© 1991 Karger A G . Basel 0011-9075/91/1822-0094 $2.75/0
Dermatológica 1991;182:94-97
Pseudohomozygous Type II Hyperlipoproteinemia M. Fujita", 5. Okamotoa, K. Shirat’, Y. Saitob, S. Yoshidah 'Department of Dermatology and '’2nd Department of Internal Medicine, School of Medicine, Chiba University, Chiba. Japan
Key Words. Pseudohomozygosity • Hyperlipoproteinemia ■Low-density lipoprotein receptor ■Xanthoma
In 1974. Morganroth et al. [1] reported on 2 patients with type II hyperlipoproteinemia and planar xanthoma in early childhood. Although the findings were consistent with the homozygous type of familial hypercholesterol emia (FHC), the family history and responsiveness to diet and drug therapy were quite different from FHC so that the term o f ‘pseudohomozygous type II hyperlipoprotein emia’ was proposed. There are a few reports describing similar cases, but the cause of this type of hypercholester olemia and xanthoma formation has not been studied. We report a case of pseudohomozygous type II hyperlipopro teinemia with normal low-density lipoprotein (LDL) receptor activity in fibroblasts.
Case Report A 4-year-old girl came to our hospital because of multiple xantho mas. She had normal growth and development. There was no family history of hypercholesterolemia (father: cholesterol 200 mg/dl. triglyc eride 54 mg/dl; mother: cholesterol 161 mg/dl. triglyceride 49 mg/dl;
elder sister; cholesterol 202 mg/dl. triglyceride 73 mg/dl). ischemic heart disease or diabetes mellitus. nor was there any record of consan guinity for three generations. She was noticed by her mother to have flat yellow streaks on the intergluteal area at 12 months of age. Hyper cholesterolemia was identified at 18 months of age. When she came to our hospital, she had streak-like xanthomas on the intergluteal area (fig. 1), both hand joints, popliteal fossae, dorsal surface of the feet and Achilles tendon areas, and also nodular xanthomas on both elbows, each7x7and 1 x 8 mm in size (fig. 2). Yet she had neither xanthelasma nor tendon xanthoma. She was poorly developed (height: 92 cm, weight: 13 kg) for her age. No abnormal physical trait was observed. Scrum lipid analysis was as follows: total cholesterol 327 mg/dl (normal value 130-250), free cholesterol 95 mg/dl (40-80), triglyceride 83 mg/dl (55-130), phospholipids 257 mg/dl (150-230). Lipoprotein lipids were determined by the method of Bronzert [2]: very-low-density lipoprotein (VLDL) cholesterol 45 mg/dl (22±10), LDL cholesterol 284 mg/dl (116±25), high-density lipoprotein (HDL) cholesterol 47 mg/dl (52± 11), VLDL triglyceride 43 mg/dl (80±22). LDL triglyceride 47 mg/dl (29± 16). HDL triglyceride 42 mg/dl (23±8). Plasma apolipoprotein was determined by the immunoturbidimetric method using a kit obtained from Daiichi Kagaku Co. (Japan) [3]: Al 136 mg/dl (95-180), All 26 mg/dl (20-40), B 151 mg/dl (45-125). C1I 4.1 mg/dl (1.1-5.0). CIII 8.0 mg/dl (4.0-14.0) and E 6.6 mg/dl (2.2-6.4). The apolipoprotein E phenotype was 3/3.
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
Abstract. Nodular xanthomas on both elbows and a streak-like xanthoma on the intergluteal area developed in a 4year-old girl with type Ila hyperlipoproteinemia. She had no disease associated with secondary hypercholesterolemia and no family history of hypercholesterolemia. Her xanthomas regressed under fat restriction diet and cholestyramine therapy. She was diagnosed as having pseudohomozygous type II hyperlipoproteinemia. The low-density lipoprotein (LDL) receptor activities of her cultured fibroblasts in terms of binding, internalization and degradation rate of LDL were normal. These results arc consistent with a new syndrome of pseudohomozygous type II hyperlipoproteinemia and suggest that the mechanism of hypercholesterolemia, which induced xanthoma, differs from familial hypercholes terolemia.
