Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in ironmetabolism

Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant he patitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, n o test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 famil ies. We have moreover carried out a molecular analysis of candidate genes ( beta (2)-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iro n metabolism. No pathogenic mutations in these genes were identified that s egregate consistently with the disease phenotype in multiplex pedigrees. Ho wever, excluding four pedigrees with clear evidence of maternal infection a ssociated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two fa milies with possible matrilineal inheritance of disease in maternal half si bs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants we re the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transm ission of disease in a manner suggesting autosomal recessive inheritance, w e also provide the basis for further genome wide studies to define chromoso mal determinants of iron storage disease in the newborn.