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Primary type I hyperlipoproteinemia with normal lipoprotein lipase activity
Volume 90 Number 5
Brief cfinical and laboratory observations
consanguineous marriage is important to record as suggesting evidence of the possibility of an autossomal recessive pattern of transmission. The authors express their gratitude to I. Tamir, M.D., and Ora Lev Tov, M.Sc., from the Pediatric Metabolic Unit, MunicipalGovernment Medical Centre, Hadassah Hospital, Tel Aviv, for the PHLA determination and to P. Segal, M.D., from the Metabolic Research Laboratory, Chaim Sheba Medical Centre, Tel Hashomer, Tel Aviv, for the performance of serum lipoproteins examination by ultracentrifugation.
4. 5.
6.
7.
REFERENCES
1. Fredrickson DS, Levy RI, and Lees RS: Fat transport in lipoproteins-an integrated approach to mechanisms and disorders, N Engl J Med 276:32, 94, 148, 215, 273, 1967. 2. Fredrickson DS, and Lees R S Familial hyperlipoproteinemia, in Stanbury JB, Wyngaarden JB, and Fredrickson DS, editors: The metabolic basis of inherited diseases, New York. 1966, McGraw-HiU Book Company, Inc., pp 429485. 3. Fredrickson DS, and Levy RI: Familial hyperlipoproteinemia, in Stanbury JB, Wyngaarden JB, and Fredrickson DS,
Primary type I hyperlipop ro teinemia with normal lipoprotein lipase activity Barbara K. Burton and
Henry L. Nadler,* Chicago, 1ll. FAMILIAL TYPE I HYPERLIPOPROTEINEMIA is a rare, autosomal recessive disorder characterized clinically by eruptive xanthomatosis, lipemia retinalis, recurrent abdominal pain, pancreatitis, and hepatosplenomegaly with onset in early childhood? Plasma triglycerides in affected individuals are greatly elevated while cholesterol is normal or only slightly elevated. Lipoprotein electrophoresis reveals a type 1 pattern, defined as hyperchylomicronemia with normal or decreased levels of the other lipoproteins. Patients with this "fat-induced" form of From the Division of Genetics, Children's Memorial Hospital, Department of Pediatrics, Northwestern University Medical School. Supported in part by The National Institutes of Health, RR 00199, The National Foundation-March of Dimes, the Kroc Foundation, and the Chicago Community Trust. *Reprint address: Children's Memorial Hospital, 2300 ChildrenS" Plaza. Chicago, IL 60614.
8.
9.
10.
777
editors: The metabolic basis of inherited diseases, New York, 1972, McGraw-Hill Book Company, Inc., pp 545614. SMA 12/60 Cholesterol Method, Technical Publication THO-0160-11, Technicon Instruments Corporation. Foster LB, and Dunn DT: Stable reagents for determination of serum triglycerides by a colorimetric Hantzch condensation method, Clin Chem 19:338, 1973. Havel RJ, Eder HA, and Bragdon JH: The distribution of ultracentrifugally separated lipoproteins in human serum, J Clin Invest 34:1345, 1955. Fredrickson DS, Ono K, and Davis LL: Lipolytic activity of post heparin plasma in hyperglyceridemia, J Lipid Res 4:24, 1963. Krauss RM, Levy RI, and Fredrickson RS: Selective measurement of two lipase activities in post-heparin plasma from normal subjects and patients with hyperlipoproteinemia, J Clin Invest 54:1107, 1974. Greten H, Degrella R, Klose G, Rascher W, DeGennes JL, and Gjone E: Measurment of two plasma triglyceride lipases by an immunochemical method: Studies in patients with hypertriglyceridemia, J Lipid Res 17:203, 1976. Lloyd JK: Hyperlipoproteinemia in childhood, Aust Paediat J 8:264, 1972.
