Migratory polyarthritis in familial hypercholesterolemia (type IIa hyperlipoproteinemia)

Metabolic disorders are often encountered in clinical practice. Some of these diseases are associated with dermatological and musculoskeletal manifestations. Familial hypercholesterolemia is a disorder of lipoprotein metabolism characterized by elevated cholesterol, low-density lipoprotein cholesterol, xanthomas and early onset atherosclerosis. Tendinitis and arthritis have been rarely reported in patients with familial hypercholesterolemia. Here is presented a case of a young girl with migratory polyarthritis, who was diagnosed as probable homozygote familial hypercholesterolemia with hypercholesterolemic arthritis. A proper knowledge of cutaneous manifestations helps to identify patients at risk, establish the underlying diagnosis, and start early and effective therapy.     

Squalene and noncholesterol sterols in serum and lipoproteins of children with and without familial hypercholesterolemia

Squalene and noncholesterol sterols, e.g. lathosterol and plant sterols, the respective markers of cholesterol synthesis and absorption, are transported with cholesterol in serum lipoproteins. Their concentrations and ratios to cholesterol in serum and lipoproteins have not been carefully compared, especially in children and in marked hypercholesterolemia. Thus, we measured these variables with gas-liquid chromatography in 18 children with and 29 without familial hypercholesterolemia, all aged 5-17 y. Concentrations of most noncholesterol sterols were higher in serum, LDL, and intermediate density lipoprotein in the children with than those without familial hypercholesterolemia. Despite accumulation of noncholesterol sterols mainly in LDL (75% in familial hypercholesterolemia and 55% in non-familial hypercholesterolemia, p < 0.001), their ratios were mostly similar in serum and lipoproteins of the two groups. The ratios of squalene and lathosterol were higher in VLDL and intermediate density lipoprotein, whereas in LDL that of lathosterol was lower than the respective serum values in both groups. Absorption marker sterol ratios were highest in HDL in both groups. Thus, even though the ratios of noncholesterol sterols to cholesterol in serum reflect, in general, synthesis and absorption of cholesterol, their ratios in different lipoproteins could give additional information of cholesterol metabolism.     

Usefulness of serum apolipoprotein B levels for screening children with primary dyslipoproteinemias.

OBJECTIVE--To assess the use of serum apolipoprotein B levels for screening children with primary dyslipoproteinemia (those with elevated levels of low-density lipoprotein cholesterol [LDL-C]) and to know the types of dyslipoproteinemias we can identify. DESIGN--Criterion standard. SETTING--Referral center. PARTICIPANTS--We have studied 267 children. Of these, 31 had parents with dyslipoproteinemia, 38 had parents with ischemic heart disease, and 43 had hypercholesterolemia detected by routine analyses. One hundred fifty-five were considered healthy children and comprised the control group. INTERVENTIONS--None. MEASUREMENTS AND MAIN RESULTS--Sensitivity was 87% for total serum cholesterol levels and 73% for serum apolipoprotein B levels. Of the children studied, 31 had elevated levels of serum LDL-C. The types of dyslipoproteinemia in children with both elevated levels of serum LDL-C and apolipoprotein B consisted of heterozygous familial hypercholesterolemia, found in 12 (50%) of 24 patients; familial combined hyperlipidemia, found in 11 (46%) of 24 patients; and polygenic hypercholesterolemia, found in one (4%) of 24 patients. CONCLUSIONS--Serum apolipoprotein B level appears to be a good tool for screening children with elevated levels of LDL-C and is equivalent to using total serum cholesterol levels. In children with elevated serum LDL-C and apolipoprotein B levels, we can identify not only patients with heterozygous familial hypercholesterolemia but also those with familial combined hyperlipidemia or polygenic hypercholesterolemia.     

