Clinico-haematological profile of pure red cell aplasia in children

Pure red cell aplasia (PRCA) is a rare disorder, characterized by isolated failure of erythropoiesis. The clinico-haematological profile of 16 patients with PRCA is presented in this communication. Fourteen patients had Diamond-Blackfan anaemia (DBA), one had transient erythroblastopenia of childhood, and one patient had PRCA secondary to carbamazepine. Physical abnormalities were observed in 50 per cent of patients with DBA. Of the nine patients with DBA who were administered prednisolone and had a regular follow-up, four (44.4 per cent) had no response, three (33.3 per cent) responded fully, and two (22.2 per cent) were steroid dependent.     

Ectopic atrial tachycardia in an infant with transient erythroblastopenia of childhood

Transient erythroblastopenia of childhood is a self-limited anemia occurring in previously healthy children, secondary to temporary cessation of erythrocyte production. Although the precise etiology is unclear, most cases are associated with a viral illness. The anemia may be severe, with associated pallor, tachypnea, and tachycardia; treatment is supportive. We present an unusual case of a child with viral-induced transient erythroblastopenia of childhood and associated ectopic atrial tachycardia, requiring therapy with antiarrhythmics.     

A novel initiation codon mutation in the ribosomal protein S17 gene (RPS17) in a patient with Diamond‐Blackfan anemia

Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by pure red cell aplasia, various congenital anomalies, and cancer predisposition. We report a novel mutation in the RPS17 gene in a Korean patient with DBA. The mutation occurred in the translation initiation codon, changing Atg to Gtg (c.1A>G), thus disrupting the natural start of the RPS17 protein biosynthesis. This is the third case of DBA from a RPS17 mutation in the literature and is the second case of a RPS17 mutation in the translation initiation codon, following c.2T>G. Pediatr Blood Cancer 2010;54:629–631. © 2009 Wiley‐Liss, Inc.     

Diamond-Blackfan anemia

Diamond-Blackfan Anemia (DBA) is a rare, congenital hypoplastic anemia often diagnosed early in infancy. A moderate to severe aregenerative anemia is found in association with erythroblastopenia in an otherwise normocellular bone marrow. In 40% of these infants with DBA, diverse developmental abnormalities are also noted. A majority of patients with DBA respond to steroid therapy. Recent molecular studies have identified mutations in the gene encoding the ribosomal protein RPS19 on chromosome 19 in 25% of patients with DBA. In another subset of patients, linkage analysis has identified another locus on chromosome 8p in association with DBA. There are, however, other cases of DBA that are linked neither to the RPS19 gene nor to the locus on 8p, implying the involvement of yet-to-be-defined genetic defects in the cause of DBA. The pathogenesis of DBA is still to be fully defined and it is anticipated that further molecular studies will lead to a better understanding of this complex disease.     

Transient erythroblastopenia of childhood. A review of 26 cases and reassessment of indications for bone marrow aspiration

Clinical and hematological presentations of 26 consecutive patients with transient erythroblastopenia of childhood diagnosed during July 1979 to September 1986 were compared with 26 patients with acute leukemia who presented with anemia and a normal platelet count. It was easy to distinguish acute leukemia from transient erythroblastopenia of childhood on a clinical and laboratory basis. In most cases, bone marrow examination was not necessary.     

Reduced gene expression of clustered ribosomal proteins in Diamond-Blackfan anemia patients without RPS19 gene mutations

Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia occasionally presenting physical anomalies. Ribosomal protein S19 gene (RPS19) is one of the causative genes for DBA; however, the pathologic mechanism of erythroblastopenia and abnormal morphology has not been clarified. To assess the pathophysiology of DBA, the gene expression profile of 2 representative patients carrying no RPS19 mutations was compared with that of aplastic anemia (AA) patients, assessed by the microarray analyses. The K-mean clustering analysis revealed the significant categorization of 28 ribosomal protein (RP) genes into a small set of group (994 genes) (P=2.39E-17), all of which were expressed at lower levels in DBA than in AA patients. RPS19 was categorized into the set of low expressing genes in DBA patients. No mutations were determined in the promoter and coding sequences of top 10 RP genes expressed at the levels over 1.2 of the AA/DBA ratio, in 3 DBA patients. These results indicated that the lower expression of RP gene group, even without the mutation, was a distinctive feature of DBA from AA, although the study number was small. The reduced RP gene expression, by itself, may suggest an underlying mechanism of the constitutional anemia.     

A neonate with a unique non‐Down syndrome transient proliferative megakaryoblastic disease

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM).³² Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations. TMD cases without trisomy 21 are rare, and recurrent genetic aberrations that aid in clinical decision‐making are scarcely described. We describe here a TMD patient without trisomy 21 or GATA1 mutation in whom single‐nucleotide polymorphism analysis of leukemic blasts revealed a novel combined submicroscopic deletion (5q31.1–5q31.3 and 8q23.2q24).     