hyperlipoproteinemia respond rapidly to a fat-free diet with a remarkable decrease in plasma lipids and disappearance of clinical symptoms. They also have a deficiency of plasma post-heparin lipoprotein lipase activity that results in diminished uptake of chylomicra by adipose tissue? -4 The demonstration of this biochemical defect has become a necessary diagnostic criterion for the documentation of this diagnosis. '-~ We present here a 12-year-old girl whose clinical course, response to diet, and lipoprotein pattern are typical of primary type I hyperlipoproteinemia but who exhibits normal post-heparin lipoprotein lipase activity. These findings suggest that primary type I hyperlipoproteinemia, previously referred to as lipoprotein lipase deficiency, may actually represent a heterogeneous group of biochemical disorders, only one of which is characterized by this specific biochemical defect. CASE R E P O R T Patient L. M. is a 12-year-old white girl who was the product of a normal term pregnancy, labor, and delivery. Growth and development were normal for the first year of life; there were no significant illnesses. At the age of 16 months, she was hospitalized with vomiting, diarrhea, and dehydration. Subsequently, she suffered recurrent episodes of vomiting, abdominal cramps, and diarrhea which usually responded to a clear liquid diet. At five years of age, she developed intermittent skin rashes over the lower extremities, which were thought to be allergic in origin. These persisted over the next several years during which time chronic abdominal pain became a major problem. At the age of 11 years, she developed severe abdominal pain, vomiting, and
778
Brief clinical and laboratory observations
The Journal of Pediatrics May 1977
Table I. Post-heparin triglyceride tipase activity
grnoles FFA /mUhr Protamine ] Protamine inactivated resistant Patient L . M . Controls (girls, ages 7-16) Type I hyperlipoproteinemia
8.9 3.8 +_ 1.1 0.1 +_ 0.1
10.4 11.1 _+ 3.8 10.5 +_ 3.8
Table II. Fasting serum lipids in the family members of Patient L. M.
Mr. M Mrs. M Siblings B. M. (female, age 17) G. M. (female, age 15) V. M. (female, age 13)
Cholesterol (normal." 135-315)
Triglycerides (normal." 30-135)
i85 264
86 170
119 131 105
28 76 185
Center of Children's Memorial Hospital. At this time, her serum cholesterol was 129 mg/dl (normal: 135 to 315) and her triglycerides were 192 mg/dl (normal: 30 to 135). Lipoprotein electrophoresis revealed a normal pattern. A complete blood count and urinalysis were unremarkable. Blood urea nitrogen was 13 mg/dl, creatinine, 0.7 mg/dl; uric acid, 5.1 mg/dl; calcium, 4.7 mEq/1; all were within normal limits. An oral glucose tolerance test revealed a normal response. Thyroxine was 5.6 ug/dl (normal: 2 to 7.5), and anti-nuclear antibody was negative. Quantitative immunoglobulins were all within normal limits, and immunoglobulin electrophoresis was unremarkab!e. Serum lipoproteins were examined in family members and are listed in Table II. The mother and one sibling exhibited mild elevations of serum triglycerides; all family members were asymptomatic. Following completion of these studies, a regular diet was resumed in an attempt to document the diagnosis of type I hyperlipoproteinemia. Within six weeks, eruptive xanthomata appeared on the lower extremities. Serum cholesterol at this time was 225 mg/dl (normal: 20 to 230 mg/dl) and triglycerides 1,645 mg/dl (normal: 10 to 140). Lipoprotein electrophoresis again revealed a type I phenotype. A fat-free diet was resumed, and the patient has remained asymptomatic. DISCUSSION
fever and was hospitalized with a presumptive diagnosis of peritonitis secondary to a ruptured appendix. At laparotomy, she was found to have acute pancreatitis and an abdomen filled with a creamy white sterile fluid. A clinicaI diagnosis of type I hyperiipoprotememia was made at this time. The postoperative course was uneventful: following resumption of a regular diet. serum lipids were measured. On a regular diet, serum cholesterol was 230 mg/dl (normal: 120 to 230) and triglycerides were 1.785 mg/dl (normal: 10 to 140). Lipoprotein electrophoresis revealed a type 1 phenotype (hyperchYlomicronemia). Upon standing for 18 hours at 4~ the plasma separated into a thick creamy supernatant layer with a clear infranatant layer. A diet with fat intake restricted to 10 gm/ day was prescribed. The skin lesions disappeared and there were no recurrences of abdominal pain. Eight months following institution of the diet, she was referred to Children's Memorial Hospital for evaluation. At this time. the physical examination was unremarkable. Serum cholesterol was 103 mg/dl (normal: 114 to 209) and triglycerides were 258 mg/dl (normal: 10 to 140). To confirm the diagnosis of type I hyperlipoproteinemia, post-heparin lipolytic activity was measured. Intravenous heparin. 