THE FATTY ACID COMPOSITION OF SERUM LOW DENSITY LIPOPROTEIN- AND LYMPHOCYTE CHOLESTEROL ESTERS IN CHILDREN WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

Abstract. Andersen, G. E. and Johansen, K. B. (The Neonatal Department, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark). Fatty acid composition of serum low density lipoprotein- and lymphocyte cholesterol esters in children with heterozygous familial hypercholesterolemia. Acta Paediatr Scand, 69:453, 1980.—The content of free and esterified cholesterolin serum low density lipoprotein (LDL) was measured in 19 children with heterozygous familial hypercholesterolemia (FH) and in 10 normal siblings. In FH both free and esterified cholesterol were found to be elevated. Furthermore the fatty acid composition of serum LDL- and lymphocyte cholesterol esters was determined. However, no difference was found between FH heterozygotes and normals thus indicating that LDL-hypocatabolism typically found in FH does not correlate with an abnormal fatty acid composition of LDL-cholesterol esters nor with an impaired cholesterol esterification intracellularly in lymphocytes.     

Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate.

Seven prepubertal children (age range 5.3 to 10.8 years) with severe heterozygous familial hypercholesterolemia (serum cholesterol concentration 416 +/- 85 mg/dL and low-density lipoprotein [LDL] cholesterol concentration 360 +/- 90 mg/dL) were first treated by dietary intervention, second by sitosterol (3 x 2 g/d), and third by bezafibrate (2 x 200 mg/d). Each treatment period lasted 3 months. Subsequently, a treatment combining half the dose of sitosterol and bezafibrate was administered for the following 24 months. Diet alone reduced total and LDL cholesterol values by 4.5% (not significant) and 6.6% (P less than .05), respectively. Sitosterol lowered total and LDL cholesterol values by 17% (P less than .05) when compared with diet alone. Compared with sitosterol, bezafibrate produced a more pronounced effect on total and LDL cholesterol values (-18% and -28%, P less than .05), and high-density lipoprotein cholesterol concentration increased significantly from 48 mg/dL to 55 mg/dL. Combined treatment with half the dose each of sitosterol and bezafibrate was as effective as the higher dose of bezafibrate, and reduction averaged almost 40% and 50% for total and LDL cholesterol values; this lipid-lowering effect persisted for the next 24 months. Laboratory safety parameters and physical examination revealed no obvious side effects. This study indicates that the combination of sitosterol (3 x 1 g/d) plus bezafibrate (1 x 200 mg/d) is an alternate, acceptable, safe, and effective therapeutic approach for treatment of severe hypercholesterolemia in children with high-risk familial hypercholesterolemia.     

The effect of oral calcium carbonate administration on serum lipoproteins of children with familial hypercholesterolaemia (type II-A)

The effect of oral calcium carbonate on serum lipoprotein concentrations was tested in 50 children with familial hypercholesterolemia (type II-A) consuming a low cholesterol high polyunsaturated fat diet, using a cross-over design versus a placebo. Cholesterol was measured in serum and in the individual lipoprotein density classes. Serum apolipoprotein B (the protein moiety of low density lipoprotein) and apolipoprotein A-I (the main protein of high density lipoprotein) were measured by specific immunoassays. Calcium carbonate treatment induced only a slight increase in serum apolipoprotein A-I (+4%) and a slight decrease in low density lipoprotein cholesterol (-4%), both changes being significant at the P=0.05 level.     

THE EFFECTS OF COLESTIPOL HYDROCHLORIDE ON SERUM LIPOPROTEIN LIPID AND APOLIPOPROTEIN B AND A-I CONCENTRATIONS IN CHILDREN HETEROZYGOUS FOR FAMILIAL HYPERCHOLESTEROLEMIA

ABSTRACT. Colestipol hydrochloride was administered to 28 children with familial hypercholesterolemia type II-A, and its effects on serum lipoproteins were tested against a placebo in a cross-over design. All children consumed a diet low in cholesterol and high in linoleic acid. Colestipol therapy resulted in a 15.7% decrease in serum very low plus low density lipoproteins and in a 13.5% decrease in serum apolipoprotein B. High density lipoprotein cholesterol, serum apolipoprotein A-I and serum triglycerides remained unaltered.     