Pseudohomozygous Type II Hyperlipoproteinemia
The following blood laboratory assays were within the normal limits: peripheral blood count, hemogram, glutamic oxaloacetic trans aminase, glutamic pyruvic transaminase, lactic dehydrogenase, alka line phosphatase, blood urea nitrogen, uric acid, bilirubin, erythrocyte sedimentation rate. Urinalysis, an electrocardiogram and a roentgeno gram of the chest were also within the normal limits. Histologic Findings
A nodular xanthoma on the right elbow was examined. The epider mis was almost normal, except for some atrophy. There were nests of foam cells in the entire dermis. These cells were stained yellow-brown by the Sudan III stain. Touton's giant cells and inflammatory infiltrate were not observed. In the peripheral part, incipient infiltration of foam cells seemed to have occurred in the perivascular areas. L D L Receptor Activity in Cultured Fibroblasts
The LDL receptor activities of the patient’s fibroblasts were investigated. The fibroblasts were obtained from a biopsy at the periph ery of the lesion on her right elbow and cultured in Dulbecco’s modi fied Eagle’s (DME) (Gibco) culture medium containing 10% fetal calf serum. Three criteria of LDL metabolism were checked at the cell level according to the method of Goldstein et al. [5]: (1) LDL-binding activ ity of LDL receptor at the cell surface (binding capacity of [!H]cholesterol LDL at 4 °C; fig. 3a), (2) internalization (cholesterol synthesis inhibition from [1JC]acetate; fig.3b), (3) degradation (cholesterol esterification rate from [l4C]oleate; fig. 3c). The results shown in figure 3a-c indicate that her fibroblasts were not different from normal fibro blasts. Binding of the patient’s LDL to control fibroblasts was also normal (data not shown).
Fig. 2. Nodular xanthoma on her left elbow.
Therapy and Course
The course of her condition is shown in figure4. Plasma cholesterol ranged from 324 to 356 mg/dl prior to the low-cholesterol diet. After 4 months of low-cholesterol diet therapy consisting of cholesterol 400 mg/day and total energy 35 keal/kg/day, plasma cholesterol had decreased to 247 mg/dl. Cholestyramine resin (2 g/day) was then administered in addition to the diet therapy. Plasma cholesterol fell down to 156 mg/dl. and the xanthomas regressed in all areas except the intergluteal one.
Discussion Xanthomas occur in various types of hyperlipoprotein emia, the most frequent being FHC. Clinically FHC is characterized by an elevation of the LDL plasma level, development of xanthomas, ischemic heart disease and autosomal heredity. There is a considerable difference in the occurrence of xanthomas between homozygotes and heterozygotes. In homozygotes, xanthomas are noted in mostly all cases at birth or during the first decade. In het erozygotes. xanthomas are usually observed after the age of 10 or 20 years. FHC is known to be due to LDL receptor deficiency as shown by Goldstein and Brown [4]. Morganroth et al. [1] reported on 2 children with xan thomas and hypercholesterolemia suggesting homozy-
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
Fig. 1. Streak-like xanthoma in the intergluteal area.
95
96
Fujita/Okamoto/Shirai/Saito/Yoshida
Day
□
(-)
Fig. 3a-c. LDL metabolism of her cultured fibroblasts, a Binding capacity of LDL cholesterol, b Cholesterol synthesis from [IJC]acetate. c Cholesterol ester synthesis from [IJC]oleic acid.
