Diagnosis Of Diamond-Blackfan Anemia Research Articles

Associated Congenital Abnormalities and Physical Phenotype in Patients with Diamond-Blackfan Anemia May Be Overlooked.

Diamond-Blackfan anemia (DBA) is a rare and inherited form of erythroid aplasia, characterized by severe macrocytic anemia, congenital malformations, and predisposition to cancer. The purpose of this study is to determine the congenital abnormalities and dysmorphological features of DBA patients in a cross-sectional manner. The study group included patients who had diagnosis of DBA between 1983 and 2017. Dysmorphological examinations of the patients were performed by an experienced dysmorphologist and also echocardiography and abdominal ultrasonography were performed in order to figure out cardiac and urogenital abnormalities. A total of 45 patients were examined in this study. Dysmorphological examination, echocardiography, and abdominal ultrasonography revealed the rate of congenital abnormalities as high as 88.7%. In consideration of the congenital abnormalities, the most common findings were craniofacial, followed by skeletal abnormalities. The rate of anomalies was found higher in our series of patients than that have been previously reported, most probably due to the evaluations being performed by a dysmorphologist in our cohort and not only depending on patient records or hematologists' physical examination.

Blackfan diamond anemia: Case presentation

Introduction: Blackfan Diamond Anemia is a congenital disorder characterized by normochromic macrocytic anemia, with decreased or absent erythroid precursors in the bone marrow, which occurs in the early stages of life, once diagnosed, steroids and red blood cells transfusions are mainstays of treatment, although some patients require bone marrow transplantation. Objective: To describe the characteristics of a female infant with Blackfan Diamond Anemia. Case presentation: A 5-month-old female patient with severe macrocytic anemia and reticulopenia with transfusion requirements from two months of age, in addition to variable phenotypic abnormalities, for which a medullogram was performed, confirming a selective depression of the erythropoietic system. Conclusions: The diagnosis of Diamond Blackfan Anemia should be suspected in infants with or without malformations who present anemia and reticulopenia from early stages of life.

A Case Report of Diamond-Blackfan Anaemia with RPS19 Mutation

Diamond Blackfan Anaemia (DBA) is a rare disorder which presents with anaemia in early childhood. This heterogenous disorder is mainly autosomal dominantly inherited. Significantproportions of the cases are associated with craniofacial anomalies and some cases may end up developing malignancy. The diagnosis is established by blood investigations, and bone marrow studies in which red cell precursors are reduced or absent. Screening for the mutations including those encoding for ribosomal proteins in the patient and the family members is confirmatory for diagnosis. Human Leukocyte Antigen (HLA) matched hemopoietic stem cell transplantation is the definitive treatment of choice. In other cases, corticosteroids have been tried. The haemoglobin level is maintained with packed red cell transfusion. We are presenting here a male baby who had anaemia soon after birth and was brought to us at the age of 1 year 3 months. The diagnosis of DBA was made since the patient presented with anaemia and supportive biochemical and histological evidence. Genetic screening revealed mutation in ribosomal protein S19 (RPS19) gene in the baby.

Allogeneic Hematopoietic Stem Cell Transplant Offer Good Outcomes in Pediatric Aplastic Anemia: Experience From Developing World.

Between 2014 and 2020, 31 patients with severe aplastic anemia (SAA) underwent full match allogeneic hematopoietic stem cell transplantation at our center. Of the 31 patients with SAA, 19 had acquired aplastic anemia, 2 had Diamond Blackfan anemia and 10 had Fanconi anemia. Donors were either matched sibling (n=29), related donors (n=2), or unrelated donors (n=3). Peripheral blood stem cells were the graft source in all the cases except 1. Fludarabine-based reduced intensity conditioning was used in all except for patients with a diagnosis of Diamond Blackfan anemia. All patients except 1 achieved hematologic recovery in the form of neutrophil engraftment at 13 days (range, 9 to 17), whereas platelet engraftment occurred at 14 days (range, 10 to 18). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate ±antithymocyte globulin (horse/rabbit). Acute GvHD developed in 12.9% patients, whereas no patients developed chronic GvHD till the time of last follow-up. The 2-year overall survival for the entire cohort was 93.21±4.6%. In patients with SAA, allogeneic stem cell transplant using fludarabine-based conditioning regimens are very well tolerated and have excellent outcomes in a full match setting.

