Heart Block, Congenital

A rather large number of families with multiple affected sibs and normal parents have been reported. Latta and Crittenden (1964) studied the hearts of 2 sibs (the seventh and eighth offspring) who died neonatally of congenital heart block. In neither was an atrioventricular node found, nor were myocardial fibers present in the lower part of the interatrial septum. Both hearts showed foci of calcification, fibrosis, increased vascularization and a few small accumulations of inflammatory cells. Thus, fetal infection (or autoimmune reaction, as discussed later) could have been responsible. In the same family, Crittenden et al. (1964) described 4 of 8 sibs with congenital heart block. A fifth may have been affected. One died at age 14 and the others died in the neonatal period. The parents were normal and of Czechoslovakian ancestry. No mention of consanguinity was made. Cannom and Hancock (1974) described a distinctive syndrome of cardiomyopathy, probably congenital, with mitral regurgitation, complete heart block, and atrial arrhythmia in 4 unrelated male patients. The disorder is relatively benign. No familial occurrence was observed. Congenital cardiomyopathy may be the basis for other instances of congenital complete heart block which might appear in an otherwise normal heart. This appears particularly likely in cases of associated atrial arrhythmia and atrioventricular block.

McCue et al. (1977) pointed out an important nongenetic cause of congenital heart block, which, furthermore, can show familial aggregation. Of 22 affected children, 14 were born to 11 mothers with clinical or laboratory evidence of connective tissue disease, mainly systemic lupus erythematosus (SLE; 152700). In adults with SLE, changes in connective tissue around the conduction system can lead to heart block. Placental transmission of antinuclear antibodies of the IgG class is documented. Newborns have been reported with transient skin lesions of lupus. Chameides et al. (1977) also observed familial congenital heart block on this basis. James et al. (1975) observed affected brother and sister and made anatomic observations on the latter. This is probably an example of simulation of mendelism by the effects of maternal autoimmunity. Parke and Rothfield (1985) pointed out that complete heart block appears to be due to transplacental passage of maternal IgG antibody to the RNP antigen Ro. They reported the presence of anti-Ro antibody in the serum of a woman with SLE who had 2 infants with congenital heart block. The improved understanding of the pathogenesis of congenital heart block makes understandable the histopathologic findings of Latta and Crittenden (1964), noted earlier, and also raises doubts about the existence of a mendelian form of congenital heart block. Reichlin et al. (1988) described a family in which an asymptomatic woman gave birth to a son who had complete congenital heart block and who, although clinically well at age 33, developed precipitating antibodies to the Ro/SSA antigen. In the mother, features of both SLE and Sjogren syndrome (270150) developed 26 years after the birth of her son. Deutscher et al. (1988) presented a molecular analysis of human Ro ribonucleoprotein by recombinant methods.

Behan et al. (1989) studied 10 patients with congenital heart block due to maternal autoantibodies, together with the mother and sibs in each case. The seropositive mother of 1 affected child had a similar conduction block (bifascicular block) to that in her affected child. None of the sibs had cardiac lesions. Six mothers had Ro or La antibody 5 to 17 years after the birth of the affected child. Four mothers examined 11 to 32 years after the birth of an affected child were seronegative. Three of the mothers had evidence of a connective tissue disorder. It is surprising that heart block develops in some pregnancies of these women. Behan et al. (1989) suggested that the sequence of events is as follows: before or during an early stage of pregnancy, the mother sustains a mild, perhaps unrecognized viral infection, to which she produces Ro or La antibodies. The virus crosses the placenta and damages the infant myocardium while a specific maternal antibody, also crossing the placenta, localizes in the same area. The infection in the child is self-limiting, but it may persist in the mother so that a series of infants are affected. The mother's heart may also be damaged. An obvious viral candidate is a Coxsackie virus, since these viruses are common causes of myocarditis, show sequence homology with some intracellular proteins, and may persist in connective tissue diseases such as dermatomyositis. Manthorpe and Manthorpe (1992) found 4 children with congenital complete heart block among the offspring of 91 Swedish mothers and 71 Danish mothers with primary Sjogren syndrome--a relative risk of about 500, making the incidence of congenital heart block in the general population to be 1 per 20,000. Julkunen et al. (1993) did a retrospective clinical study of 33 mothers at a mean period of 11.2 years after the delivery of their first child with congenital heart block. By the time of the analysis, 2 of the 33 mothers had died and 6 had met the criteria for SLE. As a group, the mothers had clinical and immunologic characteristics more closely related to primary systemic sclerosis than to SLE or any other connective tissue disease. The predominant autoantibody response was to the SS-A/Ro antigens, notably to the 52-kD SS-A/Ro protein (109092), which was present in 97%.

Orth et al. (1996) found increased autoantibody titers against human calreticulin (109091) in infants with complete congenital heart block.

Cooley et al. (1997) described 2 pairs of monozygotic twins discordant for congenital complete heart block. Both mothers were positive for anti-Ro 52 and anti-Ro 60 antibodies, and neither had anti-La antibody on immunoblot. These cases demonstrated that there can be discordance in the development of congenital complete heart block despite identical genetics and presumably very similar exposure to anti-Ro antibody.