gous FHC. but their parents had no lipid abnormalities. Mishkel [6] reported a similar case and also a case with hyperlipoproteinemia without xanthoma. This prompted him to use the term of ‘pseudohomozygous et heterozy gous type 11 hyperlipoproteinemia’. Hamada el al. [7| summarized the characteristics of this disease as follows: (1) the occurrence of xanthoma, with serum lipid and lipo protein patterns compatible with those of homozygous FHC. (2) no lipid abnormality in parents and relatives, (3) potential secondary causes of hypercholesterolemia excluded, (4) the combined use of diet and cholestyr amine producing an extreme reduction of serum total cholesterol, thus causing the xanthomas to regress and disappear. The clinical features or our case met these criteria. Then we examined the LDL receptor activities of the patient’s fibroblasts. As shown in figure3a-c, her fi broblasts were not different from normal fibroblasts. Hamada et al. (7] had already reported that no abnormal ity in the fibroblasts of pseudohomozygous type II hy perlipoproteinemia could be detected. Goldstein and Brown [4] stated that the fibroblasts from the 2 patients reported by Morganroth et al. [1) had normal activities. Our results are in accordance with these observations. These findings suggest that the mechanism by which hyper cholesterolemia develops in pseudohomozygous type II hyperlipoproteinemia is different from that of FHC. The type of xanthoma in pseudohomozygous type II hyperlipoproteinemia has not been precisely analyzed. Morganroth ct al. [1] stated that the xanthoma was pla-
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
Fig. 4. Clinical course. • =Total cholesterol; 0 = triglyceride.
97
Pseudohomozygous Type II Hyperlipoproteinemia
References 1 Morganroth J . Levy RI. McMahorn AE. Gotto A M : Pseudohomo zygous type II hyperlipoproteinemia. J Pediatr 1974;85:639-643. 2 Bronzcrt TJ. Brewer HB: New micromethods for measuring cholesterol in plasma lipoprotein fraction. Clin Chcm 1977:23: 2089-2098.
3 Goto Y. Akanuma Y. Harano Y. et al: Determination by the SRID method of normal values of serum apolipoprotein (A-I, A-II. B. CILC-IIl and E)in normolipidemic healthy Japanese subjects. J Clin Biochem Nutr 1986:1:73-83. 4 Goldstein JL, Brown MS: The LDL receptor locus and the genetics of familial hypercholesterolemia. Annu Rev Genet 1979:13: 259-289. 5 Goldstein JL. Basu SK, Brown MS: Rcccptor-mcdiated endocytosis of LDL in cultured cells. Methods Enzymol 1983:98:241-260. 6 Mishkel MA: Pseudohomozygous and pseudoheterozygous type II hyperlipoproteinemia. Am J Dis Child 1976:130:991-993. 7 I lamada K. Tanaka T. Yoshii O. et al: Pseudohomozygous type II hyperlipoproteinemia. Jpn J Hum Genet 1976:27:259-264. 8 Mabuchi A. Iki M. Hasegawa Y, Yasuhara M: Each case of pseudo heterozygous and pseudohomozygous type lia hyperlipoprotein emia (in Japanese). Hifu 1984:26:1223-1232.
Received: May 29. 1990 Accepted: August 31. 1990 Dr. Masru Fujita Department of Dermatology School of Medicine Chiba University inohana 1-8-1. Chiba 280 (Japan)
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
nar. Mishkel [6], however, noted that it was a streak-like xanthoma in neonatal clefts. Streak-like xanthoma in the intergluteal area, antecubital fossae or popliteal fossae have also been observed in the first case of Morganroth et al. [ 1], in MishkcTscase [6], in the second case of Mabuchi ct al. [8] and in our case. On the other hand, cases with xanthoma formation on both the flexural and extension sides of the extremities (the dorsal side of hands and Achilles tendon areas) have been seen, as in the second case of Morganroth et al. [1], in the case of Hamada et al. [7] and in the second case of Mabuchi etal. [8], Yet nodu lar xanthoma has been observed in ours and the first case of Mabuchi ct al. [8]. No cases of xanthelasma and tendon xanthoma have been reported. Therefore it may be assumed that the type of xanthoma diagnosed as pseudohomozygous type II hyperlipoproteinemia is different from FHC.