Leucine for the Treatment of Transfusion Dependence in Patients with Diamond Blackfan Anemia

▪Diamond Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome characterized by anemia, congenital anomalies and a predisposition to cancer. The patients usually present during infancy or early childhood, but can also present in adulthood. In the majority of cases DBA is due to a mutation in a small or large ribosomal protein (RP) subunit leading to RP haploinsufficiency. The only treatments for the anemia of DBA are red cell transfusions (accompanied by iron chelation), oral corticosteroid therapy or stem cell transplantation. Pospisilova et al. (Haematologica 2007; 92(5):e66-67) reported one complete and two partial erythroid responses after the use of the branched chain amino acid L-leucine in 6 select patients. In skeletal muscle, leucine supplementation can upregulate components of the protein synthetic machinery, including ribosomal proteins, promoting protein translation. Mouse and fish models of DBA respond with amelioration of anemia to L-leucine. We therefore proposed to study the effect of L-leucine on transfusion dependence and growth in subjects with DBA.Methods: The primary objectives were to determine the feasibility of administering L-leucine in subjects with DBA who are red cell transfusion-dependent and to determine the efficacy of L-leucine to produce a hematologic and growth response. The secondary objective was to determine the safety profile of L-leucine. Twelve study sites were involved in this multi-center, Phase I/II study with an anticipated accrual of 50 subjects. A dose of 700 mg/M2 orally three times per day for 9 months was used. Inclusion criteria included age > 2 years, the diagnosis of DBA and transfusion dependence with adequate kidney and liver function. Response was evaluated at 9 months with Complete Response (CR) defined as no further transfusions required and Hb >9; Partial Response (PR): Hb < 9 gm/dL with an increase in reticulocyte count and transfusion interval; and No Response (NR): no change in transfusion needs, Hb or reticulocyte count . Growth percentiles were evaluated at baseline and at completion of 9 months of treatment and the growth velocity change was calculated.Results: The study opened July 2014 and closed February 2017; 55 subjects were consented; 12 were screen failures; 43 subjects were evaluable. There were 21 males; the median age was 9 years 1 month (2 years 5 months - 46 years 1 month). There were no untoward side effects experienced by any subject that were attributable to the L-leucine. Two subjects had an erythroid CR and 1 subject had a PR. The CRs occurred at 1 month and 3 months after start of L-leucine. The subject with PR had an elevated reticulocyte count but was not able to maintain a Hb >9 gm/dL without a transfusion and thus was not transfusion independent. Of the 30 subjects with growth potential who received L-leucine 10 experienced a positive growth velocity change at 9 months of therapy compared to baseline. At a median age of 7.5 years, the mean pre-leucine height percentile was 27 +/- 17.9 and the post-leucine height percentile was 35 +/- 19.9 (p <0.01). The mean weight percentile pre-leucine was 35.4 +/- 26.6 versus the post-Leucine weight percentile of 38.4 +/- 28.1.Conclusions: The administration of L-leucine is safe. L-leucine administration resulted in an erythroid response in 7% of subjects and an increased growth velocity in 33% of growing subjects. Based upon extrapolation from animal models, it is likely that this dose was suboptimal. We hypothesize that higher doses of L-leucine will lead to hematologic responses in more subjects who are transfusion dependent. The potential benefit of added growth in children with DBA may improve final adult height. DisclosuresGlader:Agios: Consultancy, Research Funding.

LHX3 deficiency presenting in the United States with severe developmental delay in a child of Syrian refugee parents.

