Diamond-Blackfan anemia

Costa, Lydie Da; Marié, Isabelle; Leblanc, Thierry

doi:10.1182/hematology.2021000314

Cited by 16 publications

(32 citation statements)

References 45 publications

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“…Most of the family members in our study presented with steroid-responsive anemia in infancy and subtle congenital malformations, consistent with recent genotype-phenotype studies for RPS19 and RPS vs. RPL-DBA (Arbiv et al, 2018;Iskander et al, 2021). Wide variations in phenotypic expression have been previously observed in families with both small deletions and missense mutations in RPS19 (Willig et al, 1999;Ichimura et al, 2017;Da Costa et al, 2021). Missense mutations in RPS19 have also been reported to be less penetrant than loss of function mutations (Ulirsch et al, 2018), which may help explain the two individuals in our study who were largely unaffected from a hematologic standpoint.…”

Section: Discussionsupporting

confidence: 90%

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19

et al. 2022

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Introduction:Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here.Case Description:Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germlineRPS19testing was done on all family members. A pathogenic heterozygous missense mutation inRPS19(p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies.Discussion:This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies ofRPSDBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.

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Section: Discussionsupporting

confidence: 90%

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19

et al. 2022

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“…55 Rpl5 (uL18) and Rps24 (eS24) RPL5 (uL18) is one of the most commonly mutated RP gene found in DBA patients (7%). 1 In 2016, Kazerounian et al 56 reported 2 mouse models with conditional knockout of Rpl5 or Rps24 (eS24). A pGK-gb2 Loxp/FRT-flanked neomycin cassette was inserted into either Rpl5 or Rps24, resulting in deletion of exons 1-8 for Rpl5 and exons 2-3 for Rps24, respectively.…”

Section: Rpl11 (Ul5)mentioning

confidence: 99%

“…Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia which manifests with moderate or severe macrocytic anemia associated with short stature, physical anomalies involving bone development, and predisposition for malignancies [1][2][3][4][5] . More than 90% of patients are diagnosed during their first year of life (median age 12 weeks).…”

Section: Introductionmentioning

confidence: 99%

“…However, chronic lifelong exposures to these treatments often lead to intolerance. 1,7,8 Currently, hematopoietic stem cell transplantation is the only curative therapy. 6,9 Erythroid failure in DBA patients is characterized by a significant reduction of erythroid precursor/progenitors in bone marrow (BM), specifically, a blockade between the BFU-E and CFU-E stages or between the EPO-independent and EPO-dependent stages of erythroid development.…”

Section: Introductionmentioning

confidence: 99%

“…Heterozygous mutations in one of the 16 RP genes or 3 non-RP genes are found in approximately 70-80% of DBA patients. 1,7,[12][13][14] Mutations in RPS19, RPL5, RPS26, RPL11, RPL35a, RSL10, RPS24, and RPS17 have been identified in 70% of DBA patients. Mutations on GATA1 and TSR2 (a chaperone protein of eS26/RPS26) were also detected in DBA patients.…”

Section: Introductionmentioning

confidence: 99%

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Animal models of Diamond-Blackfan anemia: updates and challenges

et al. 2022

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Diamond-Blackfan anemia (DBA) is a ribosomopathy that is characterized by macrocytic anemia, congenital malformations, and early onset during childhood. Genetic studies have demonstrated that most patients carry mutations in one of the 20 related genes, most of which encode ribosomal proteins (RP). Treatment of DBA includes corticosteroid therapy, chronic red blood cell transfusion, and other forms of immunosuppression. Currently, hematopoietic stem cell transplantation is the only cure for DBA. Interestingly, spontaneous remissions occur in 10-20% of transfusion-dependent DBA patients. However, there is no consistent association between specific mutations and clinical manifestations. In the past decades, researchers have made significant progress in understanding the pathogenesis of DBA, but it remains unclear how the ubiquitous RP haploinsufficiency causes the erythroid-specific defect in hematopoiesis in DBA patients, and why there is a difference in penetrance and spontaneous remission among individuals who carry identical mutations. In this paper, we provide a comprehensive review of the development of DBA animal models and discuss the future research directions for these important experimental systems.

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