Pathophysiology and genetic mutations in congenital sideroblastic anemia

Sideroblastic anemias are heterogeneous congenital and acquired disorders characterized by anemia and the presence of ringed sideroblasts in the bone marrow. Congenital sideroblastic anemia (CSA) is a rare disease caused by mutations of genes involved in heme biosynthesis, iron–sulfur [Fe‐S] cluster biosynthesis, and mitochondrial protein synthesis. The most common form is X‐linked sideroblastic anemia, due to mutations in the erythroid‐specific δ‐aminolevulinate synthase (ALAS2), which is the first enzyme of the heme biosynthesis pathway in erythroid cells. Other known etiologies include mutations in the erythroid specific mitochondrial transporter (SLC25A38), adenosine triphosphate (ATP) binding cassette B7 (ABCB7), glutaredoxin 5 (GLRX5), thiamine transporter SLC19A2, the RNA‐modifying enzyme pseudouridine synthase (PUS1), and mitochondrial tyrosyl‐tRNA synthase (YARS2), as well as mitochondrial DNA deletions. Due to its rarity, however, there have been few systematic pathophysiological and genetic investigations focusing on sideroblastic anemia. Therefore, a nationwide survey of sideroblastic anemia was conducted in Japan to investigate the epidemiology and pathogenesis of this disease. This review will cover the findings of this recent survey and summarize the current understanding of the pathophysiology and genetic mutations involved in CSA.     

Transient abnormal myelopoiesis in non‐Down syndrome neonate

We encountered a case of neonatal acute megakaryoblastic leukemia not associated with Down syndrome (DS). Molecular cytogenetic analysis of leukemic blast cells indicated that increased blast cell status was caused by transient abnormal myelopoiesis with trisomy 21 and GATA1 mutation. Based on these molecular cytogenetic data, intensive chemotherapy was avoided, and the patient was successfully cured with low‐dose cytarabine. Morphologically, leukemic blast cells of acute megakaryoblastic leukemia in a non‐DS neonate are indistinguishable from a blast cell of transient abnormal myelopoiesis. The possibility of transient abnormal myelopoiesis should be carefully considered before intensive chemotherapy is adopted.     

A novel mutation in GATA6 causes pancreatic agenesis

Heterozygous mutations in GATA6 have been linked to pancreatic agenesis and cardiac malformations. The aim of this study was to describe a new mutation in GATA6 in an infant with pancreatic agenesis, associated with truncus arteriosus and absent gallbladder. Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA. The patient was a female infant diagnosed shortly after birth with a severe cardiac malformation, absent gallbladder, anomalous hepatic blood flow, unilateral hydronephrosis and hydroureter, neonatal diabetes, and pancreatic exocrine insufficiency. Despite prolonged intensive management care, she died at 3 months of age because of cardiac complications. Analysis of her genomic DNA revealed a novel missense mutation of GATA6. The novel mutation described in this case extends the list of GATA6 mutations causing pancreatic agenesis and cardiac malformations.     

Hodgkin lymphoma in a child with Diamond Blackfan anemia

Diamond Blackfan anemia (DBA) is a rare disease characterized by aplasia or hypoplasia of erythroid lineage. Normochromic, usually macrocytic, but occasionally normocytic anemia and reticulocytopenia are characteristic findings of DBA. DBA is associated with an increased risk of malignancy. Most of the reported malignancies are acute myeloid leukemia. Solid tumors including hepatocellular carcinoma and osteosarcoma have also been identified. We could find 29 reported cases with DBA and malignancy. Two of them were diagnosed as Hodgkin lymphoma at 15 and 23 years, respectively. Here we report a 7-year-old boy with DBA who developed Hodgkin disease.     

Diamond-Blackfan Anemia Associated with Treacher-Collins Syndrome

We describe a 2-year-old girl with a rare combination of congenital red cell aplasia or Diamond-Blackfan anemia (DBA) and Treacher-Collins syndrome (TCS). The anemia is only marginally responsive to high-dose corticosteroid, and the child is transfusion dependent. There is no one in the family affected with either DBA or TCS. A hypothesis is advanced that the simultaneous occurrence of the dysmorphism and erythroid agenesis in this case may have been the consequences of an insult to the fetus at the critical stage of development of maxilloman-dibular structure and the stage of primitive erythroid cell migration from the yolk sac to the fetal liver and bone marrow.     