Dermatológica 1991;182:94-97
Pseudohomozygous Type II Hyperlipoproteinemia M. Fujita", 5. Okamotoa, K. Shirat’, Y. Saitob, S. Yoshidah 'Department of Dermatology and '’2nd Department of Internal Medicine, School of Medicine, Chiba University, Chiba. Japan
Key Words. Pseudohomozygosity • Hyperlipoproteinemia ■Low-density lipoprotein receptor ■Xanthoma
In 1974. Morganroth et al. [1] reported on 2 patients with type II hyperlipoproteinemia and planar xanthoma in early childhood. Although the findings were consistent with the homozygous type of familial hypercholesterol emia (FHC), the family history and responsiveness to diet and drug therapy were quite different from FHC so that the term o f ‘pseudohomozygous type II hyperlipoprotein emia’ was proposed. There are a few reports describing similar cases, but the cause of this type of hypercholester olemia and xanthoma formation has not been studied. We report a case of pseudohomozygous type II hyperlipopro teinemia with normal low-density lipoprotein (LDL) receptor activity in fibroblasts.
Case Report A 4-year-old girl came to our hospital because of multiple xantho mas. She had normal growth and development. There was no family history of hypercholesterolemia (father: cholesterol 200 mg/dl. triglyc eride 54 mg/dl; mother: cholesterol 161 mg/dl. triglyceride 49 mg/dl;
elder sister; cholesterol 202 mg/dl. triglyceride 73 mg/dl). ischemic heart disease or diabetes mellitus. nor was there any record of consan guinity for three generations. She was noticed by her mother to have flat yellow streaks on the intergluteal area at 12 months of age. Hyper cholesterolemia was identified at 18 months of age. When she came to our hospital, she had streak-like xanthomas on the intergluteal area (fig. 1), both hand joints, popliteal fossae, dorsal surface of the feet and Achilles tendon areas, and also nodular xanthomas on both elbows, each7x7and 1 x 8 mm in size (fig. 2). Yet she had neither xanthelasma nor tendon xanthoma. She was poorly developed (height: 92 cm, weight: 13 kg) for her age. No abnormal physical trait was observed. Scrum lipid analysis was as follows: total cholesterol 327 mg/dl (normal value 130-250), free cholesterol 95 mg/dl (40-80), triglyceride 83 mg/dl (55-130), phospholipids 257 mg/dl (150-230). Lipoprotein lipids were determined by the method of Bronzert [2]: very-low-density lipoprotein (VLDL) cholesterol 45 mg/dl (22±10), LDL cholesterol 284 mg/dl (116±25), high-density lipoprotein (HDL) cholesterol 47 mg/dl (52± 11), VLDL triglyceride 43 mg/dl (80±22). LDL triglyceride 47 mg/dl (29± 16). HDL triglyceride 42 mg/dl (23±8). Plasma apolipoprotein was determined by the immunoturbidimetric method using a kit obtained from Daiichi Kagaku Co. (Japan) [3]: Al 136 mg/dl (95-180), All 26 mg/dl (20-40), B 151 mg/dl (45-125). C1I 4.1 mg/dl (1.1-5.0). CIII 8.0 mg/dl (4.0-14.0) and E 6.6 mg/dl (2.2-6.4). The apolipoprotein E phenotype was 3/3.
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
Abstract. Nodular xanthomas on both elbows and a streak-like xanthoma on the intergluteal area developed in a 4year-old girl with type Ila hyperlipoproteinemia. She had no disease associated with secondary hypercholesterolemia and no family history of hypercholesterolemia. Her xanthomas regressed under fat restriction diet and cholestyramine therapy. She was diagnosed as having pseudohomozygous type II hyperlipoproteinemia. The low-density lipoprotein (LDL) receptor activities of her cultured fibroblasts in terms of binding, internalization and degradation rate of LDL were normal. These results arc consistent with a new syndrome of pseudohomozygous type II hyperlipoproteinemia and suggest that the mechanism of hypercholesterolemia, which induced xanthoma, differs from familial hypercholes terolemia.
