Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn.

OBJECTIVES: Few data are available in the literature regarding the long-term outcome of newborns with congenital complete heart block (CHB). The aims of this retrospective study were to assess neonatal morbidity and mortality, incidences of dilated cardiomyopathy (DCM), and associated heart defects, and to establish prenatal and postnatal factors that might predict adverse outcome in children with CHB. DESIGN AND SETTING: The cohort includes 91 infants with CHB diagnosed in 5 tertiary centers in Finland between 1950 and 1998. PATIENTS: Maternal connective tissue disease was evident in 89% of the patients. At birth, the median gestational age was 37.1 weeks, and the median weight was 2969 g. Of the 91 infants, 60 (66%) were girls and 7 (8%) were twins. RESULTS: Incidences of perinatal morbidity and mortality were 58% and 7%, respectively. The total mortality of CHB was 16%; 11 of 15 (73%) died during the first 12 months. Cumulative probability of survival at 10 years old was 82%. Pacing as a newborn was indicated in 48 of 90 cases (53%), and 36 received pacemakers at older ages. Cardiac defects not causally related to CHB were found in 38 of 90 patients (42%), of whom 22 were operated on. DCM was found in 21 (23%), of whom 13 died. During the follow-up, among 75 survivors with a median age of 9 years, 54 (72%) are free from symptoms. Poor outcome defined as clinically or pathologically evident congestive DCM was associated with intrauterine hydrops, low fetal and neonatal heart rate, low birth weight, male sex, and neonatal problems attributable to prematurity or neonatal lupus. CONCLUSIONS: Despite early pacing, CHB carries high mortality during the first 12 months of life. High incidences of DCM and associated heart defects indicate close echocardiographic monitoring of all children with CHB.

Recurrent miscarriage, congenital heart block and systemic lupus erythematosus.

We report the obstetric history of a woman, who between 15 spontaneous abortions, gave birth to a child with congenital heart block. She later developed systemic lupus erythematosus, had antibodies to SS-A/Ro and SS-B/La but was repeatedly negative for antiphospholipid antibodies.

Tracing past population migrations: genealogy of steroid 21-hydroxylase (CYP21) gene mutations in Finland.

The genealogic origin of steroid 21-hydroxylase gene (CYP21) mutations and associated haplotypes was determined in 74 unrelated Finnish families with CYP21 deficiency (congenital adrenal hyperplasia, CAH). These families account for two thirds (85/119) of all diagnosed patients of Finnish descent found in this country. We recently demonstrated that multiple founder mutations each associated with a particular haplotype can be found in Finland. Interestingly, some of the haplotypes were identical to those observed in various European populations, whereas others have not been described elsewhere, indicating a local and perhaps a more recent origin. In the present report we show that each of the major founder haplotypes originates from a particular geographic region of Finland. Thus many local genetic isolates are to be expected in Finland. Our finding is in a clear contrast to the genetic diseases known as the 'Finnish disease heritage', in which only one mutation usually predominates. Some of the CYP21 haplotypes proved very informative for analysis of the history of the Finnish population. For example, the origin of one frequent haplotype was shown to cluster in a region assumed by archaeological data to be a major site of immigration by settlers of either Scandinavian or Baltic origin during the first centuries AD. As this haplotype is frequent in many European patient populations, we provide independent genetic evidence of this Iron Age immigration. On the other hand, another frequent haplotype found solely in Finland reflects a more recent (post 15th century) settlement expansion. Consequently, well characterised and sufficiently frequent autosomal gene markers can provide useful information on migrations both between and within populations.

Role of HLA in congenital heart block: susceptibility alleles in mothers.

