The Pathology of Tangier Disease A Light and Electron AMicroscopic Study Victor J. Ferrans, MD, PhD and Donald S. Fredrickson, MD Tangier disease (deficiency of high density plasma lipoprotems) is characterized clinically by: low levels of plasma cholesterol; enlarged, orange-yellow to yellow- gray tonsils and, frequently, penpheral neuropathy. Histologic and ultrastructural studies were made of various tissues from 5 patients with Tangier disease, and comparisons were made of these findings wih those in the 12 other patients thus far known to have this disease. Deposits of cholesteryl esters were found in: reticu- loendothelial cells (foam cells) in tonsils, bone marrow, skin and jejimal sub- mucosa; Schwann cells in peripheral nerves and myenteric plexus; and in non- vascular smooth muscle cells. These deposits appeared elecron lucent and in- tensely birefringent, varied from spherical to crystalline in shape, often were extensively confluent throughout large areas of cytoplasm, and were not limited by membranes. Certain foam cells in bone marrow also contained membrane- limited clusters of lipid particles resembling chylomicrons. The foam cells in Tangier disease differ morphologically from those in numerous lysosomal enzyme deficiency states, particularly Wolman's disease and cholesteryl ester storage disease, and in proliferative diseases of the reticuloendothelial system in which cholesteryl esters also accumulate in abnormal histiocytes. Morphologic and bio- chemical data suggest several hypothses to explain the accumulation of cholesteryl esters in tissues of patients with Tangier disease. Among these hypotheses, the most likely are considered to be the presence in plasma of abnormal lipoprotein particles that are subject to phagocytic removal by reticuloendothelial cells, and the failure of a process that normally removes locally synthesized cholesterol from cells to plasma. (Am J Pathol 78:101-158, 1975) TANGIER DISEASE is a rare disorder of plasma lipid transport thought to be due to a mutant autosomal gene.' The homozygous abnormal patient has the following features: a) low plasma cholesterol and normal or elevated triglyceride concentrations; b) absence of the usual high density lipoproteins (HDL) and abnormal composition of other lipoproteins in plasma; c) enlargement and distinctive colora- tion of the tonsils; d) widespread tissue storage of cholesteryl esters, especially prominent in reticuloendothelial cells in lymph nodes, thymus, tonsils, bone marrow and rectal mucosa; and often, e) neuropathy. The combination of low plasma cholesterol and enlarged, yellow- From the Section of Pathology and the Molecular Disease Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Accepted for publication September 10, 1974. Address reprint requests to Dr. Victor J. Ferrans, Section of Pathology, National Heart and Lung Institute, National Institutes of Health, Bethesda, MID 20014. 101 102 FERRANS AND FREDRICKSON American Journal of Pathology orange or yellow-gray tonsils or tonsillar remnants is considered pathognomonic of the disease.' Tangier disease was discovered in 1960 and given its name from Tangier Island, which lies off the coast of Virginia in the Chesapeake Bay and is the home of the original patients.2'3 As of this writing, 17 patients 2-14 have been discovered, representing 13 kindreds, none of which are known to be related. They include 10 Americans,2458 2 Germans,10 14 2 Australians,7'11'13 and 1 each from Switzerland,9 En- gland '7 and New Zealand.12 Fourteen have been described in previous reports,2-13 and 1 of these represented a presumptive diagnosis made at autopsy.13 Two patients are reported here for the first time (patients 15 and 16 in Tables 1 and 2). The seventeenth has been described to us in a personal communication,14 and is also included here. Some of the histopathologic features of Tangier disease have been described in reports of individual patients, but these have not been collated and reviewed. The ultrastructure of the foam cells has not been described in detail. This report provides light and electron micro- scopic observations in various tissues from 5 homozygotes with Tangier disease, as well as bone marrow studies in 1 obligate heterozygote, and reviews all other reported pathologic lesions in the context of current knowledge concerning the possible pathogenesis of Tangier disease. Case Reports Clinical and morphologic data on the 5 patients described in detail in this com- munication are summarized in Tables 1 and 2. All patients known to have Tangier disease are included in these tables, in which they are numbered according to chronologic order of diagnosis. This numbering system is also followed in the reports of individual patients and throughout the remainder of this communication. Patient 2 ELa (CC No. 03-28-36), a white girl borm in 1954, was first seen at the Clinical Center of the National Institutes of Health in 1960. This patient and her brother TLa (patient 1 in