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Familial Splenomegaly: Macrophage Hypercatabolism of Lipoproteins Associated with Apolipoprotein E Mutation [Apolipoprotein E (149 Leu)]

Divisions of Endocrinology (T.T.N., T.O., I.D.H.), Molecular Genetics (K.E.K., J.F.O.), Medical Genetics (P.S.K.), and Laboratory Medicine and Pathology (T.B.C.), Mayo Clinic and Foundation, Rochester, Minnesota 55905; and Gladstone Institute of Cardiovascular Disease (Z.-S.J., R.W.M.), Cardiovascular Research Institute, and Departments of Pathology and Medicine (R.W.M.), University of California, San Francisco, California 94141

Address all correspondence and requests for reprints to: Tu T. Nguyen, M.D., Division of Endocrinology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: nguyen.tu{at}mayo.edu

Splenomegaly with sea-blue histiocytes is not associated with dyslipidemia, except in severe cases of hypertriglyceridemia, Tangier disease, or lecithin cholesterol acyltransferase deficiency. We describe two kindreds in which the sea-blue histiocyte syndrome was associated with an apoE variant in the absence of severe dyslipidemia. Both patients presented with mild hypertriglyceridemia 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 (149 Leu)]. Although both probands were unrelated, they were of French Canadian ancestry, suggesting the possibility of a founder effect. In summary, we describe two 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 background of an apoE 3 allele that causes a derangement in lipid metabolism and leads to splenomegaly in the absence of severe hypertriglyceridemia.

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