Transient erythroblastopenia of childhood: Varied pathogenesis

The mechanism of anemia in four patients with transient red cell aplasia of childhood (“erythroblastopenia”) was studied at the time of diagnosis by assessing the colony growth of marrow erythroid progenitors in methylcellulose tissue cultures. Marrow from Patient 1 yielded high normal numbers of BFU-E colonies that were completely abolished on addition of autologous serum or IgG. Patient 2 had normal BFU-E growth that markedly declined when autologous serum or IgM was added to the cultures, but growth remained unchanged with added autologous IgG or peripheral blood mononuclear cells (PBMC). Marrow from Patient 3 yielded low CFU-E and BFU-E numbers with standard plating techniques, but colonies strikingly increased when marrow fractions from an albumin density gradient were cultured. PBMC from Patient 3 suppressed control marrow CFU-E and BFU-E, but serum had no effect. Patient 4 had normal CFU-E and BFU-E that increased with autologous serum and remained unchanged with autologous PBMC. We conclude that the red cell aplasia in Patients 1, 2, and 3 was due to suppressed erythropoiesis via IgG, IgM, and cell-mediated inhibition, respectively. In contrast, in Patient 4 no immune mechanism was demonstrated. Whereas transient red cell aplasia has a uniform clinical presentation, there are at least four pathogenetic mechanisms that can be detected in vitro.     

Familial transient erythroblastopenia of childhood is associated with the chromosome 19q13.2 region but not caused by mutations in coding sequences of the ribosomal protein S19 (RPS19) gene

Transient erythroblastopenia of childhood (TEC) is a rare condition, which at onset may be difficult to distinguish from Diamond-Blackfan anaemia (DBA). We have previously shown that mutations in the ribosomal protein S19 gene (RPS19) cause DBA. In order to clarify whether TEC and DBA are allelic, we investigated the segregation of markers spanning the RPS19 gene region on chromosome 19q13.2 and performed sequence analysis of all exons in the RPS19 gene in seven TEC sibling pairs. Linkage analysis supported allelism for TEC and DBA at the RPS19 gene locus and implies molecular mechanisms other than structural mutations in the RPS19 gene.     

Heart transplantation for congenital heart disease in the first year of life

Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance.     

N-Acetylglucosamine kinase and N-acetylglucosamine 6-phosphate deacetylase in normal human erythrocytes and Plasmodium falciparum

The U.K. Diamond-Blackfan Anaemia (DBA) Registry was established with the aim of providing a representative database for studies on the aetiology, pathophysiology and treatment of DBA. We have analysed retrospective data from 80 cases (33 male, 47 female) born in the U.K. in a 20-year period (1975–94), representing an annual incidence of 5 per million live births. Ten children from seven families had an apparently familial disorder. 13% were anaemic at birth, and 72.5% had presented by the age of 3 months. 67% had macrocytosis at presentation. 72% responded initially to steroids, and at the time of study 61% were transfusion-independent (45% steroid-dependent) and 39% required regular transfusions. Unequivocal physical anomalies, predominantly craniofacial, were present in 37%, and were more likely in boys (52%) than girls (25%). 18% had thumb abnormalities. Height was below the third centile for age in 28%, and 31% had neither short stature nor physical anomalies. Four children without physical abnormalities had normal red cell indices, and achieved steroid-independent remission, suggesting transient erythroblastopenia of childhood rather than DBA. The birth month distribution of children with sporadic DBA and craniofacial dysmorphism showed a possible seasonality, consistent with a viral aetiology.     

Ventricular septal defect in the first year of life.

Of approximately 22,000 live births in the region under study during the last 4 years, ventricular septal defect (VSD) was identified as the primary or isolated congenital heart lesion in 124 infants who were followed up from birth for a minimum of 1 year (incidence, 5.7 per 1,000 live births). Doppler color flow mapping was performed in 93 of 124 patients; 47 had a muscular VSD and 46 had a perimembranous VSD. Only 1 patient had 2 muscular VSDs. None had a subpulmonic type of defect. Of 124 patients, 14 were lost to follow-up. Spontaneous closure was seen in 18 patients (42%) in the muscular group, in 9 (23%) in the perimembranous group and in 10 patients (37%) in the unclassified group by the end of the first year. The overall rate of spontaneous closure was 34% by the end of the first year. Congestive heart failure developed in 2 of 46 patients with muscular VSD and in 12 of 47 patients with perimembranous VSD. In the first year, 2 patients with muscular VSD as opposed to 5 with perimembranous VSD required surgery. Doppler color flow mapping is a valuable aid in the diagnosis of VSD and may be one reason for the observed increase in the incidence of VSD. The overall prognosis appeared much better in the muscular than the perimembranous type of VSD.     