An Infantile Case of Transient,Severe Hypercholesterolemia with Normalization after Complete Weaning from Breast-feeding

A 20-d-old boy was referred to our department because of hyperthyrotropinemia at neonatal mass screening and diagnosed with neonatal transient hyperthyrotropinemia. A follow-up examination when the patient was 5 mo old revealed severe hypercholesterolemia. Familial hypercholesterolemia was first suspected because of the patient’s significantly high levels of total and low-density lipoprotein cholesterol. The parent’s serum lipid profiles were examined and found to be normal. He was completely breast-fed until 6 mo of age. Breast milk was still the main source of food for a period following weaning. At 14 mo old, the patient was weaned completely from breast milk, and his serum cholesterol levels decreased dramatically. According to the normal lipid profiles of the patient’s parents and the spontaneous normalization of serum cholesterol levels after complete weaning from breast milk, breast-feeding was suggested to be responsible for his transient severe hypercholesterolemia. It is well documented that breast-fed infants have higher serum cholesterol levels than formula-fed infants. However, there is no reported case with severe hypercholesterolemia equivalent to or higher than the levels observed in the case of familial hypercholesterolemia. Although the exact mechanism is unknown, it is necessary to consider that a small number of cases develop severe hypercholesterolemia related to breast-feeding.     

Treatment of children with homozygous familial hypercholesterolemia: Safety and efficacy of low-density lipoprotein apheresis

We evaluated the safety and efficacy of dextran sulfate low-density lipoprotein (LDL) apheresis in the treatment of three children (aged 6, 7, and 10 years) with severe familial homozygous hypercholesterolemia and undetectable LDL receptor activity. A total of 35 double plasma volume procedures were performed. The ranges of the mean decreases of the three patients in plasma lipid concentrations after LDL apheresis (p less than 0.0001) were as follows: total cholesterol, 76% to 79%; LDL-cholesterol, 78% to 81%; very low density lipoprotein cholesterol, 69% to 75%; high-density lipoprotein cholesterol, 27% to 40%; and triglycerides, 34% to 68%. There were statistically significant but clinically and biologically irrelevant changes in hematologic indexes, serum chemistry values, immunoglobulin levels, complement activity, and plasma concentrations of fat-soluble vitamins. Simple correlation analysis of the variables affecting total cholesterol removal showed significant correlation coefficients (r values) for preapheresis total cholesterol values (r = 0.70; p less than 0.01) and preapheresis LDL-cholesterol values (r = 0.61; p less than 0.01). A multiple regression model explained 82% of the variance based on the preapheresis cholesterol concentration, volume of whole blood processed, and the serum albumin concentration. Side effects of the LDL-apheresis treatments were rare and included abdominal cramping and urticaria. Two procedures were aborted because of intravenous access problems in the younger children. This study confirms that LDL apheresis using a dextran sulfate affinity column is efficacious in rapidly lowering total and LDL-cholesterol concentrations. Furthermore, the procedure is safe and well tolerated by children as young as 6 years of age. This treatment may prevent the progression of atherosclerosis in children with homozygous familial hypercholesterolemia and may therefore avert early death.     

Effect of Continuous LDL Apheresis with Dextran-Sulfate Cellulose Column System on a Child with Homozygous Familial Hypercholesterolemia

A new system for selective low density lipoprotein apheresis with an automated regenerating column using dextran-sulfate (DS) as ligand was evaluated for six months in a 13-year-old boy homozygous for familial hypercholesterolemia. Two columns each containing 150 ml of DS cellulose were alternately used after rinsing with a regenerating solution. The patient could well tolerate the volume in the system. The values of plasma total cholesterol decreased by 79.4 ± 4.9% of the pretreatment levels after a total of 5ℓ plasma apheresis, while those of high density lipoprotein cholesterol did not change. Although the values of CH₅₀ decreased, no adverse reaction was seen during the period of treatment. It was concluded that the present apheresis system was highly efficacious and safe for children homozygous for the mutant LDL receptor gene.     