SummaryIn this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient’s clinical course as well as a review of LHX3 mutations and the associated phenotype.Learning points:Describe an unusual presentation of undertreated pituitary hormone deficiencies in early lifeCombined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations

An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia.

Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

Response to L-Leucine Therapy in Patients with Daimond-Blakfan Anemia and Serum L-Leucine Concentrations

Background: Diamond-Blackfan anaemia (DBA) is a congenital bone marrow failure syndrome of childhood manifested as normochromic macrocytic anemia with absence or insufficient erythroid precursors in the bone marrow. The common basis for the anemia is haploinsufficiency of ribosomal proteins. The first line of therapy for patients with DBA is oral corticosteroids. Initially 80% of the patients respond and less than a half of the responders remain on therapy for extended periods. The majority of the DBA patients receive regular blood transfusions. Animal models showed efficacy of L-leucine, a translation enhancer, in the DBA and 5q- syndrome, which has similar altered ribosome function as the DBA. It was observed that treatment with L-leucine improves hemoglobin level and induce transfusion independence in patients with DBA and 5q- syndrome. L-leucine activates the mTOR (mammalian target of rapamycin) signaling pathway that controls cell growth and mRNA translation.Aims: The aim of our study is to determine the correlation of serum L-leucine and molecular lesions with response to L-leucine in DBA patients.Methods: After approval by Local Ethics Committee and signed informed consent, 8 DBA patients (aged 2 - 13 years, 5 girls and 3 boys) were enrolled in the study (NCT02386267). The diagnosis of DBA in all patients was established according to the criteria of the DBA Working Group of the European Society for Paediatric Haematology and Immunology. L-leucine (700 mg/ m2) was given orally 3 times a day during 9-12 months. The efficacy criteria for L-leucine therapy were haemoglobin (Hb) level, reticulocytes count (Retic) and serum level of soluble transferring receptor (sTFR). Complete response (CR) - Hb > 9 g/dL and transfusion-independence; partial response (PR) - Hb <9 gd/L and increased Retic >1% and increased interval between transfusions compare to baseline; no response (NR) - no change in transfusion requirements and no significant change in Hb or Retic. Baseline Retic range in all cases was 0.1-0.5%; transfusion's frequency - every 3 weeks. Serum L-leucine concentration was detected by LCMS-8030 Triple Quadrupole Liquid Chromatograph Mass Spectrometer (LC-/MS/MS).Results: CR was achieved in 3 (37,5%) cases (all are girls, 2 and 13 years old). One of these patients has mutation in RPL11 ex.2 c.65delT (p.Cys21Ser_fs*33) hetero. In the other two cases the whole genome sequencing (WGS) is in progress. In one case (4-year old girl) PR was achieved, characterized by increased intervals between blood transfusions. No response was seen in 4 cases (50%); their genotype: RPS19 ex.2 c.3G>А (Met1Ile) hetero; RPL5 ex.3 c.187C>T (Gln63*); RPS19 ex.2 c.31 C>T (Gln11*) hetero. Increased level of serum sTfR was observed in 7 patients, however only 4 patients have shown respose. Significant increase of Retic count was noticed in 3 cases with CR. Growth velocity was increased in all cases. None of the patients showed any adverse events. The blood chemistry parameters were within reference range in all cases. The serum L-leucine level was 22±1,0 for the patients with CR/PR - ng/ml, for non-responders - 42±10,3 ng/ml, Mann-Whitney p = 0,053.Conclusions: The L-leucine therapy induces hematological response and affects growth in a proportion of DBA patients.Our preliminary data show a trend of lower serum L-leucine concentartion among the responders. Further study is needed to make firm conclusions regarding the correlation of serum L-leucine and molecular lesions with response to L-leucine in DBA patients. DisclosuresOff Label Use: Therapeutic Use of the Amino Acid Leucine in the Treatment of Transfusion-Dependent Diamond Blackfan Anemia Patients.

