Pure red cell aplasia in Swedish children : clinical features, epidemiological and etiological aspects of transient erythroblastopenia of childhood and Diamond-Blackfan anemia

Abstract

Background: Anemia due to impaired erythropoiesis is a rare condition that is more common in children than in adults. Pure red cell aplasia (PRCA) is the term used to denote anemia due to failure of the bone marrow that affects only the erythropoietic cell line. PRCA exists in two forms only presented in children. One is a usually chronic, congenital disorder called congenital hypoplastic anemia or Diamond-Blackfan anemia (DBA), while the other is an acquired, transient condition called transient crythroblastopenia of childhood (TEC).

DBA is a macrocytic anemia, the severity of which can be either mild or serious. It is usually diagnosed in early infancy, and its pathophysiological mechanism is not yet known. Congenital malformations are seen in about 40% of the cases and there is evidence both of autosomal dominant and of recessive inheritance of the disease, although most cases are sporadic. About 50% respond to cortisone, while the rest depend on erythrocyte transfusions, which in the long-term will lead to iron overload and consequently a risk for hemosiderosis and organ dysfunction.

TEC was described as a distinct entity in 1970. It is an acquired self-limited disorder of unknown etiology and pathophysiology, affecting otherwise healthy young children, usually six months to four years of age. The disease presents with a significant normocytic anemia and reticulocytopenia due to reduced erythropoiesis in bone marrow. Spontaneous recovery within a few weeks from diagnosis is usual and the disease does not recur.

Objectives and methods: The objectives of the work presented in this thesis were to estimate the incidences of TEC and DBA, to describe the common pattern of TEC and DBA in Sweden, to study some specific viruses as possible causes of TEC, to study the treatment and outcome of patients with DBA, and to identify possible prognostic features of DBA. Information on patients with TEC and DBA, respectively, was collected from all pediatric departments in Sweden in two different population-based surveys. Specimens were obtained for viral diagnostics in a third prospective study of 10 patients with TEC from five Swedish pediatric departments.

Materials, results and conclusions: TEC was diagnosed in 53 cases during the years 1987 to 1989 in children less than 10 years of age. Almost all (51/53) were less than 3 years of age. In this group, the incidence was 4.3/105/year, which means 15-20 cases per year in Sweden. A meta-analysis showed that data from the present study were comparable to those previously reported. There were four pairs of siblings, including one pair of identical female twins among these children. This is a much higher familial occurrence than expected. The probability of finding 4 pairs of siblings with this disease in 50 families is less than one in a million, if the disease does not contain a hereditary component. The findings indicate that TEC involves hereditary factors, and they suggest that inheritance is autosomal dominant (Papers I and II).

During the years 1994 to 1998, 10 consecutive cases of TEC were prospectively included in a study of etiological aspects of the disease, with special reference to human parvovirus B 19 (B 19), human herpesvirus 6 (F1HV-6), cytomegalovirus (CMV) and Epstein-Barr virus (EBV). An acute EBV infection was revealed in one child, but no other IgM positivity was found at presentation. Some cases were IgG positive at presentation (HHV-6 (2 cases), EBV (1 case) and CWV (1 case)), but it was not possible to determine in any of these cases when the child had been infected. No child gave positive results for B 19 or HEIV-6 from PCR performed on sera and bone marrow collected at presentation. Cultures for virus on bone marrow, stools, and aspirates from the nasopharynx were negative in all cases but one, who showed rotavirus in stool. These results suggest that neither HHV-6, B 19, EBV, nor CMV is a single causative agent of TEC (Paper III).

Finally, all cases with DBA diagnosed in children born in Sweden 1980 to 1997 were identified. Twenty patients (10 boys and 10 girls) were included, and the incidence was calculated to be 10.6/106 live births, which is twice the incidence reported from England in 1996. A balanced reciprocal X;19 translocation was identified in one child. This suggested that DBA is linked to the 19q-chromosome region. This linkage was later confirmed by others in 25% of DBA-cases and it has recently been shown that at least 3 different genes, one of which has been identified, can independently be responsible for DBA when mutated. The clinical course and the treatment of DBA were the same as those reported in the literature. No prognostic factors could be identified. The final outcome was 55% transfusion-dependent children, one of whom subsequently underwent a successful bone marrow transplant. All transfusion-dependent patients were also treated with desferrioxamine in order to reduce iron overload. The compliance is high, but iron-overload, with its risk for related complications, is seen despite regular chelation therapy. (Papers IV and V).