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.

An unusual cause of neonatal hypothermia and shock in the emergency department: Diamond Blackfan Anemia.

Diamond Blackfan Anemia (DBA) is a rare disease characterized by anemia secondary to impaired red blood cell production from bone marrow failure. We present a case of infantile hypothermia and shock caused by this clinical pathology. A seven-week-old infant was brought to the emergency department by the father with the chief complaint of abnormal breathing and low activity level throughout the day. Medical history was unremarkable for both the patient and the family. On examination, the infant was breathing 30 breaths per minutes, had a heart rate of 116, and a core temperature of 33 degrees Celsius. The infant was ashen in color, limp, with grunted breathing and minimal movement. Numerous abnormal laboratory readings were reported, with the most significant being a hemoglobin of 1.7 and a hematocrit of 7.4. Emergent blood transfusion was initiated, and the patient was eventually air-lifted to a pediatric hospital two hours away. This case highlights the imperative of a thorough history and examination and consideration of a broad differential for neonatal hypothermia and shock, especially in the setting of no obvious bleeding.

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 anaemia with iron overload: A serious issue.

Transfusion-dependent Diamond-Blackfan anaemia (DBA) patients rapidly develop iron overload and frequently experience cardiac complications. The report by Lecornec and colleagues offers useful details on indications and the management of deferiprone, a highly efficient chelator in removing excess cardiac iron but associated with a high risk of agranulocytosis in DBA patients. Commentary on: Lecornec et al. Agranulocytosis in patients with Diamond-Blackfan anaemia (DBA) treated with deferiprone for post-transfusion iron overload: A retrospective study of the French DBA cohort. British Journal of Haematology 2022;199:285-288.

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.

Czech and Slovak Diamond-Blackfan Anemia (DBA) Registry update: Clinical data and novel causative genetic lesions.

Diamond-Blackfan anemia (DBA) is a rare congenital erythroid aplasia, underlied by haploinsufficient mutations in genes coding for ribosomal proteins (RP) in approximately 70% of cases. DBA is frequently associated with somatic malformations, endocrine dysfunction and with an increased predisposition to cancer. Here we present clinical and genetic characteristics of 62 patients from 52 families enrolled in the Czech and Slovak DBA Registry. Whole exome sequencing (WES) and array comparative genomic hybridization (aCGH) were employed to identify causative mutations in newly diagnosed patients and in cases with previously unrecognized molecular pathology. RP mutation detection rate was 81% (50/62 patients). This included 8 novel point mutations and 4 large deletions encompassing some of the RP genes. Malignant or predisposing condition developed in 8/62 patients (13%): myelodysplastic syndrome in 3 patients; breast cancer in 2 patients; colorectal cancer plus ocular tumor, diffuse large B-cell lymphoma and multiple myeloma each in one case. These patients exclusively harbored RPL5, RPL11 or RPS19 mutations. Array CGH is beneficial for detection of novel mutations in DBA due to its capacity to detect larger chromosomal aberrations. Despite the importance of genotype-phenotype correlation in DBA, phenotypic differences among family members harboring an identical mutation were observed.

Massive iron overload and acute-on-chronic liver failure in a patient with Diamond-Blackfan anaemia: a case report.

BACKGROUND: Genetic anaemias lead us to reflect on the classic 'trolley dilemma', when there are two choices but neither one is satisfactory. Either we do not treat anaemia and the patient suffers from chronic tiredness and fatigue, or we do treat it through blood transfusions, leading to iron overload, which is a quite harmful consequence. CASE PRESENTATION: We present the case of a 34-year-old woman with Diamond-Blackfan anaemia (DBA). Bone marrow stem cell transplantation had not been accessible during her childhood, so she had been submitted to monthly blood transfusions throughout her life, leading to a hepatitis C virus infection (which was treated, achieving a sustained virological response when she was 18 years old), and secondary haemochromatosis. Despite chelation therapy, diffuse iron deposition was occurring in multiple organs, markedly in the heart and liver. Her serum ferritin was higher than 21,000 ng/mL and transferrin saturation reached 102%. When she faced heart decompensation, this congestive condition led to an acute liver injury overlapping pre-existing hepatic fibrosis. She progressed to haemodynamic and hepatic failure, with clinical features of acute-on-chronic liver failure (ACLF). Despite therapeutic optimisation, she died of respiratory insufficiency. An autopsy was performed and revealed the macroscopic and microscopic findings of a massive iron deposition in the liver, heart, lungs, spleen, bone marrow, thyroid and adrenal glands. We found marked advance of liver fibrosis (chronic damage), as well as necrosis of hepatocytes in zone 3 of the Rappaport acinus (acute damage), supporting the hypothesis of ACLF. The main feature responsible for acute liver decompensation seemed to be heart insufficiency. CONCLUSION: This is the first case reporting the sequence: DBA, multiple blood transfusions, secondary haemochromatosis, advanced liver fibrosis, heart failure, ACLF and death. A multidisciplinary team is essential to care for DBA patients, since there is a significant emotional burden related to the disease, which might impair an effective chelation therapy and lead to severe consequences due to iron deposition.

Improvement of native pulmonary alveolar proteinosis after contralateral single living-donor lobar lung transplantation: A case report.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation.

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled "Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease" held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group.