CHRONIC AUTOIMMUNE HEMOLYTIC ANEMIA IN CHILDHOOD WITH COLD ANTIBODIES, APLASTIC CRISES, AND FAMILIAL OCCURRENCE

A report is given of two sisters who developed chronic autoimmune hemolytic anemia in their fourth and twelfth years of age, respectively. The serological findings were different in the two cases. In patient 1, a typical cold agglutinin with a titer of 256 at 4^oC was found in the serum, and only complement on the red cells by the direct Coombs' test. The serum hemolysed trypsinized red cells at 37^oC. Her sister had warm type hemolytic anemia with a γG antibody on her red cells. In case 1, the clinical course has been severe, with several exacerbations of the hemolytic process accompanied by erythroid aplasia in the bone marrow. Whereas acute autoimmune hemolytic anemia with cold antibodies is not rare in children, and may be elicited by mycoplasma or viral infections, chronic autoimmune hemolytic anemia is rarely seen before adulthood. The typical, chronic cold hemagglutinin disease with hemoglobinuria and Raynaud's phenomena has not been described in childhood, and was not present in our case. It is suggested that the disease in the case presented may have started as the result of an acute infection, and that for one reason or another (genetic predisposition?) the process has not shown the usual self-limited course. Although a familial–probably genetic– predisposition exists for several autoimmune diseases, familial occurrence of autoimmune hemolytic anemia has rarely been observed. The authors have found nine convincing reports in the literature, and in only one of the reported families did the hemolytic anemia develop in childhood. In families predisposed to autoimmune diseases, a variety of γ-globulin disturbances and autoimmune disorders are often found. The presence of a more fundamental, genetic aberration of the immune apparatus, preventing a normal immune homeostasis, may therefore be postulated. A brief comment is made on the possible mechanism of the repeated periods of erythroid aplasia in the patient with cold antibodies. It is suggested that a second antibody, causing hemolysis of trypsinized red cells at 37^oC may be of importance by damaging the red cell precursors. The presence of this antibody may also possibly explain why the severity of the clinical picture of the patient did not seem to be related to exposure to cold.     

Transient erythroblastopenia of childhood presenting with papilledema

A 4-year-old boy with transient erythroblastopenia of childhood (TEC) presented with papilledema and transient hemiparesis. Upon spontaneous hematologic recovery, the papilledema resolved. It is concluded that TEC, like other forms of anemia, may present with papilledema and even focal neurologic deficit, from which spontaneous recovery may be anticipated.     

Transient erythroblastopenia of adolescence

This case report describes a 16-year-old girl with pure red cell aplasia of 7 months duration. The erythrocyte characteristics and in vitro culture of erythroid progenitors was similar to that found in transient erythroblastopenia of childhood (TEC), a disorder most commonly seen in children 2 to 6 years of age. This case may represent the adolescent equivalent of TEC.     

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Neonates with Down syndrome (DS) have a propensity to develop the unique myeloproliferative disorder, transient abnormal myelopoiesis (TAM). TAM usually resolves spontaneously in ≤3 months, but approximately 10% of patients with TAM die from hepatic or multi‐organ failure. After remission, 20% of patients with TAM develop acute myeloid leukemia associated with Down syndrome (ML‐DS). Blasts in both TAM and ML‐DS have trisomy 21 and GATA binding protein 1 (GATA1) mutations. Recent studies have shown that infants with DS and no clinical signs of TAM or increases in peripheral blood blasts can have minor clones carrying GATA1 mutations, referred to as silent TAM. Low‐dose cytarabine can improve the outcomes of patients with TAM and high white blood cell count. A number of studies using fetal liver cells, mouse models, or induced pluripotent stem cells have elucidated the roles of trisomy 21 and GATA1 mutations in the development of TAM. Next‐generation sequencing of TAM and ML‐DS patient samples identified additional mutations in genes involved in epigenetic regulation. Xenograft models of TAM demonstrate the genetic heterogeneity of TAM blasts and mimic the process of clonal selection and expansion of TAM clones that leads to ML‐DS. DNA methylation analysis suggests that epigenetic dysregulation may be involved in the progression from TAM to ML‐DS. Unraveling the mechanisms underlying leukemogenesis and identification of factors that predict progression to leukemia could assist in development of strategies to prevent progression to ML‐DS. Investigation of TAM, a unique pre‐leukemic condition, will continue to strongly influence basic and clinical research into the development of hematological malignancies.     

Transient erythroblastopenia of childhood presenting with echovirus 11 infection

We report a case of transient erythroblastopenia in a three-year-old girl presenting with echovirus 11 infection. Viral infection was demonstrated by isolation of echovirus 11 in stool cultures and the presence of echovirus 11-specific IgM antibody in serum. We suggest that echovirus may have played a role in the pathogenesis of transient erythroblastopenia of childhood in this patient.