Understanding the Role of Erythrocyte Adenosine Deaminase in the Ribosomopathies

Diamond Blackfan anemia (DBA) is congenital bone marrow failure syndrome characterized by red cell aplasia and a predisposition to cancer. It was the first disease linked to ribosomal dysfunction with 70% of patients having haploinsufficiency of a ribosomal protein (RP) gene with RPS19 being the most frequently mutated. The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) also characterized by a severe anemia that is caused by heterozygous loss of RPS14 on chromosome 5q. These patients also have a predisposition to cancer. The reciprocal relationship between these two diseases, which are now collectively known as the ribosomopathies, has spurred interest in how we may be able to better understand the pathophysiology of these ribosomopathies to broaden therapeutic options, and to improve diagnosis.Erythrocyte adenosine deaminase (eADA) levels have been used for last three decades in the diagnosis of Diamond Blackfan anemia based on the finding in 1983 that eADA enzyme levels are significantly elevated in patients with DBA. It is now known the eADA levels are elevated in >75% of patients with DBA. Furthermore, it has a sensitivity of 84%, specificity of 95% and positive and negative predictive values of 91% for the diagnosis of DBA compared with other inherited bone marrow failure syndromes. Our goal was to study the levels of eADA in patients with the 5q- syndrome to determine whether they were elevated (suggesting that eADA may be specific to ribosomal haploinsufficiency in general) or normal (suggesting that eADA may be specific to DBA).Under a Stanford approved IRB, we are testing adult patients with the 5q syndrome who have not been transfused in the previous 3 months (which would affect the results of the test) and who have a confirmed deletion of the 5q- region by cytogenetics. To date, all of the 4 MDS samples, sent to us from collaborating hematologists, have had a normal eADA level. These findings suggest that elevation of eADA may be specific to DBA and not a general feature of ribosomal haploinsufficiency although our sample size is small and we plan to test additional samples. DisclosuresNo relevant conflicts of interest to declare.

A Case of Diamond Blackfan Anemia with Mutation in Ribosomal Protein S19

Diamond Blackfan Anemia (DBA) is a rare disorder which presents with anemia in early infancy. This disorder is genetically and clinically heterogeneous in nature. The inheritance is mainly autosomal dominant. Approximately 25% of the cases are associated with craniofacial anomalies and some cases may end up in malignancy. The diagnosis is made by blood investigations, and bone marrow studies in which red cell precursors are reduced or absent. Screening for the mutations including those encoding for ribosomal proteins in the patient and the family members confirms the diagnosis. Human Leukocyte Antigen (HLA) matched hemopoietic stem cell transplantation is the treatment of choice. In other cases, corticosteroids and cyclosporine A have been tried. The haemoglobin level is maintained with packed red cell transfusion. We are presenting here a female baby who had anemia at birth and was brought to us at the age of 2 months. The diagnosis of DBA was made since the patient presented with anemia and showed reticulocytopenia, gross reduction in Red Blood Cell (RBC) count, and reduction in red cell precursors in the bone marrow. Genetic screening revealed mutation in ribosomal protein S19 (RPS19) gene in both the infant and the father.

Severe Anemia Leading to Hypodensity of Cerebral Venous Sinuses on Computed Tomography Imaging

A previously healthy 7-month-old boy presented with new onset seizures. His physical examination was nonfocal. Initial laboratory evaluation was significant for hemoglobin 1.1 g/dL and hematocrit 3.8%. A head computed tomography (CT; Figure 1 ) showed hypodensity of the transverse sinuses bilaterally. Further evaluation resulted in a suspected diagnosis of Diamond Blackfan anemia. Subsequent brain magnetic resonance imaging showed multifocal ischemic infarcts. Figure 1. Computed tomography imaging demonstrating decreased attenuation in the transverse sinuses and torcula. The attenuation of blood on CT is primarily a function of the protein fraction of hemoglobin.1 A linear relationship has been established between hemoglobin levels and CT attenuation.2 Thus, in patients with elevated hematocrit due to polycythemia, for example, CT imaging may demonstrate hyperdensity within the cerebral vasculature.2,3 Conversely, very low hemoglobin levels may cause decreased attenuation of blood, making it appear less dense than brain on CT imaging1 and leading to the hypodensity seen in the transverse sinuses and torcula.