Pseudohomozygous Type II Hyperlipoproteinemia
The following blood laboratory assays were within the normal limits: peripheral blood count, hemogram, glutamic oxaloacetic trans aminase, glutamic pyruvic transaminase, lactic dehydrogenase, alka line phosphatase, blood urea nitrogen, uric acid, bilirubin, erythrocyte sedimentation rate. Urinalysis, an electrocardiogram and a roentgeno gram of the chest were also within the normal limits. Histologic Findings
A nodular xanthoma on the right elbow was examined. The epider mis was almost normal, except for some atrophy. There were nests of foam cells in the entire dermis. These cells were stained yellow-brown by the Sudan III stain. Touton's giant cells and inflammatory infiltrate were not observed. In the peripheral part, incipient infiltration of foam cells seemed to have occurred in the perivascular areas. L D L Receptor Activity in Cultured Fibroblasts
The LDL receptor activities of the patient’s fibroblasts were investigated. The fibroblasts were obtained from a biopsy at the periph ery of the lesion on her right elbow and cultured in Dulbecco’s modi fied Eagle’s (DME) (Gibco) culture medium containing 10% fetal calf serum. Three criteria of LDL metabolism were checked at the cell level according to the method of Goldstein et al. [5]: (1) LDL-binding activ ity of LDL receptor at the cell surface (binding capacity of [!H]cholesterol LDL at 4 °C; fig. 3a), (2) internalization (cholesterol synthesis inhibition from [1JC]acetate; fig.3b), (3) degradation (cholesterol esterification rate from [l4C]oleate; fig. 3c). The results shown in figure 3a-c indicate that her fibroblasts were not different from normal fibro blasts. Binding of the patient’s LDL to control fibroblasts was also normal (data not shown).
Fig. 2. Nodular xanthoma on her left elbow.
Therapy and Course
The course of her condition is shown in figure4. Plasma cholesterol ranged from 324 to 356 mg/dl prior to the low-cholesterol diet. After 4 months of low-cholesterol diet therapy consisting of cholesterol 400 mg/day and total energy 35 keal/kg/day, plasma cholesterol had decreased to 247 mg/dl. Cholestyramine resin (2 g/day) was then administered in addition to the diet therapy. Plasma cholesterol fell down to 156 mg/dl. and the xanthomas regressed in all areas except the intergluteal one.
Discussion Xanthomas occur in various types of hyperlipoprotein emia, the most frequent being FHC. Clinically FHC is characterized by an elevation of the LDL plasma level, development of xanthomas, ischemic heart disease and autosomal heredity. There is a considerable difference in the occurrence of xanthomas between homozygotes and heterozygotes. In homozygotes, xanthomas are noted in mostly all cases at birth or during the first decade. In het erozygotes. xanthomas are usually observed after the age of 10 or 20 years. FHC is known to be due to LDL receptor deficiency as shown by Goldstein and Brown [4]. Morganroth et al. [1] reported on 2 children with xan thomas and hypercholesterolemia suggesting homozy-
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
Fig. 1. Streak-like xanthoma in the intergluteal area.
95
96
Fujita/Okamoto/Shirai/Saito/Yoshida
Day
□
(-)
Fig. 3a-c. LDL metabolism of her cultured fibroblasts, a Binding capacity of LDL cholesterol, b Cholesterol synthesis from [IJC]acetate. c Cholesterol ester synthesis from [IJC]oleic acid.