Tables 1 and 2) were the first patients diagnosed as having Tangier disease. As reported in detail elsewhere;2'3 the detection of foam cells in the operatively removed tonsils of TLa led to a survey of his family on Tangier Island. ELa was asymptomatic and in good health except for enlarged, orange- yellow tonsils similar to those of her brother. The only abnormal findings disclosed by extensive laboratory studies were in plasma lipids and lipoproteins. Concentra- tions of plasma lipids, given in mg/100 ml of plasma and followed within paren- theses by mean normal values for children,2 were as follows: total cholesterol, 85 (170), of which 23 (46) was in the form of free cholesterol; triglycerides, 237 (40), and total phospholipids, 82 (230). After paper electrophoresis of plasma, no stain- able lipid was visible in the a-lipoprotein region. The high density lipoprotein fraction (density 1.063 to 1.21) contained only 2 mg/100 ml of cholesterol (mean Vol. 78, No. 1 TANGIER DISEASE 103 January 1975 normal for females, age 1 to 19 years, 56). Her tosils were removed, and they contained many large, foamy histiocytes similar to those in her brother's tonsils. Tonslar lipids, in mg/g dry weight of tissue, followed within parentheses by normal values 15 were: total lipids, 162 (69); cholesteryl esters, 89 (1); free cholesterol, 20 (1), and total phspholipids, 63 (49). All of the sterol present in the tonsils was cholesterol and the major (61%) acyl component of the cholesteryl esters was oleic acid.15 The patient has been followed regularly at the Clinical Center. In 1969 she developed left peroneal nerve palsy with foot drop. ITis disappeared, recurred for several months, and finaly subsided entirely. In 1972, she also develped transient right foot drop. Her plasma lipoprotein abnormalities have perssted. In July, 1971, her plasma cholesterol was 62 mg/100 ml, and the triglycerides were 186 mg/100 ml; cholesterol concentrations in lipoprotein fractions were (in mg/100 ml of plasma, followed by normal values, ie, 90% fiducial limits for females ages 1 to 19 years,16 given within parentheses): very low density lipoproteins (VLDL) 17 (5- 25); low density hpoproteins (LDL) 44 (50-170); and high density lipoproteins (HDL), 1 (40-5). Examination of bone marrow (1961) by phase contrast and polarization microscopy revealed foam cells resembling those in her tonsils. A few foam cells with similar characteristics were found in bone marrow of her mother, but not of her father. Histologic study of punch biopsy (1965) of her slin failed to demon- strate the lipid-contaiing cells which have been found4 in the dermis of other patients with Tangier disease. Ught and electron microscopic observations on foam cells observed in the lamina propria of jejunal mucosa obtained by peroral biopsy in 1972 are described in this report. Patient 4 PeLo, (CC No. 05-32-90-3), a 19-year-old white girl, was diagnosed as having Tangier disease at age 7, when she had a tonsillectomy for greatly enlarged, orange tonsils. The tonsils were shown to contain deposits of cholesteryl esters and the patient was referred for evaluation to the Clinical Center of the National Institutes of Health. The patient was found to have a low plasma cholesterol and absence of a-lipoproteins. She also had congenital pulmonic valvular stenosis, a lesion which was operatively corrected when she was 10 years old. At that time, extensive deposits of cholesteryl esters were found in foam ceHls in the thymus and lymph nodes; small, focal deposits also were found in the wall of the pulmonary artery; atrial myocardium appeared free of lipid deposits.15 The patient did well postoperatively and has had no significant cardiac symptoms since then. She de- veloped insulin-dependent diabetes mellitus at age 14 and has had adequate control of this disease. She has no signs or symptoms of peripheral neuropathy and no hepatosplenomegaly. Her sister (patient 3 in Tables 1 and 2) also has Tangier disease. When last seen at the Clinical Center, in November of 1973, her plasma cholesterol was 101 mg/100 ml; triglycerides were 178 mg/100 mL Cholesterol concentrations in plasma lipoprotein fractions (in mg/100 ml of plasma) were: VLDL, 19; LDL, 73; and HDL, 9. A biopsy of chnically normal sin was taken for ulrastructural study. Patint 5 CNo, (CC No. 04-93-64-8), a 55-vear-old man, was first diagnosed as having Tangier disease in 1962,5 when he underwent evaluation of splenomegaly, mild anemia and intermittent diarrhea of several years' duration. His tonsils had been removed at age 14 because of marked enlargement. Physical examination disclosed fine comeal deposits such as those seen in other adults with Tangier disease,5 104 FERRANS AND FREDRICKSON American Journal of Pathology U) = ~~ 0CL 4--0a )-( 3: :p C) (n E uko ow. E E.~~E~L~~ ~ 0 a-4*- bt 0 a) 4.O '0 (U C )(-( E 0 E -c M CL4-1- 0 W) E3 :6 + +o o + + ++ + o ++ 0 + 0 o 76) a- 0 0 -a)0 I + + + I + + I ++ o a1) ' C 0 nU) 0tn (Ua) Eo a) U) + + + +0 + + .