100 u/kg, was administered and blood samples were collected in EDTA at 0 timel 15, 30. and 45 minutes. These samples were assayed for protamine-inactivated and protamine-resistant triglyceride lipase activity by Dr. Peter Herbert of The National Institutes of Health. The protamine-inactivated activity represents the lipoprotein lipase of adipose tissue origin that is deficient in patients with type I hyperlipoproteinemja whereas the protamine-resistant activity, of hepatic origin, is normal in affected individuals.4 The peak activity in patient L. M. is presented in Table I with the comparable values in normal and affected individuals. Following the demonstration of normal lipoprotein lipase activity, patient L. M. was admitted to the Clinical Research
The results of the protamine inactivated triglyceride lipase assay dearly indicate that patient L.M. does not have a deficiency of plasma lipoprotein lipase activity. Her peak activity as illustrated in Table I is actually higher than the values derived for age-matched controls, although this may simply reflect the higher dose of heparin used in obtaining her samples than is usually utilized in this test. A dose of 10 g/kg is routinely employed in these studies but higher doses have failed to r e l e a s e s i g n i f i c a n t levels of activity in patients with lipoprotein lipase deficiency.' Type I hyperlipoproteinemia may be difficult to differentiate from type V on the basis of electrophoretic pattern alone. The appearance of patient L. M.'s plasma at 4~ and her response to a fat-restricted diet, however, are typical of the type 1 patients and would be unusual in type V hyperlipoproteinemia. Phenocopies of type I hyperlipoproteinemia have been reported in a n u m b e r of disorders including lymphoma and systemic lupus erythematosis with dysglobulinem i a ? ; Phenocopies of other types of hyperlipoproteinemia have been observed with pancreatitis, ~ uncontrolled diabetes mellitus, '~ and hypothyroidism. TM The evaluation of our patient revealed no evidence for any of these disorders and the ten-year history makes all of these unlikely. It seems clear that the hyperlipoproteinemia in patient L.M. is a primary p h e n o m e n o n ; added support for this assumption is derived from the presence of hypertriglyceridemia in one of the parents and in one sibling, a finding that has been reported in heterozygotes for type I hyperlipoproteinemia.
Volume 90 Number 5
Brief clinical and laboratory observations
Thus, patient L. M. appears to be a unique example of primary type I hyperlipoproteinemia in a patient with normal lipoprotein lipase activity. One other patient with typical type I hyperlipoproteinemia was initially reported as having normal post-heparin lipolytic activity; with the development of separate assays for the various components of post-heparin lipolytic activity, however, he was found to have a deficiency of protamine inactivated triglyceride lipase with a relative increase in the protamineresistant lipase. 4 The combination of findings in our patient suggest that primary type I hyperlipoproteinemia may represent a heterogeneous group of disorders, only one of which is associated with a deficiency of lipoprotein lipase activity.
3.
4.
5. 6.
7.
We thank Dr. Peter N. Herbert of The National Institutes of Health for his help in performing the triglyceride lipase enzyme assay.
8.
REFERENCES
9.
1. Fredrickson DS, and Levy RI: Familial hyperlipoproteinemia, In Stanbury JB, Wyngaarden JB, and Fredrickson DS, editors: Metabolic basis of inherited disease, New York, 1975, McGraw-Hill Book Company, Inc, pp 545614. 2, Harlan WR, Winesett PS, and Wasserman AJ: Tissue
Combined yon Willebrand disease and Hageman factor
deficiency George R. Buchanan, M.D., Daniel M. Green, M,D., and Robert I. Handin, M.D.,* Boston,
Mass. From the Division of Hematology-Oncology of the Department Of Medicine, Children's Hospital Medical Center, Division of Hematology, Department of Medicine, Peter Bent Brigham Hospital, and the Departments of Pediatrics and Medicine, Harvard Medical School Supported by United States Public Health Service Grant Nos. HL 05581, HL 17513, and HL 05392.
10.