Protein S in the first year of life

Total protein S, free protein S and C4b binding protein were measured in healthy term infants in order to establish the normal levels of these proteins during the first year of life. Total protein S rose from 36.5% of the adult mean level on day 1 of life to 90% between 6 and 12 months of age. Free protein S was 54.2% of the adult mean on day 1 of life, all values were in the adult range by 2 months and the mean value was no different from the adult at 4 months. This relatively high level of free and presumably active protein S reflects low levels of C4bBP at birth (28.8% of the adult mean) and a slow postnatal rise.     

Balloon pulmonary valvotomy performed in the first year of life.

OBJECTIVE: Evaluation of the global results after percutaneous pulmonary valvotomy with a balloon catheter performed in the first year of life. METHODS: We assessed retrospectively the data of 27 patients with pulmonary stenosis who underwent balloon valvotomy in the first 12 months of life, from January 1994 to July 2002. The following data were evaluated: gender, age at diagnosis, clinical presentation, echocardiographic features, other cardiac anomalies, age at balloon valvotomy, diameter of pulmonary annulus, initial and final pressure gradient across the valve, complications and follow-up. We used the median and the Wilcoxon test. For other variables we present the mean and standard deviation. RESULTS: Fourteen patients (52%) were female. We had two prenatal diagnoses. Age at diagnosis ranged between one and 60 days (median: 28.0). With regard to clinical presentation, one (4%) had isolated cyanosis, seven (28%) a systolic murmur and 17 (68%) both cyanosis and a systolic murmur. Associated malformations included: ventricular septal defect--two, dilatation of left pulmonary artery--one, supravalvar stenosis--one, and subvalvular membrane--one. The pulmonary annulus ranged between 4.5 and 11 mm (mean: 8.3 +/- 1.8). The procedure was performed in 23 patients aged 2 to 357 days (median: 60), 43.5% of cases in the first 28 days of life. Balloon diameter ranged from six to 14 mm (mean: 10.7 +/- 2.3). The median value of right ventricular peak systolic pressure before dilatation was 115 mmHg (variation: 60-212) and decreased to 48 mmHg (variation: 20-120) (p < 0.001). Significant infundibular stenosis was documented in five cases and propranolol was initiated after the procedure. In four cases the procedure was abandoned before dilatation. The follow-up period ranged from 0 to 101 months (mean: 40.1 +/- 32.1). The maximum instantaneous gradient between the right ventricle and the pulmonary artery ranged between 0 and 95 mmHg (mean: 23.7 +/- 19.5), and was more than 40 mmHg in 13% of the cases. CONCLUSIONS: Percutaneous pulmonary valvotomy with a balloon catheter performed in the first year of life is effective in relieving obstruction of the right ventricular outflow tract. The success rate was 78% (21 of 27 patients).     

Surgery for cyanotic heart disease in the first year of life

Data are reviewed on 248 patients less than 1 year old who presented with a diagnosis of cyanotic heart disease between January 1976 and January 1982. No infant had had prior surgical treatment. The patients were classified according to diagnosis: tetralogy of Fallot, transposition of the great arteries, pulmonary atresia and anomalies of the tricuspid atresia or single ventricle type. Other remote forms of cyanotic heart disease were excluded from the analysis. Management of these patient groups is discussed in relation to their potential for corrective surgery early in infancy or later. The proper selection of palliative procedures that will permit bilateral growth and development of pulmonary arteries and equal distribution of pulmonary blood flow is emphasized. Morbidity and mortality in each patient group are discussed.     