In congenital heart block (CHB), abnormal maternal immunisation leads to autoantibody production against SS-A/Ro and SS-B/La antigens. These maternal antibodies are transferred across the placenta to the unborn child and are believed to transmit irreversible immunological injury in developing foetal heart tissue, thus causing 3rd-degree atrioventricular block. The mothers may suffer from systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (SS), but they may be asymptomatic. Women with primary SS show a typical autoimmune HLA antigen pattern, namely higher frequency of HLA B8 and DR3 than in the normal population. The HLA pattern may affect individual ability to resist infecting bacteria and viruses and to response in various ways to autoantigens. It is probable that other factors such as genetic regulation of immune response are involved in CHB. We compared the HLA class I and class II alleles of mothers having CHB children with those of women suffering from primary SS and having healthy children, and with those of healthy Finns. Antibodies against 52-kD and 60-kD SS-A/Ro and 48-kD SS-B/La antigens were compared between the two groups of mothers. Our results show that anti-SS-A/Ro antibody-positive mothers all show a strong association with known autoimmune-predisposing HLA alleles, however, the mothers of CHB children differ in some HLA class I alleles, and especially in HLA haplotypes, from mothers of healthy children. Mothers with HLA A1, Cw7, B8 and without B15 are at particularly high-risk of having CHB children.

Role of HLA in congenital heart block: susceptibility alleles in children.

Congenital heart block (CHB) is a syndrome of uncertain pathogenesis leading to cardiac conduction disturbances in the foetus and newborns. It has been proposed that maternal antibodies transmit immunological injury in the developing foetal heart, thus causing irreversible damage of the atrioventricular node, leading to third-degree atrioventricular block. However, some genetic or environmental factors may also be involved. We have searched for genetic markers that play a role in immune response and that would be pathognomonic for the disease, either in mothers by regulating their immune response or in children by affecting antigen presentation and target for the maternal immune response. We have compared HLA class I and II alleles of the children with their mother and with healthy individuals and searched for HLA markers that would be emphasized in children. We have shown that particular DQ alleles in the child predispose to CHB, perhaps serving as antigen-presenting molecules on site. In addition, the HLA-Cw3 allele is involved, although its function remains to be clarified. In our results, children with CHB were often identical to their mothers in alleles of DRB, DQA and DQB loci, thus affecting foetomaternal recognition and suggesting that cell-mediated mechanisms could be involved in the pathogenesis.

Serious adverse events after HPA-incompatible platelet transfusions in an alloimmunized patient with leukaemia.

We describe an alloimmunized female patient who developed serious adverse reactions when receiving HPA-incompatible platelet transfusions. She had received 13 transfusions with random platelets before the first allergic reactions. Antibodies against both the human leucocyte antigens (HLA) and several human platelet antigens (HPA) were detected at the time of transfusions. When the patient received HLA- and HPA-compatible platelets, no reactions followed the transfusions and platelet count increments were good. When she was transfused with platelets from donors with one foreign HLA antigen, her reactions were fever, chills and headache and the response to platelet transfusions was poor. When the platelets were HLA compatible but HPA incompatible, the reactions were repeatedly rapid pulse, shortness of breath, tightness of chest and wheezing interpretable as anaphylactoid reactions. Platelet count increments were satisfactory. When rare side-effects occur after transfusion, detailed immunohaematological studies are indicated.

Immune-mediated congenital heart block (CHB): identifying and counseling patients at risk for having children with CHB.

OBJECTIVE: To identify patterns of maternal antibodies associated with an increased risk of having a child with congenital heart block (CHB) and to provide a basis for counseling women with a previously affected child. METHODS: This retrospective clinical study of the obstetric histories of 46 Finnish women with a CHB child compared the strength and specificity of the immune response to SS-A/Ro and SS-B/La, as determined by immunoblot and ELISA, in 44 affected women with 85 women with systemic lupus erythematosus (SLE) and 32 women with primary Sjögren's syndrome (SS) with healthy children. RESULTS: High levels of anti-SS-A/Ro and anti-SS-B/La by practically all assays were associated with a significantly increased risk of having a CHB child. The best single test to identify high-risk mothers was anti-52 kd SS-A/Ro by immunoblot (OR 18.9), and it was the only assay to detect mothers at increased risk of CHB as compared with controls with primary SS. Low risk of CHB was indicated by undetectable or low levels of antibodies in the ELISA assays and no reactivity on immunoblot. Mothers with a previous child with CHB had a history of fetal loss (mostly spontaneous abortions) or a history of recurrent fetal losses (> or = 3) slightly more often than controls. Late-trimester obstetric complications in non-CHB pregnancies were insignificant. The relative risk for a female child compared with a male child to have CHB was 1.9 (1.2-2.9, P = .009), and the risk of the mother having another child with CHB was 12% (4 of 34). CONCLUSION: Although there is no unique antibody profile specific for CHB, mothers with a high or low risk of having a child with CHB can be identified. Female children appear to have an increased risk of CHB, but the risk of the mother having another child with CHB is low.