779
lipoprotein lipase in normal individuals and in individuals with exogenous hypertriglyceridemia and the relationship of this enzyme to assimilation of fat, J Clin Invest 46:239, 1967. Schreibman PH, Arons DL, Saudek CD, and Arky RA: Abnormal lipoprotein lipase in familial exogenous hypertriglyceridemia, J Clin Invest 52:2075, 1973. Krauss RM, Levy RI, and Fredrickson DS: Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia, J Clin Invest 54:1107, 1974. Motulsky AG: The genetic hyperlipidemias, N Engl J Med 294:823, 1976. Glueck CJ, Kaplan AP, Levy RL Greten H, Ga'alnick H, and Fredrickson DS: A new mechanism of exogenous hyperglyceridemia, Ann Intern Med 71:1051, 1969. Glueck CJ, Levy RI, Glueck HI, Gralnick HR, Greten H, and Fredrickson DS: Acquired type I hyperlipoproteinemia with systemic lupus erythematosus, dysglobulinemia and heparin resistance, Am J Med 47:318, 1969. Kessler JI, Kniffen JC, and Janowitz HD: Lipoprotein lipase inhibition in the hyperlipemia of acute alcoholic pancreatitis, N Engl J Med 269:943, 1963. Bierman EL, Bagdade JD, and Porte D: A concept of the pathogenesis of diabetic lipemia, Trans Assoc Am Physicians 79:348, 1966. Porte D, O'Hara DD, and Williams RH: The relation between postheparin lipolytic activity and plasma triglyceride in myxedema, Metabolism 15:107, 1966.
COMBtNAa'IONS of hemophilia A or yon Willebrand disease with other clotting factor deficiencies', '-' or with intrinsic platelet abnormalities 3~' have been observed but are probably chance events in most circumstances. Several patients have been described who have evidence of VWD and slightly decreased levels Of Factor XII (Hageman factor)." Unfortunately, family studies were not performed to document joint inheritance of the two defects. We describe a child who has both VWD and Hageman factor deficiency, with a similar defect in the patient's father, suggesting linked auiosomal dominant transmission of both disorders.
Abbreviations used VWD: von Willebrand disease PTT: activated partial thromboplastin time VIIIvwv: plasma levels of yon Willebrand factor VIIIAc~x: Factor VIII antigen
*Cancer Research Scholar, Massachusetts Division American
Cancer Society. Reprint address: George R. Buchanan, M.D.. Division of Hematologv-Oncology, Children"s Hospital Medical Center. 300 Longwood Ave., Boston, MA 02114.
CASE REPORT
Patient C.R. is a 6-year-old white girl who was noted to have a long activated partial thr0mboplastin time. There was no history
Brief cfinical and laboratory observations
consanguineous marriage is important to record as suggesting evidence of the possibility of an autossomal recessive pattern of transmission. The authors express their gratitude to I. Tamir, M.D., and Ora Lev Tov, M.Sc., from the Pediatric Metabolic Unit, MunicipalGovernment Medical Centre, Hadassah Hospital, Tel Aviv, for the PHLA determination and to P. Segal, M.D., from the Metabolic Research Laboratory, Chaim Sheba Medical Centre, Tel Hashomer, Tel Aviv, for the performance of serum lipoproteins examination by ultracentrifugation.
4. 5.
6.
7.
REFERENCES
1. Fredrickson DS, Levy RI, and Lees RS: Fat transport in lipoproteins-an integrated approach to mechanisms and disorders, N Engl J Med 276:32, 94, 148, 215, 273, 1967. 2. Fredrickson DS, and Lees R S Familial hyperlipoproteinemia, in Stanbury JB, Wyngaarden JB, and Fredrickson DS, editors: The metabolic basis of inherited diseases, New York. 1966, McGraw-HiU Book Company, Inc., pp 429485. 3. Fredrickson DS, and Levy RI: Familial hyperlipoproteinemia, in Stanbury JB, Wyngaarden JB, and Fredrickson DS,
Primary type I hyperlipop ro teinemia with normal lipoprotein lipase activity Barbara K. Burton and
Henry L. Nadler,* Chicago, 1ll. FAMILIAL TYPE I HYPERLIPOPROTEINEMIA is a rare, autosomal recessive disorder characterized clinically by eruptive xanthomatosis, lipemia retinalis, recurrent abdominal pain, pancreatitis, and hepatosplenomegaly with onset in early childhood? Plasma triglycerides in affected individuals are greatly elevated while cholesterol is normal or only slightly elevated. Lipoprotein electrophoresis reveals a type 1 pattern, defined as hyperchylomicronemia with normal or decreased levels of the other lipoproteins. Patients with this "fat-induced" form of From the Division of Genetics, Children's Memorial Hospital, Department of Pediatrics, Northwestern University Medical School. Supported in part by The National Institutes of Health, RR 00199, The National Foundation-March of Dimes, the Kroc Foundation, and the Chicago Community Trust. *Reprint address: Children's Memorial Hospital, 2300 ChildrenS" Plaza. Chicago, IL 60614.