Homozygous familial hypercholesterolemia: case report of a rare cause of dyslipidemia

A 4-year-old boy was evaluated for severe hypercholesterolemia (cholesterol: 831 mg/dL) and disseminated xanthomas. Both parents had hypercholesterolemia: mother (cholesterol: 308 mg/dL) and father (cholesterol: 281 mg/dL). There was no family history of cardiovascular disease. Skin examination showed: intertriginous xanthomas of feet and hands, tuberous xanthomas in knees and elbows, tendinous xanthomas in Achilles tendon and xanthomas in the gluteal region, associated with corneal arc bilaterally. Laboratory work-up excluded secondary causes of hypercholesterolemia and a diagnosis of homozygous familial hypercholesterolemia was made. Echocardiogram showed bicuspid aortic valve and mild aortic insufficiency. Doppler ultrasound of carotid arteries and computerized tomography of the thorax for assessment of calcium scoring were normal. The patient's serum lipids were reduced by approximately 40% after a diet, atorvastatin and ezetimibe. Homozygous familial hypercholesterolemia is an important risk factor for atherosclerosis and premature coronary artery disease in children and young adults. Early diagnosis and treatment with screening of first-degree relatives is essential to minimize the progression of cardiovascular disease in these patients.     

Preemptive liver transplantation in a child with familial hypercholesterolemia

Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M, Monti L, Gennari F, Torre G, de Ville de Goyet J, Bartuli A. Preemptive liver transplantation in a child with familial hypercholesterolemia.
Pediatr Transplantation 2011: 15:E25–E29. © 2010 John Wiley & Sons A/S. Abstract: Familial hypercholesterolemia is an autosomal codominant disorder associated with markedly elevated plasma concentration of LDL‐cholesterol and increased cardiovascular risk. Homozygous patients have rapid development of atherosclerosis with death from cardiovascular disease even in childhood. Life‐long recurrent apheresis to reduce plasma LDL‐cholesterol is considered the gold standard for treatment. Liver transplantation can be curative for this condition, but is usually only considered after the development of cardiovascular disease. We report a 5.5‐yr‐old child initially misdiagnosed with heterozygous familial hypercholesterolemia and treated by low‐fat diet only. In view of persistent hypercholesterolemia and development of xanthomatosis, new molecular studies indicated the presence of two different mutations in the LDL receptor gene, with one being a deletion of two exons not identifiable with standard sequencing analysis. Recurrent plasma apheresis in combination with statins lowered, but did not normalize plasma LDL‐cholesterol levels. It caused progressive reduction of the size of xanthomas and prevented the development of vascular complications. After two yr, liver transplantation normalized LDL‐cholesterol levels and completely resolved the skin lesions. Preemptive liver transplantation is a definitive cure of familial homozygous hypercholesterolemia and might be more effective if performed before development of vascular complications.     

LDL RECEPTOR STUDIES IN TERM AND PRE-TERM INFANTS: MEASUREMENT OF STEROL SYNTHESIS IN CORD BLOOD LYMPHOCYTES

Abstract. Andersen, G. E. and Johansen, K. B. (The Neonatal Department, Rigshospitalet, University of Copenhagen, Denmark). LDL receptor studies in term and pre-term infants: Measurement of sterol synthesis in cord blood lymphocytes. Acta Paediatr Scand, 69: 577, 1980.—Low density lipoprotein (LDL) receptor activity was measured in lymphocytes from pre-term and term infants in order to elucidate if the hypercholesterolemia found in pre-term infants might be secondary to a block in cholesterol transport across the cell membrane, analogous to that seen in familial hypercholesterolemia (FH). LDL receptor activity was found to be fully developed in pre-term infants and no different from that of term infants and of a normal adult control.     