gous FHC. but their parents had no lipid abnormalities. Mishkel [6] reported a similar case and also a case with hyperlipoproteinemia without xanthoma. This prompted him to use the term of ‘pseudohomozygous et heterozy gous type 11 hyperlipoproteinemia’. Hamada el al. [7| summarized the characteristics of this disease as follows: (1) the occurrence of xanthoma, with serum lipid and lipo protein patterns compatible with those of homozygous FHC. (2) no lipid abnormality in parents and relatives, (3) potential secondary causes of hypercholesterolemia excluded, (4) the combined use of diet and cholestyr amine producing an extreme reduction of serum total cholesterol, thus causing the xanthomas to regress and disappear. The clinical features or our case met these criteria. Then we examined the LDL receptor activities of the patient’s fibroblasts. As shown in figure3a-c, her fi broblasts were not different from normal fibroblasts. Hamada et al. (7] had already reported that no abnormal ity in the fibroblasts of pseudohomozygous type II hy perlipoproteinemia could be detected. Goldstein and Brown [4] stated that the fibroblasts from the 2 patients reported by Morganroth et al. [1) had normal activities. Our results are in accordance with these observations. These findings suggest that the mechanism by which hyper cholesterolemia develops in pseudohomozygous type II hyperlipoproteinemia is different from that of FHC. The type of xanthoma in pseudohomozygous type II hyperlipoproteinemia has not been precisely analyzed. Morganroth ct al. [1] stated that the xanthoma was pla-
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
Fig. 4. Clinical course. • =Total cholesterol; 0 = triglyceride.
97
Pseudohomozygous Type II Hyperlipoproteinemia
References 1 Morganroth J . Levy RI. McMahorn AE. Gotto A M : Pseudohomo zygous type II hyperlipoproteinemia. J Pediatr 1974;85:639-643. 2 Bronzcrt TJ. Brewer HB: New micromethods for measuring cholesterol in plasma lipoprotein fraction. Clin Chcm 1977:23: 2089-2098.
3 Goto Y. Akanuma Y. Harano Y. et al: Determination by the SRID method of normal values of serum apolipoprotein (A-I, A-II. B. CILC-IIl and E)in normolipidemic healthy Japanese subjects. J Clin Biochem Nutr 1986:1:73-83. 4 Goldstein JL, Brown MS: The LDL receptor locus and the genetics of familial hypercholesterolemia. Annu Rev Genet 1979:13: 259-289. 5 Goldstein JL. Basu SK, Brown MS: Rcccptor-mcdiated endocytosis of LDL in cultured cells. Methods Enzymol 1983:98:241-260. 6 Mishkel MA: Pseudohomozygous and pseudoheterozygous type II hyperlipoproteinemia. Am J Dis Child 1976:130:991-993. 7 I lamada K. Tanaka T. Yoshii O. et al: Pseudohomozygous type II hyperlipoproteinemia. Jpn J Hum Genet 1976:27:259-264. 8 Mabuchi A. Iki M. Hasegawa Y, Yasuhara M: Each case of pseudo heterozygous and pseudohomozygous type lia hyperlipoprotein emia (in Japanese). Hifu 1984:26:1223-1232.
Received: May 29. 1990 Accepted: August 31. 1990 Dr. Masru Fujita Department of Dermatology School of Medicine Chiba University inohana 1-8-1. Chiba 280 (Japan)
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 7:55:38 PM
nar. Mishkel [6], however, noted that it was a streak-like xanthoma in neonatal clefts. Streak-like xanthoma in the intergluteal area, antecubital fossae or popliteal fossae have also been observed in the first case of Morganroth et al. [ 1], in MishkcTscase [6], in the second case of Mabuchi ct al. [8] and in our case. On the other hand, cases with xanthoma formation on both the flexural and extension sides of the extremities (the dorsal side of hands and Achilles tendon areas) have been seen, as in the second case of Morganroth et al. [1], in the case of Hamada et al. [7] and in the second case of Mabuchi etal. [8], Yet nodu lar xanthoma has been observed in ours and the first case of Mabuchi ct al. [8]. No cases of xanthelasma and tendon xanthoma have been reported. Therefore it may be assumed that the type of xanthoma diagnosed as pseudohomozygous type II hyperlipoproteinemia is different from FHC.