8.
9.
10.
777
editors: The metabolic basis of inherited diseases, New York, 1972, McGraw-Hill Book Company, Inc., pp 545614. SMA 12/60 Cholesterol Method, Technical Publication THO-0160-11, Technicon Instruments Corporation. Foster LB, and Dunn DT: Stable reagents for determination of serum triglycerides by a colorimetric Hantzch condensation method, Clin Chem 19:338, 1973. Havel RJ, Eder HA, and Bragdon JH: The distribution of ultracentrifugally separated lipoproteins in human serum, J Clin Invest 34:1345, 1955. Fredrickson DS, Ono K, and Davis LL: Lipolytic activity of post heparin plasma in hyperglyceridemia, J Lipid Res 4:24, 1963. Krauss RM, Levy RI, and Fredrickson RS: Selective measurement of two lipase activities in post-heparin plasma from normal subjects and patients with hyperlipoproteinemia, J Clin Invest 54:1107, 1974. Greten H, Degrella R, Klose G, Rascher W, DeGennes JL, and Gjone E: Measurment of two plasma triglyceride lipases by an immunochemical method: Studies in patients with hypertriglyceridemia, J Lipid Res 17:203, 1976. Lloyd JK: Hyperlipoproteinemia in childhood, Aust Paediat J 8:264, 1972.
hyperlipoproteinemia respond rapidly to a fat-free diet with a remarkable decrease in plasma lipids and disappearance of clinical symptoms. They also have a deficiency of plasma post-heparin lipoprotein lipase activity that results in diminished uptake of chylomicra by adipose tissue? -4 The demonstration of this biochemical defect has become a necessary diagnostic criterion for the documentation of this diagnosis. '-~ We present here a 12-year-old girl whose clinical course, response to diet, and lipoprotein pattern are typical of primary type I hyperlipoproteinemia but who exhibits normal post-heparin lipoprotein lipase activity. These findings suggest that primary type I hyperlipoproteinemia, previously referred to as lipoprotein lipase deficiency, may actually represent a heterogeneous group of biochemical disorders, only one of which is characterized by this specific biochemical defect. CASE R E P O R T Patient L. M. is a 12-year-old white girl who was the product of a normal term pregnancy, labor, and delivery. Growth and development were normal for the first year of life; there were no significant illnesses. At the age of 16 months, she was hospitalized with vomiting, diarrhea, and dehydration. Subsequently, she suffered recurrent episodes of vomiting, abdominal cramps, and diarrhea which usually responded to a clear liquid diet. At five years of age, she developed intermittent skin rashes over the lower extremities, which were thought to be allergic in origin. These persisted over the next several years during which time chronic abdominal pain became a major problem. At the age of 11 years, she developed severe abdominal pain, vomiting, and
778
Brief clinical and laboratory observations
The Journal of Pediatrics May 1977
Table I. Post-heparin triglyceride tipase activity
grnoles FFA /mUhr Protamine ] Protamine inactivated resistant Patient L . M . Controls (girls, ages 7-16) Type I hyperlipoproteinemia
8.9 3.8 +_ 1.1 0.1 +_ 0.1
10.4 11.1 _+ 3.8 10.5 +_ 3.8
Table II. Fasting serum lipids in the family members of Patient L. M.