Congenital heart block: HLA differences between affected children and healthy siblings in four Finnish families.

Congenital heart block without intracardiac anatomic malformations is a potentially lethal disease affecting children and newborns. The mother often has an autoimmune disorder with autoantibodies against SS-A/Ro and/or SS-B/La antigens. However, only a minority of the children of these mothers develop complete heart block. It is believed that the maternal antibodies are pathogenic, but other immunological mechanisms such as cell-mediated injury cannot be excluded. Maternal cells may recognize fetal antigens adjacent to fetal HLA, and thus some children may be more susceptible to heart block than others, depending on their HLA genetics. The purpose of this study was to evaluate whether there are HLA differences between children with heart block and their healthy siblings. Six affected children in four families and their siblings were studied. MHC class I were typed serologically and class II and some non-HLA alleles were typed by DNA techniques. DQB1*03/04 were seen more often in the affected children than in the siblings. Some other differences were also seen in the other antigens of the MHC area.

Unique HLA antigen frequencies in the Finnish population.

The Finnish Bone Marrow Donor Registry was established 1992 to serve Finnish patients in urgent need of bone marrow transplantation. This study details the HLA antigen frequencies, including those of the A 19 subtypes, in the Finnish population. Large regional variations were found in antigen frequencies between the different geographical areas of Finland. In particular, antigens A9, B12, B35, Cw4 and DR3 display regional frequency deviations, but B7, B8 and B15 also exhibit regional variations. The present population is the largest (n = 10,000) ever HLA-typed in Finland. 97% of the donors were HLA-A-B-DR typed. Confirmation of the serological HLA type was performed by DNA typing on 3% of the donors in the registry. A potential donor was found for 52% of Finnish patients in need of a matched unrelated donor for a bone marrow transplantation. Due to the ethnic origin of the Finns, it is not easy to find suitable bone marrow donors for Finnish patients in worldwide registries. It is thus important to maintain a national bone marrow donor registry which recruits donors from all over the country.

Pretransplant cytotoxic donor T-cell activity specific to patient HLA class I antigens correlating with mortality after unrelated BMT.

Unrelated bone marrow transplantation (BMT) is associated with increased post-transplant complication rates, partly because more transplantation antigens are mismatched than in HLA-identical related BMT. We have shown previously that the cytotoxic T-lymphocyte precursor (CTLp) test performed before transplantation specifically detects HLA class I mismatches demonstrating its usefulness for the identification of new HLA class I alleles. In this study we analysed the clinical relevance of the CTLp test in 41 patients who underwent unrelated BMT between 1990 and 1994. All patient-donor pairs were HLA-A, -B, -DR compatible as defined by AB-serology and oligotyping for DR1-14. The host-reactive CTLp test was performed using previously frozen peripheral blood mononuclear cells (PBMC) as stimulators and PHA blasts as target cells. We found 10 CTLp-positive and 31 CTLp-negative patient-donor pairs. Between the two groups there were no significant differences for age, diagnosis, sex, preconditioning and GvHD prophylaxis. The clinical results for the CTLp positive and the CTLp negative transplants were: severe acute GvHD III-IV 67% and 26% (P = 0.0315), transplant-related mortality 60% and 26% (P = 0.0085), and patient survival at 3.5 years 10% and 54% (P = 0.0006). Seven patient-donor pairs were mismatched for HLA-DR and/or -DQ subtypes. Only one of these seven class II mismatched pairs had a positive CTLp test. In the remaining nine CTLp positive pairs the CTL reactivity was directed against HLA-A, -B or -C antigens, revealing a statistically significant (P < 0.005) correlation between the CTLp frequency and HLA class I matching. In conclusion, the CTLp test helped to select optimally matched bone marrow donors and was particularly useful in association with high resolution oligotyping for DR- and DQ-subtypes for precise matching of both classes of HLA antigens.

