant abnormal findings. As a teenager the patient was diagnosed with Diamond-Blackfan anemia through an exome-based gene panel which revealed a mutation in the RPL11 gene. Interpretation: Congenital bone marrow failure syndromes do not always present in the classical way, leading to a delayed diagnosis. The increasing availability of different gene panels for patients with persistent abnormal hematological laboratory parameters offers the possibility of a more accurate diagnostic pathway, which is important for adequate follow-up and genetic counselling.

Normal Erythroid Precursors in Diamond-Blackfan Anemia: A Rare Case Highlighting Challenges That Remain.

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.

Probable digenic inheritance of Diamond-Blackfan anemia.

A 26-year-old female proband with a clinical diagnosis and consistent phenotype of Diamond-Blackfan anemia (DBA, OMIM 105650) without an identified genotype was referred to the Undiagnosed Diseases Network. DBA is classically associated with monoallelic variants that have an autosomal-dominant or -recessive mode of inheritance. Intriguingly, her case was solved by a detection of a digenic interaction between non-allelic RPS19 and RPL27 variants. This was confirmed with a machine learning structural model, co-segregation analysis, and RNA sequencing. This is the first report of DBA caused by a digenic effect of two non-allelic variants demonstrated by machine learning structural model. This case suggests that atypical phenotypic presentations of DBA may be caused by digenic inheritance in some individuals. We also conclude that a machine learning structural model can be useful in detecting digenic models of possible interactions between products encoded by alleles of different genes inherited from non-affected carrier parents that can result in DBA with an unrealized 25% recurrence risk.

A De Novo Frameshift Mutation in RPL5 with Classical Phenotype Abnormalities and Worsening Anemia Diagnosed in a Young Adult-A Case Report and Review of the Literature.

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome associated with malformations. DBA is related to defective ribosome biogenesis, which impairs erythropoiesis, causing hyporegenerative macrocytic anemia. The disease has an autosomal dominant inheritance and is commonly diagnosed in the first year of life, requiring continuous treatment. We present the case of a young woman who, at the age of 21, developed severe symptomatic anemia. Although, due to malformations, a congenital syndrome had been suspected since birth, a confirmation diagnosis was not made until the patient was referred to our center for an evaluation of her anemia. In her neonatal medical history, she presented with anemia that required red blood cell transfusions, but afterwards remained with a stable, mild, asymptomatic anemia throughout her childhood and adolescence. Her family history was otherwise unremarkable. To explain the symptomatic anemia, vitamin deficiencies, autoimmune diseases, bleeding causes, and myeloid and lymphoid neoplasms were investigated and ruled out. A molecular investigation showed the RPL5 gene variant c.392dup, p.(Asn131Lysfs*6), confirming the diagnosis of DBA. All family members have normal blood values and none harbored the mutation. Here, we will discuss the unusual evolution of this case and revisit the literature.

Diamond-Blackfan anemia in adults: In pursuit of a common approach for a rare disease.

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome, usually caused by loss-of function variants in genes encoding ribosomal proteins. The hallmarks of DBA are anemia, congenital anomalies and cancer predisposition. Although DBA usually presents in childhood, the prevalence in later life is increasing due to an expanding repertoire of implicated genes, improvements in genetic diagnosis and increasing life expectancy. Adult patients uniquely suffer the manifestations of end-organ damage caused by the disease and its treatment, and transition to adulthood poses specific issues in disease management. To standardize and optimize care for this rare disease, in this review we provide updated guidance on the diagnosis and management of DBA, with a specific focus on older adolescents and adults. Recommendations are based upon published literature and our pooled clinical experience from three centres in the United Kingdom (U·K.). Uniquely we have also solicited and incorporated the views of affected families, represented by the independent patient organization, DBA U.K.

Unusual Association of Diamond-Blackfan Anemia and Severe Sinus Bradycardia in a Six-Month-Old White Infant: A Case Report and Literature Review.

Diamond-Blackfan anemia is a rare (6-7 million live births), inherited condition manifesting as severe anemia due to the impaired bone marrow production of red blood cells. We present the unusual case of a six month old infant with a de novo mutation of the RPS19 gene causing Diamond-Blackfan anemia who additionally suffers from severe sinus bradycardia. The infant was diagnosed with this condition at the age of four months; at the age of 6 months, she presents with severe anemia causing hypoxia which, in turn, caused severe dyspnea and polypnea, which had mixed causes (hypoxic and infectious) as the child was febrile. After correction of the overlapping diarrhea, metabolic acidosis, and severe anemia (hemoglobin < 3 g/dL), she developed severe persistent sinus bradycardia immediately after mild sedation (before central venous catheter insertion), not attributable to any of the more frequent causes, with a heart rate as low as 49 beats/min on 24 h Holter monitoring, less than the first percentile for age, but with a regular QT interval and no arrhythmia. The echocardiogram was unremarkable, showing a small interatrial communication (patent foramen ovale with left-to-right shunting), mild left ventricular hypertrophy, normal systolic and diastolic function, and mild tricuspid regurgitation. After red cell transfusion and appropriate antibiotic and supportive treatment, the child's general condition improved dramatically but the sinus bradycardia persisted. We consider this a case of well-tolerated sinus bradycardia and foresee a good cardiologic prognosis, while the hematologic prognosis remains determined by future corticoid response, treatment-related complications and risk of leukemia.