Mr. M Mrs. M Siblings B. M. (female, age 17) G. M. (female, age 15) V. M. (female, age 13)
Cholesterol (normal." 135-315)
Triglycerides (normal." 30-135)
i85 264
86 170
119 131 105
28 76 185
Center of Children's Memorial Hospital. At this time, her serum cholesterol was 129 mg/dl (normal: 135 to 315) and her triglycerides were 192 mg/dl (normal: 30 to 135). Lipoprotein electrophoresis revealed a normal pattern. A complete blood count and urinalysis were unremarkable. Blood urea nitrogen was 13 mg/dl, creatinine, 0.7 mg/dl; uric acid, 5.1 mg/dl; calcium, 4.7 mEq/1; all were within normal limits. An oral glucose tolerance test revealed a normal response. Thyroxine was 5.6 ug/dl (normal: 2 to 7.5), and anti-nuclear antibody was negative. Quantitative immunoglobulins were all within normal limits, and immunoglobulin electrophoresis was unremarkab!e. Serum lipoproteins were examined in family members and are listed in Table II. The mother and one sibling exhibited mild elevations of serum triglycerides; all family members were asymptomatic. Following completion of these studies, a regular diet was resumed in an attempt to document the diagnosis of type I hyperlipoproteinemia. Within six weeks, eruptive xanthomata appeared on the lower extremities. Serum cholesterol at this time was 225 mg/dl (normal: 20 to 230 mg/dl) and triglycerides 1,645 mg/dl (normal: 10 to 140). Lipoprotein electrophoresis again revealed a type I phenotype. A fat-free diet was resumed, and the patient has remained asymptomatic. DISCUSSION
fever and was hospitalized with a presumptive diagnosis of peritonitis secondary to a ruptured appendix. At laparotomy, she was found to have acute pancreatitis and an abdomen filled with a creamy white sterile fluid. A clinicaI diagnosis of type I hyperiipoprotememia was made at this time. The postoperative course was uneventful: following resumption of a regular diet. serum lipids were measured. On a regular diet, serum cholesterol was 230 mg/dl (normal: 120 to 230) and triglycerides were 1.785 mg/dl (normal: 10 to 140). Lipoprotein electrophoresis revealed a type 1 phenotype (hyperchYlomicronemia). Upon standing for 18 hours at 4~ the plasma separated into a thick creamy supernatant layer with a clear infranatant layer. A diet with fat intake restricted to 10 gm/ day was prescribed. The skin lesions disappeared and there were no recurrences of abdominal pain. Eight months following institution of the diet, she was referred to Children's Memorial Hospital for evaluation. At this time. the physical examination was unremarkable. Serum cholesterol was 103 mg/dl (normal: 114 to 209) and triglycerides were 258 mg/dl (normal: 10 to 140). To confirm the diagnosis of type I hyperlipoproteinemia, post-heparin lipolytic activity was measured. Intravenous heparin. 100 u/kg, was administered and blood samples were collected in EDTA at 0 timel 15, 30. and 45 minutes. These samples were assayed for protamine-inactivated and protamine-resistant triglyceride lipase activity by Dr. Peter Herbert of The National Institutes of Health. The protamine-inactivated activity represents the lipoprotein lipase of adipose tissue origin that is deficient in patients with type I hyperlipoproteinemja whereas the protamine-resistant activity, of hepatic origin, is normal in affected individuals.4 The peak activity in patient L. M. is presented in Table I with the comparable values in normal and affected individuals. Following the demonstration of normal lipoprotein lipase activity, patient L. M. was admitted to the Clinical Research
The results of the protamine inactivated triglyceride lipase assay dearly indicate that patient L.M. does not have a deficiency of plasma lipoprotein lipase activity. Her peak activity as illustrated in Table I is actually higher than the values derived for age-matched controls, although this may simply reflect the higher dose of heparin used in obtaining her samples than is usually utilized in this test. A dose of 10 g/kg is routinely employed in these studies but higher doses have failed to r e l e a s e s i g n i f i c a n t levels of activity in patients with lipoprotein lipase deficiency.' Type I hyperlipoproteinemia may be difficult to differentiate from type V on the basis of electrophoretic pattern alone. The appearance of patient L. M.'s plasma at 4~ and her response to a fat-restricted diet, however, are typical of the type 1 patients and would be unusual in type V hyperlipoproteinemia. Phenocopies of type I hyperlipoproteinemia have been reported in a n u m b e r of disorders including lymphoma and systemic lupus erythematosis with dysglobulinem i a ? ; Phenocopies of other types of hyperlipoproteinemia have been observed with pancreatitis, ~ uncontrolled diabetes mellitus, '~ and hypothyroidism. TM The evaluation of our patient revealed no evidence for any of these disorders and the ten-year history makes all of these unlikely. It seems clear that the hyperlipoproteinemia in patient L.M. is a primary p h e n o m e n o n ; added support for this assumption is derived from the presence of hypertriglyceridemia in one of the parents and in one sibling, a finding that has been reported in heterozygotes for type I hyperlipoproteinemia.