Endocrine Dysfunction in Diamond-Blackfan Anemia (DBA): A Report from the DBA Registry (DBAR).

BACKGROUND: Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long-term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies. PROCEDURE: In a pilot study, retrospective data were collected for 12 patients with DBA. Subsequently, patients with DBA aged 1-39 years were recruited prospectively. Combined, 57 patients were studied; 38 chronically transfused, 12 glucocorticoid-dependent, and seven in remission. Data were collected on anthropometric measurements, systematic screening of pituitary, thyroid, parathyroid, adrenal, pancreatic, and gonadal function, and ferritin levels. Descriptive statistics were tabulated and group differences were assessed. RESULTS: Fifty-three percent of patients had ≥ 1 endocrine disorder, including adrenal insufficiency (32%), hypogonadism (29%), hypothyroidism (14%), growth hormone dysfunction (7%), diabetes mellitus (2%), and/or diabetes insipidus (2%). Ten of the 33 patients with available heights had height standard deviation less than -2. Low 25-hydroxy vitamin D (25(OH)D) levels were present in 50%. A small proportion also had osteopenia, osteoporosis, or hypercalciuria. Most with adrenal insufficiency were glucocorticoid dependent; other endocrinopathies were more common in chronically transfused patients. CONCLUSIONS: Endocrine dysfunction is common in DBA, as early as the teenage years. Although prevalence is highest in transfused patients, patients taking glucocorticoids or in remission also have endocrine dysfunction. Longitudinal studies are needed to better understand the etiology and true prevalence of these disorders.

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes.

BACKGROUND: The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. METHODS: Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. RESULTS: Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. CONCLUSIONS: FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss.

The Stomatological Complications of Diamond-Blackfan Anemia: A Case Report.

Diamond-Blackfan Anemia (DBA) is a rare heterogeneous genetic disease characterized by severe anemia, reduction or absence of erythroid progenitors, and pro-apoptoptic hematopoiesis, which culminates in bone marrow failure. The disease generally manifests in infancy, as craniofacial, cardiac, genitourinary, and upper limb congenital anomalies. Therapy with corticoids is the treatment of choice, while blood transfusion is adopted during diagnosis and as a chronic approach if the patient does not respond to corticoids. This case report describes DBA in a patient that presented with lesions on the oral mucosa caused by secondary neutropenia. The stomatologist plays an important role in a transdisciplinary team and must remain attentive to the general health conditions of patients, since some oral lesions may be associated with systemic events.

[Laparoscopic Nephrectomy in Infant with Diamond Blackfan Syndrome].

An 8-month-old girl with Diamond Blackfan syndrome and idiopathic neutropenia needed steroid therapy for anemia, but the left multicystic dysplastic kidney was often infected. We performed laparoscopic nephrectomy for infection control without any complications. Neutrocytes increased and the infection decreased after nephrectomy even with steroid therapy. Finally, she underwent bone marrow transplantation, as the anemia was not responding to steroid therapy.

Growth hormone improves short stature in children with Diamond-Blackfan anemia.

BACKGROUND: Diamond-Blackfan anemia (DBA), an inherited marrow failure syndrome, has severe hypoplastic anemia in infancy and association with aplastic anemia, MDS/leukemia, and other malignancies. Short stature is present in most patients. Isolated cases have demonstrated improved growth on growth hormone (GH) therapy. PROCEDURES: GH treatment data were obtained from 19 children with DBA (6 at our site and 13 from Genentech). Control data from 44 non-GH treated children were provided by Diamond Blackfan Anemia Registry. Annual growth velocity (GV) and height-for-age Z-scores (HAZ) were compared between groups and for up to 4y of GH treatment. RESULTS: Constructed DBA-specific male and female height-for-age charts for non-GH treated patients revealed short stature compared to CDC norms. GH-treated patients had significantly lower HAZ prior to treatment initiation compared to non-GH-treated controls. Among GH-treated patients, GV significantly improved in the first two years relative to pre-treatment. HAZ significantly improved in each of 4y of GH therapy compared to baseline. After 2y of therapy, HAZ for GH-treated patients were not significantly different from controls, demonstrating successful catch-up growth. CONCLUSIONS: GH treatment in children with DBA improves both GV and HAZ during treatment sustained for up to 4y. Very short children with DBA can be treated successfully with GH to restore stature to levels comparable to less affected patients. DBA height charts are useful tools for assessing age-specific growth in this typically short population. Careful consideration of individualized benefit of GH therapy versus risk is important in view of long-term underlying ∼5% malignancy risk in DBA.

Successful use of reduced-intensity conditioning and matched-unrelated hematopoietic stem cell transplant in a child with Diamond-Blackfan anemia and cirrhosis.

For patients with DBA who are transfusion dependent, HSCT is the only cure. Chronic transfusions can lead to cirrhosis secondary to iron overload, making them poor candidates for myeloablative HSCT. RIC regimens are associated with lower morbidity and mortality compared to myeloablative regimens, but use of RIC in DBA has been limited. Here we present a 14-yr-old girl with DBA and multiple comorbidities including liver cirrhosis, who underwent MUD HSCT utilizing a RIC regimen that is novel to this condition. She tolerated the regimen well, and at 21 months, she remains transfusion independent with chimerisms at 99%.

Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.

Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported. Disease-causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease-causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from six unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies. © 2014 Wiley Periodicals, Inc.