Familial splenomegaly: Macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (Delta 149 Leu)]

Splenomegaly with sea-blue histiocytes is not associated with dyslipidemia, except in severe cases of hypertriglyceridemia, Tangier disease, or lecith in cholesterol acyltransferase deficiency. We describe two kindreds in whic h the sea-blue histiocyte syndrome was associated with an apoE variant in t he absence of severe dyslipidemia. Both patients presented with mild hypert riglyceridemia and splenomegaly. After splenectomy both patients developed severe hypertriglyceridemia. Pathological evaluation of the spleen revealed the presence of sea-blue histiocytes. A mutation of apoE was demonstrated, with a 3-bp deletion resulting in the loss of a leucine at position 149 in the receptor-binding region of the apoE molecule [apoE (Delta 149 Leu)]. A lthough both probands were unrelated, they were of French Canadian ancestry , suggesting the possibility of a founder effect. In summary, we describe t wo unrelated probands with primary sea-blue histiocytosis who had normal or mildly elevated serum triglyceride concentrations that markedly increased after splenectomy. In addition, we provide evidence linking the syndrome to an inherited dominant mutation in the apoE gene, a 3-bp deletion on the ba ckground of an apoE 3 allele that causes a derangement in lipid metabolism and leads to splenomegaly in the absence of severe hypertriglyceridemia.