Volume 90 Number 5
Brief clinical and laboratory observations
Thus, patient L. M. appears to be a unique example of primary type I hyperlipoproteinemia in a patient with normal lipoprotein lipase activity. One other patient with typical type I hyperlipoproteinemia was initially reported as having normal post-heparin lipolytic activity; with the development of separate assays for the various components of post-heparin lipolytic activity, however, he was found to have a deficiency of protamine inactivated triglyceride lipase with a relative increase in the protamineresistant lipase. 4 The combination of findings in our patient suggest that primary type I hyperlipoproteinemia may represent a heterogeneous group of disorders, only one of which is associated with a deficiency of lipoprotein lipase activity.
3.
4.
5. 6.
7.
We thank Dr. Peter N. Herbert of The National Institutes of Health for his help in performing the triglyceride lipase enzyme assay.
8.
REFERENCES
9.
1. Fredrickson DS, and Levy RI: Familial hyperlipoproteinemia, In Stanbury JB, Wyngaarden JB, and Fredrickson DS, editors: Metabolic basis of inherited disease, New York, 1975, McGraw-Hill Book Company, Inc, pp 545614. 2, Harlan WR, Winesett PS, and Wasserman AJ: Tissue
Combined yon Willebrand disease and Hageman factor
deficiency George R. Buchanan, M.D., Daniel M. Green, M,D., and Robert I. Handin, M.D.,* Boston,
Mass. From the Division of Hematology-Oncology of the Department Of Medicine, Children's Hospital Medical Center, Division of Hematology, Department of Medicine, Peter Bent Brigham Hospital, and the Departments of Pediatrics and Medicine, Harvard Medical School Supported by United States Public Health Service Grant Nos. HL 05581, HL 17513, and HL 05392.
10.
779
lipoprotein lipase in normal individuals and in individuals with exogenous hypertriglyceridemia and the relationship of this enzyme to assimilation of fat, J Clin Invest 46:239, 1967. Schreibman PH, Arons DL, Saudek CD, and Arky RA: Abnormal lipoprotein lipase in familial exogenous hypertriglyceridemia, J Clin Invest 52:2075, 1973. Krauss RM, Levy RI, and Fredrickson DS: Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia, J Clin Invest 54:1107, 1974. Motulsky AG: The genetic hyperlipidemias, N Engl J Med 294:823, 1976. Glueck CJ, Kaplan AP, Levy RL Greten H, Ga'alnick H, and Fredrickson DS: A new mechanism of exogenous hyperglyceridemia, Ann Intern Med 71:1051, 1969. Glueck CJ, Levy RI, Glueck HI, Gralnick HR, Greten H, and Fredrickson DS: Acquired type I hyperlipoproteinemia with systemic lupus erythematosus, dysglobulinemia and heparin resistance, Am J Med 47:318, 1969. Kessler JI, Kniffen JC, and Janowitz HD: Lipoprotein lipase inhibition in the hyperlipemia of acute alcoholic pancreatitis, N Engl J Med 269:943, 1963. Bierman EL, Bagdade JD, and Porte D: A concept of the pathogenesis of diabetic lipemia, Trans Assoc Am Physicians 79:348, 1966. Porte D, O'Hara DD, and Williams RH: The relation between postheparin lipolytic activity and plasma triglyceride in myxedema, Metabolism 15:107, 1966.
COMBtNAa'IONS of hemophilia A or yon Willebrand disease with other clotting factor deficiencies', '-' or with intrinsic platelet abnormalities 3~' have been observed but are probably chance events in most circumstances. Several patients have been described who have evidence of VWD and slightly decreased levels Of Factor XII (Hageman factor)." Unfortunately, family studies were not performed to document joint inheritance of the two defects. We describe a child who has both VWD and Hageman factor deficiency, with a similar defect in the patient's father, suggesting linked auiosomal dominant transmission of both disorders.
Abbreviations used VWD: von Willebrand disease PTT: activated partial thromboplastin time VIIIvwv: plasma levels of yon Willebrand factor VIIIAc~x: Factor VIII antigen
*Cancer Research Scholar, Massachusetts Division American
Cancer Society. Reprint address: George R. Buchanan, M.D.. Division of Hematologv-Oncology, Children"s Hospital Medical Center. 300 Longwood Ave., Boston, MA 02114.
CASE REPORT
Patient C.R. is a 6-year-old white girl who was noted to have a long activated partial thr0mboplastin time. There was no history