The evolving spectrum of ‘non‐classical’ Diamond‐Blackfan anaemia – a case of eADA positive pancytopenia in a young adult

The evolving spectrum of ‘non‐classical’ Diamond‐Blackfan anaemia – a case of eADA positive pancytopenia in a young adult

Congenital Erythroid and Myeloid Hypoplasia Terminating Myelodysplastic Syndrome

We describe a 4-month-old infant girl with congenital erythroid and myeloid hypoplasia who developed myelodysplastic syndrome. Bone marrow examination showed severe erythroid and myeloid hypoplasia without dysplastic morphology. Flow cytometry detected autoantibodies to myeloid cells, indicating a diagnosis of Diamond-Blackfan anemia with autoimmune neutropenia. The patient was administered prednisolone and rituximab, which brought the neutrophil count and hemoglobin level to within the normal range. However, bicytopenia recurred at the age of 22 months. She was diagnosed with myelodysplastic syndrome because of trilineage dysplasia and the clonal abnormality of 46,XX,dup(1)(q21;q32) in bone marrow. She was transplanted with cord blood from an unrelated human leukocyte antigen-matched donor and has since remained in complete remission for 20 months.

Ribosomal Protein S24 Gene Is Mutated in Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.

Diamond–Blackfan anemia associated with β-thalassemia trait

A 14-month-old boy was referred to our hospital for evaluation of severe anemia. In the bone marrow aspiration smear, normal cellularity with severe erythroblastopenia (3%) was observed. The hemoglobin electrophoresis of the patient and his father were compatible with the beta-thalassemia trait. Because macrocytosis of Diamond-Blackfan anemia (DBA) is masked by microcytosis of beta-thalassemia trait, the diagnosis of DBA co-existing with beta-thalassemia trait might be challenging. We report herein a case of DBA co-existing with beta-thalassemia trait in a Turkish boy.

The First Homozygous RPS19 Mutation Identified in a Diamond-Blackfan Anemia Patient Is Not Deleterious.

Mutations in ribosomal protein S19 (RPS19) gene have been found in 25% of patients affected with Diamond-Blackfan anemia (DBA). Two of the RPS19 mutations identified in DBA patients are located in the sequence upstream of the translational start site: a missense mutation g->t at −460 and a 4 bp insertion, gcca, 3 nt upstream of the 5′ end of the RPS19 promoter. All of the RPS19 mutations identified to date are expressed in the heterozygous state. In the present study, in a DBA patient from Ivory Coast we identified the gcca insertional mutation on both alleles. Diagnosis of DBA was made at the age of 3 months. No malformations were noted. The patient responded neither to steroid nor to IL-3 therapies. The patient was regularly transfused but without an effective iron chelation therapy. As a consequence DBA was complicated by a severe hemochromatosis with thyroid, parathyroid, and liver damage. The patient was enrolled into a metoclopramide protocol in our hospital when he was 12 year old. He had a partial response, with increased time intervals between transfusions. While analysis of the RPS19 gene did not identify a mutation in the coding sequence, the 4 bp insertion, gcca at nt − 631 was noted on both alleles. Mother was heterozygous for this mutation and strikingly the father was homozygous. Both parents are apparently healthy. In screening of 200 Caucasian control chromosomes and 100 chromosomes from Ivory Coast we did not identify the 4bp insertion, ruling out the possibility that it is a common polymorphism. A parental disomy was eliminated by a genescan microsatellite analysis using the microsatellites: D19S200, D19S197, and LIPE. To evaluate the effect of this mutation on erythroid differentiation, we isolated 30,000 CD34+ cells from peripheral blood of the patient and normal individuals. CD34+ cells were cultured for 7 days in methylcellulose with EPO, SCF, and IL-3. At day 7, erythroid colonies were isolated and cultured for additional 3 and 5 days in liquid medium. At D7, D10 and D12, aliquots of cells were collected and cloning efficiency and apoptosis was quantitated. RPS19 mRNA was assayed by quantitative RT-PCR and level of protein expression determined by Western blot analysis. The cloning efficiency of DBA erythroid progenitors was decreased by 2.6 fold compared to normal between D7 and D10 and by 3.5 fold between D10 and D12. No difference in apoptosis was noted between DBA and normal erythroid progenitors. Strikingly, during terminal erythroid differentiation, RPS19 mRNA and protein expression levels was similar in the DBA and normal erythroid cells. The presence of the homozygous mutation in the healthy father in conjunction with normal expression of RPS19 in the DBA erythroid cells imply that the gcca insertion at nt −631 is not deleterious and cannot by itself account for the DBA phenotype of our patient.