Diamond-blackfan anemia: The role of immunoglobulin blocking factor in remission

Some patients with Diamond-Blackfan syndrome may have suppressor T-cells responsible for the failure of normal erythropoiesis. The capacity of Diamond-Blackfan syndrome mononuclear cells to react in mixed leukocyte culture to the stimulus of nucleated red cells was tested using bone marrow as the cell source. In all but one instance, Diamond-Blackfan mononuclear cells and cells from normal or a multiply-transfused control showed similar degrees of stimulation. Patient mononuclear cells reacted normally to phytohemagglutinin (PHA). The presence of a cytotoxic effect of Diamond-Blackfan mononuclear cells on normal nucleated red cells was examined using a ⁵⁹Fe-release assay. There was no evidence for lymphocyte-mediated erythroid cytotoxicity. Immunoglobulins (Ig) were removed from Diamond-Blackfan serum by affinity chromatography. Erythroid burst-forming units (BFU-E) failed to grow normally in Ig-depleted patient autologous serum, but growth failure was reversed when Ig eluted from the affinity column was added back to the culture. Diamond-Blackfan Ig added to autologous mononuclear cells in the absence of autologous serum normalized colony growth. T-cells of some Diamond-Blackfan syndrome patients may suppress BFU-E growth, but they do not react abnormally in mixed leukocyte culture to nucleated erythroid cells and are not cytotoxic for erythroblasts under our conditions of study. The serum-blocking factor in our patients appears to be an Ig that promotes BFU-E generation despite the presence of suppressor T-cells. Although it cannot be proved, this may be related to the remission of disease in our patients.     

Serum transferrin receptor, ferritin, and reticulocyte maturity indices during the first year of life in 'large' preterm infants

BACKGROUND: Preterm infants are at risk of developing iron deficiency; among the iron status and hemopoiesis indices the serum transferrin receptor (sTfr) has been shown to be a useful indicator in assessing iron status, while immature reticulocyte production is regarded as an estimator of erythropoiesis. OBJECTIVE: To investigate age-related changes in iron status infants born 'moderately' preterm, with a gestational age (GA) of 32-36 wk, and identify associations between sTfr and other hematological and biochemical iron indices. DESIGN: Hospital-based prospective, longitudinal study in preterm infants. METHODS: Iron and erythropoiesis parameters were evaluated in 181 formula-fed preterm infants at 2 and 6 wk and 3, 6, 9, and 12 months chronological age. Hemoglobulin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), reticulocytes, serum iron (sFe), serum ferritin (sFer), sTfr, and reticulocyte subpopulations were measured. RESULTS: A total of 756 measurements were performed. After an initial decline, Hb rose from month 3 to 12 of life. SFe and sFer and immature reticulocyte count decreased from the second week to the third month and remained stable thereafter. STfr was lower up to 6 wk and stable from month 3 to 12. Iron deficiency anemia (IDA) was found in 5.5% of infants. In 76 measurements sFer was <12 microg/L, implying storage iron deficiency (SID). A negative correlation was observed between sTfr and other indices of iron status such as Hb, Hct, MCV, sFe, and sFer. Infants with sFer <12 microg/L had lower sTfr than those with sFer >12 microg/L. Reticulocyte production was positively associated with STfr, but this association was dependent on the chronological age of the infant. CONCLUSION: Iron depletion is common in formula-fed preterm (32-36 wk GA) infants between month 3 and 12 of life. STfr appears to be an indicator of iron status in preterm infants during the first year of life.     

Endocrine testicular function in mink during the first year of life.

The endocrine testicular function in mink (Mustela vison) was investigated during the first year of life encompassing puberty, the first mating season and the phase of regression thereafter. The mink, relatively easily accessible as a semi-domesticated animal, was chosen as an example of a mammalian seasonal breeder. In plasma samples from 7 to 17 animals collected on 10 occasions between July and April testosterone and delta4-androstenedione were determined by simultaneous radioimmunoassay. A steady increase of both androgens from November to early March, when the mating season occurs, and a rapid decline to pre-pubertal levels thereafter was observed. The ratio of testosterone to delta4-androstenedione was 1:1 from November to April. These findings parallel the known morphological transitions of the testes.     