High resolution HLA matching associated with decreased mortality after unrelated bone marrow transplantation.

As compared with related HLA-identical sibling donors, bone marrow transplantation (BMT) with phenotypically HLA ABDR-compatible unrelated donors is associated with increased mortality. This may be due to hidden HLA incompatibilities not detected by conventional typing. We have analyzed 44 unrelated patient-donor pairs who were matched for HLA-A, -B, and -DR by routine tissue typing. Our comprehensive HLA typing approach consisted of serology, cytotoxic T-cell precursor (CTLp) tests, T-cell cloning, oligotyping, and DNA sequencing. Using these techniques, we identified numerous HLA allele mismatches not detected by the previously applied routine typing. Twenty-four patient-donor pairs were highly matched and had a low CTLp frequency, whereas the remaining 20 pairs were allele-mismatched for HLA-A, -B, -C, -DR, -DQ antigens and/or had a positive result of the CTLp test. Patient and donor age, diagnosis, and treatment did not differ significantly between the matched and mismatched transplants. The probability for severe acute graft-versus-host disease grades III-IV was 21% in the matched and 47% in the mismatched patients (P = .0464). Transplant-related mortality was 21% and 57% (P = .0072) and actuarial patient survival rates at 3 years were 61% and 13% (P = .0005). We conclude that both HLA class I and class II allele mismatches between unrelated phenotypically ABDR-compatible patient-donor pairs are frequent and associated with increased incidence of posttransplant complications.

Acute iritis induced by granulocyte colony-stimulating factor used for mobilization in a volunteer unrelated peripheral blood progenitor cell donor.

We describe a volunteer unrelated peripheral blood progenitor cell donor with previously diagnosed dermatitis herpetiformis in whom the administration of G-CSF for the mobilization of precursor cells induced acute iritis. G-CSF has been administered to healthy people with minimal side-effects but when used in patients with autoimmune disorders worsening of symptoms or new manifestations may be a potential concern.

Maternal HLA antigens and antibodies to SS-A/Ro and SS-B/La. Comparison with systemic lupus erythematosus and primary Sjögren's syndrome.

To study the maternal immunogenetics in congenital heart block (CHB), 31 mothers of affected children were HLA typed for class I and II antigens, and the results were compared with the corresponding HLA types in 900 healthy controls, in 45 mothers with systemic lupus erythematosus (SLE) and in 21 mothers with primary SS who had healthy children. An enzyme-linked immunosorbent assay was used to study the autoantibody responses to the recombinant 52 and 60 kDa SS-A/Ro, and 48 kDa SS-B/La proteins, and to the affinity-purified SS-A/Ro and SS-B/La antigens. Mothers of children with CHB had HLA B8 and DR3 significantly more often than healthy controls [71 vs 10%; relative risk (RR) 9.8, P < 0.00001 and 74 vs 23%; RR9.8, P < 0.001, respectively]. HLA B35 was protective (RR 0.1, P = 0.0029). Compared to controls with SLE, mothers of children with CHB were more often HLA DR3 and DQ2 positive (RR 4.1, P = 0.0057 and RR 3.1, P = 0.031, respectively), and compared to controls with primary SS less often HLA B15 positive (RR 0.1, P = 0.010). In general, the HLA antigen profile in mothers of children with CHB was more closely related to primary SS than to SLE. Levels of antibodies to all three SS-A/Ro antigens were significantly higher in mothers of children with CHB than in controls with SLE and primary SS (P = 0.0001-0.0014). With regard to SS-B/La, the autoantibody responses were similar (P = 0.32-0.66).(ABSTRACT TRUNCATED AT 250 WORDS)