Diamond-Blackfan Anaemia

Diamond Blackfan Anaemia (DBA) is a congenital disease characterised by defective erythroid progenitor maturation. It is usually diagnosed during the first year of life. The main clinical sign is profound isolated normochromic or macrocytic anaemia, with normal numbers and function of the other haemopoietic cells. Reticulocyte counts in patients with DBA are very low. Bone marrow reflects the defective erythropoiesis, showing a very low number of erythropoietic precursors and a reduction of erythroid burst-forming unit progenitor cells. The proliferation and differentiation of the other lineages are normal. More than one-third of patients have malformations, most often involving the upper limbs and head, and the urogenital or cardiovascular systems. However, the link between these malformations and defective erythropoiesis is unclear and a defect in a molecule acting on both early embryonic development and haematopoiesis has been proposed. Whereas most cases are sporadic, inheritance is observed in 10% of patients, with a dominant or, more rarely, recessive pattern. One locus on chromosome 19q13.2 encoding ribosomal protein S19 accounts for a quarter of patients with either the dominant or the sporadic form. Families not linked with this locus have also been described. The diagnosis of DBA may be difficult and differential diagnoses include Fanconi's anaemia and acquired erythroid aplasias. Erythrocyte adenosine deaminase levels are generally high in DBA patients, which may help in the diagnosis, but they are not pathognomic. Corticosteroids are the main treatment option in DBA and these agents induce erythropoiesis in over 60% of patients. Some patients achieve complete remission, which may be either corticosteroid-induced or spontaneous. The increased in vitro erythropoiesis occasionally induced by the addition of specific cytokines, namely interleukin (IL)-3 and stem cell factor (SCF), has suggested their use in vivo. However, few patients have responded to IL-3, whereas SCF administration, though interesting in theory, has not yet been attempted. Patients who do not respond to corticosteroids and those who have to discontinue treatment because of adverse events must rely on long term transfusions, and are thus exposed to all of the associated complications. Bone marrow or cord blood transplantation has been performed in some patients. The former approach is burdened with severe complications and high mortality.

Parvovirus B19 infection and Diamond‐Blackfan anaemia

It is the purpose of the study to report the frequency of parvovirus in children with a diagnosis of Diamond-Blackfan anaemia and to discuss the possible aetiological role of parvovirus in Diamond-Blackfan anaemia. We found parvovirus DNA in 3 of 11 bone marrow smears. Giant pronormoblasts showed low sensitivity (33%) and poor specificity (75%). The presence of giant pronormoblasts was associated with a very high myeloid:erythroid ratio, and may not be specific for parvovirus infection, but a feature of severely suppressed erythropoiesis. The three parvovirus-positive patients were the only children who experienced a remission, and who are free of medication. The seven surviving parvovirus-negative patients are all currently on steroid treatment.