Health-related quality of life in children with hepatitis C acquired in the first year of life

Aims: The first aim of this study was to determine the health‐related quality of life (HRQoL) of children with chronic hepatitis C virus (HCV) infection and compare HRQoL as reported by parents. The second aim was to ascertain parents' perceptions and concerns about current and future life for their child with HCV, and compare these findings with those reported by adolescents. Methods: The study group comprised children attending a tertiary pediatric HCV‐clinic in Melbourne, Australia, who acquired HCV prior to 12 months of age by vertical transmission or blood transfusion. Two validated (parent‐ and self‐reported) questionnaires of HRQoL were completed (CHQ‐PF 50 and CHQ‐CF 50). Scores for children with HCV were compared with normative data (representative sample of 3119 age‐matched Victorian children). A study‐designed questionnaire relating to the impact of the diagnosis of HCV on parent and child perceptions of current and future health was administered. Results: In total, 83% (19/23) questionnaires were returned. Physical and psychosocial summary scores were significantly lower in HCV than non‐HCV children (45.3 vs 49.6 and 44.0 vs 50.1, respectively). Nine out of 11 scale scores were significantly lower in children with HCV, most notably the General health (49.9 vs 77.1; P < 0.001) and Parent impact–emotional (45.6 vs 80.3; P < 0.001) scales. Children reported reduced physical functioning (82.8% vs 94.4%) but were otherwise less concerned than their parents about their future health. Conclusions: Despite being “asymptomatic” on routine medical history, children with early acquired HCV have significantly poorer health status than community controls. These findings suggest the need for services currently available for adult HCV patients to support families and children with HCV.     

Permanent diabetes mellitus in the first year of life

AIMS/HYPOTHESIS: The pathogenesis of permanent diabetes mellitus diagnosed early in life is heterogeneous and, in most cases, not known. We aimed at identifying markers differentiating between non-autoimmune and autoimmune diabetes. METHODS: The clinical, genetic and epidemiological features of 111 diabetic patients (62 males) who received insulin within 12 months of life were studied. RESULTS: The epidemic curve by age of diabetes onset revealed two subsets of patients at a cutoff of 180 days. In the group with diabetes onset before 180 days ("early onset" permanent diabetes) the analysis of HLA susceptibility heterodimers (available for 21 individuals) showed that 76% had a "protective" HLA genotype for Type I (insulin-dependent) diabetes mellitus as compared to 11.9% (5/42) of the later onset group. Accordingly, "early onset" children were less likely to have autoimmunity markers (4 out of 26 tested) than children with onset after 180 days (13 out 20 tested) (15.4% vs. 65.0%, p<0.01). Of note, 19 out of 20 (or the 95%) patients who were born on the island of Sardinia, an Italian region where the incidence of Type I diabetes is six times higher than continental Italy (33/100,000/year vs 5/100,000/year), were included in the later onset group (>180 days). Small-for-date birthweight, a possible sign of reduced foetal insulin secretion, was more common in the "early onset" group (OR=9.9, 95%-CI 2.6-38.6). CONCLUSION/INTERPRETATION: These results, obtained in the largest population-based cohort of diabetic infants hitherto reported, suggest that "early onset" permanent diabetes cases differ from later onset cases and that most of them do not have an autoimmune pathogenesis.     

Childhood diabetes: parents' experience of home management and the first year following diagnosis.

AIMS: To explore parents' experience of having a child diagnosed with Type 1 diabetes, managed at home, and their first year following diagnosis. METHODS: A qualitative, longitudinal study based on 40 in-depth interviews with parents of 20 children with newly diagnosed Type 1 diabetes managed at home from diagnosis in South Wales. RESULTS: Many parents were alarmed by the speed of diagnosis following the gradual progress of their child's symptoms. The provision of timely, adequate information was important to all parents. Although five parents had initial concerns about going home, all parents were subsequently pleased their children had not been hospitalized. Home management enabled parents to integrate diabetes management into the family's normal lifestyle from diagnosis. Professional support, particularly accessible telephone advice, was valued by and reassured parents. Parents experienced a loss of spontaneity, a continuing fear of hypoglycaemia and did not want their child to feel different to other children. Acutely aware of the seriousness of diabetes, they did their utmost to achieve optimal glycaemic control but felt that diabetes could not 'dominate' if they were to lead a 'normal' life. CONCLUSIONS: The experience of parents in this study suggests that parents of children with newly diagnosed diabetes are able to cope successfully when given the opportunity to start treatment at home. Therefore, if children with diabetes are clinically well at diagnosis, this study supports home management as a system of care from the parents' point of view. These findings are relevant to clinicians, policy makers and health service managers involved in planning and providing paediatric diabetes care.