Utility of Whole Exome Sequencing in the Early Diagnosis of Atypical Diamond-Blackfan Anemia.

Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome, with a hallmark of erythroblastopenia and congenital anomalies. DBA demonstrates genetic heterogeneity and variable phenotypic expression. We present two cases of atypical DBA harboring de novo mutations in the RPS-19 gene with c.49 G>C and c.357-1G>T allelic variants. The two cases presented confounding critical illness demonstrated by multiorgan failure, aplastic crisis, with case 2 meeting the criteria for hemophagocytic lymphohistiocytosis. We highlight the utility of genetic testing in the early diagnosis of DBA and the associated complexities and burden of disease in caring for DBA patients.

[Differential diagnosis of inherited bone marrow failure syndromes in erythrocyte disorders].

Diamond-Blackfan anemia (DBA), congenital dyserythropoietic anemia (CDA), and inherited sideroblastic anemia (ISA) are representative diseases of inherited bone marrow failure syndromes in erythrocyte diseases. DBA is primarily caused due to ribosomal dysfunctions. Furthermore, reticulocytes and erythroid progenitor cells decrease considerably within the peripheral blood and bone marrow, respectively. CDA is caused by a disturbance in red blood cell maturation and ineffective erythropoiesis due to hemolysis in the bone marrow. CDA is mainly classified into types I to III, and multinucleated erythroblasts observed in the bone marrow, typically in the internuclear bridge in type I. ISA is caused by iron metabolism dysfunction in the mitochondria due to defective heme synthesis. Sideroblasts appear ringed due to iron accumulation in the mitochondria of erythroid precursors. Gene mutation analysis is indispensable for the confirmatory diagnosis of these diseases; however, narrowing down the diagnosis, by examining the erythrocytes in the peripheral blood and the erythroblast morphology in the bone marrow, is also important.

GATA-1 Defects in Diamond-Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease.

Diamond−Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management.

Challenges in the management of pregnancy complicated by maternal Diamond Blackfan Anaemia: A case report.

Diamond Blackfan Anaemia (DBA) is a rare genetic disorder, affecting red blood cells. Pregnancy in women affected by DBA should be managed as a high-risk pregnancy, as it may trigger the relapse of anaemia, and is associated with both maternal and foetal complications. Corticosteroids are the first line of treatment, but a low threshold for blood transfusion should be considered to correct low haemoglobin in pregnancy. An adequate multidisciplinary input and planning is the key to ensure optimal perinatal outcome. We decided to report this case to highlight the implications of pregnancy on DBA and vice versa, taking into consideration the safest approach for the best possible outcomes for the mother and her baby.

Adult-Onset Diamond-Blackfan Anemia with RPL11 Gene Variation Case Report.

BACKGROUND Diamond-Blackfan anemia (DBA) is a rare genetic disorder associated with macrocytic anemia and reticulocytopenia, with patients usually transfusion-dependent in the first years of life. The disease inheritance is predominantly autosomal dominant, but varying presentations have been described owing to incomplete penetrance and widely variable expression. De novo mutations have been reported in about 55% of cases. This pediatric disease is commonly characterized by malformation of the extremities as well as craniofacial abnormalities and cardiac and urogenital defects. There have been reported cases of adult-onset DBA diagnosed through genetic testing. Although these adult-onset cases can vary in presentation, characteristic malformations are present in nearly half of patients. Treatment protocols include corticosteroids, blood transfusions, iron chelation, and bone marrow transplant. New investigational therapies are being evaluated. Roughly one-fourth of patients achieve remission and are able to maintain a stable hemoglobin level without intervention. CASE REPORT A 35-year-old woman with spina bifida and resultant paraplegia presented with new-onset transfusion-dependent hypoplastic anemia. Following an extensive evaluation, a RPL11 gene variant was found, confirming the diagnosis of DBA. CONCLUSIONS DBA should be considered in young adult patients with severe, transfusion-dependent, aregenerative anemia without definitive cause. Evaluation for nonclassical DBA should be considered and excluded.

Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid defect in DBA results in erythroblastopenia in bone marrow as a consequence of maturation blockade between the burst forming unit-erythroid and colony forming unit-erythroid developmental stages, leading to moderate to severe usually macrocytic aregenerative (<20 × 109/L of reticulocytes) anemia. Congenital malformations localized mostly in the cephalic area and in the extremities (thumbs), as well as short stature and cardiac and urogenital tract abnormalities, are a feature of 50% of the DBA-affected patients. A significant increased risk for malignancy has been reported. DBA is due to a defect in the ribosomal RNA (rRNA) maturation as a consequence of a heterozygous mutation in 1 of the 20 ribosomal protein genes. Besides classical DBA, some DBA-like diseases have been identified. The relation between the defect in rRNA maturation and the erythroid defect in DBA has yet to be fully defined. However, recent studies have identified a role for GATA1 either due to a specific defect in its translation or due to its defective regulation by its chaperone HSP70. In addition, excess free heme-induced reactive oxygen species and apoptosis have been implicated in the DBA erythroid phenotype. Current treatment options are either regular transfusions with appropriate iron chelation or treatment with corticosteroids starting at 1 year of age. The only curative treatment for the anemia of DBA to date is bone marrow transplantation. Use of gene therapy as a therapeutic strategy is currently being explored.

Colorectal cancer screening and surveillance strategy for patients with Diamond Blackfan anemia: Preliminary recommendations from the Diamond Blackfan Anemia Registry.

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by red cell failure, congenital anomalies, poor linear growth, and cancer predisposition. Two previous analyses from the Diamond Blackfan Anemia Registry have quantified DBA as a cancer predisposition syndrome of moderate cancer penetrance. Patients with DBA have a 4.8-fold higher relative risk of developing cancer with an overall cumulative incidence of 13.7% by age 45 years. The two most prevalent solid tumors are colorectal cancer (CRC) and osteogenic sarcoma. Current and evolving data support the institution of cancer screening and surveillance strategies for CRC in DBA.

The landscape of pediatric Diamond-Blackfan anemia in Switzerland: genotype and phenotype characteristics.

Diamond-Blackfan anemia (DBA) is caused mainly by genetic mutations in large (RPL) or small ribosomal subunit genes (RPS) and presents with macrocytic anemia and congenital malformations. Clinical differences between genotypes are insufficiently understood. The aim of this study was to assess clinical features, treatment strategies, and genotypes in the Swiss pediatric DBA population. We retrospectively reviewed medical charts of pediatric patients with DBA in Switzerland and stratified patients by RPL versus RPS mutations. We report 17 DBA patients in Switzerland who were all genetically investigated. In our cohort, patients showed a wide spectrum of clinical presentations and treatment needs. We found a high proportion of physical malformations (77%) including lower limb (17%) and anorectal (12%) malformations. The two patients with anorectal malformations presented both with antepositioning of the anus needing surgery within the first 15 months of life. One of these patients had sphincteric dysfunction, the other coccygeal agenesis. We found that included patients with an RPL mutation more frequently tended to have physical malformations and a milder anemia compared to patients with an RPS mutation (median hemoglobin at diagnosis 76 g/l versus 22 g/l).Conclusion: We illustrate the wide clinical and genetic spectrum of DBA in Switzerland. Our findings highlight the need to take this diagnosis into consideration in patients with severe anemia but also in patients with mild anemia where malformations are present. Lower limb and anorectal malformation extend the spectrum of DBA-associated malformations. What is Known? • There is a large variation in the phenotype of Diamond-Blackfan Anemia (DBA) and diversity of genetic mutations. • Malformation of the upper limbs, head and face, heart, and genitourinary system is frequently identified. What is New? • Patients with lower limb and anorectal malformations were repetitively found in our cohort enlarging the clinical spectrum of malformations. • We show two patients of the same family with a DBA-like condition where the same RPL17 variant was identified.

Dried blood spot metabolomics reveals a metabolic fingerprint with diagnostic potential for Diamond Blackfan Anaemia.

The diagnostic evaluation of Diamond Blackfan Anaemia (DBA), an inherited bone marrow failure syndrome characterised by erythroid hypoplasia, is challenging because of a broad phenotypic variability and the lack of functional screening tests. In this study, we explored the potential of untargeted metabolomics to diagnose DBA. In dried blood spot samples from 18 DBA patients and 40 healthy controls, a total of 1752 unique metabolite features were identified. This metabolic fingerprint was incorporated into a machine-learning algorithm, and a binary classification model was constructed using a training set. The model showed high performance characteristics (average accuracy 91·9%), and correct prediction of class was observed for all controls (n = 12) and all but one patient (n = 4/5) from the validation or 'test' set (accuracy 94%). Importantly, in patients with congenital dyserythropoietic anaemia (CDA) - an erythroid disorder with overlapping features - we observed a distinct metabolic profile, indicating the disease specificity of the DBA fingerprint and underlining its diagnostic potential. Furthermore, when exploring phenotypic heterogeneity, DBA treatment subgroups yielded discrete differences in metabolic profiles, which could hold future potential in understanding therapy responses. Our data demonstrate that untargeted metabolomics in dried blood spots is a promising new diagnostic tool for DBA.