Diagnosis and management of familial dyslipoproteinemia in children and adolescents

CAD results from atherosclerosis, a chronic disease process that has its origin in childhood. Children and adolescents can be at higher risk for CAD by virtue of being from families with premature CAD or familial dyslipoproteinemias. The plasma lipid and lipoprotein levels result from a number of complex metabolic processes that are under the control of genetic and environmental (e.g., diet) influences. The normal ranges of plasma lipids and lipoproteins in children are known, and children and adolescents with dyslipoproteinemia are ordinarily defined as those having levels of plasma total, LDL, or triglyceride above the 95th percentile or with a low HDL cholesterol below the 5th percentile. Children of a parent with documented dyslipoproteinemia or with family history of premature CAD may be screened in the fasting state any time after 2 years of age. Following the exclusion of secondary causes of dyslipoproteinemia, the diagnosis of primary dyslipoproteinemia can be made. Lipoprotein patterns are not diagnostic for a given genotype. Efforts to determine further the biochemical defects responsible for a given phenotype have led to the investigation of gene coding for the apolipoproteins, the key enzymes in the lipoproteins pathways (LPL, HDL, and LCAT) and the receptors that process lipoproteins, such as the LDL receptor and the chylomicron remnant receptor. From a practical standpoint, the diagnosis of the kind of dyslipoproteinemia in a child will depend upon the nature and severity of the dyslipoproteinemia, both in the child (or adolescent) and in parents and siblings. Marked increases in plasma total and LDL cholesterol in the child and in at least one of the parents often reflect the presence of familial hypercholesterolemia, an inherited dominant condition due to a defect in the LDL receptor gene. The triglyceride levels are often normal. If the child has a different dyslipoproteinemia pattern from siblings and parents, then the diagnosis of familial combined hyperlipidemia or hyperapobetalipoproteinemia should be considered. Most children with mild or borderline elevations in total and LDL cholesterol will have polygenic hypercholesterolemia. Triglyceride problems in children and adolescents are relatively uncommon, particularly the more severe hypertriglyceridemia such as that found in lipoprotein lipase and apoC-II deficiency, dysbetalipoproteinemia, and type V hyperlipoproteinemia. High levels of Lp(a) lipoprotein, in isolation or in combination with other dyslipoproteinemia, accelerate risk for CAD. Low levels of HDL cholesterol in the absence of other abnormalities suggest the diagnosis of hypoalphalipoproteinemia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover

To determine whether at least part of the fall in low density lipoprotein (LDL) levels during lovastatin therapy might be the result of a reduced secretion of lipoproteins by the liver, three children 6 to 9 years of age with receptor-negative homozygous familial hypercholesterolemia underwent treatment with lovastatin. These patients have no capacity to synthesize LDL receptors. During lovastatin therapy, at a dose of 2 mg/kg/day, there was no decrease in LDL-cholesterol levels, nor was the turnover rate of LDL affected by the drug. The only significant change was a 74% drop in very low-density lipoprotein during treatment. We conclude that lovastatin is not effective in treatment of receptor-negative homozygous familial hypercholesterolemia. The most likely mechanism of action for this drug is to increase LDL receptor activity.     

Migraine in children: association with primary and familial dyslipoproteinemias

We studied lipids and lipoprotein cholesterols in 39 children (26 boys, 13 girls) with severe migraine, to examine the hypothesis that primary and familial lipoprotein abnormalities might be associated with or predispose children to the migraine syndrome. Each of the children, 4 to 20 years of age, had severe migraine, leading to pediatric neurologic referral and therapy. Twenty-five of the 39 probands (64%) had a first degree relative with severe migraine, and 18% had a second degree relative with severe migraine. In 11 of the 39 kindreds (28%), there was a family history of premature myocardial infarction and/or cerebral vascular accident (less than age 55 years), involving one grandparent from each of ten kindreds and one parent in the 11th kindred. In nine of the 26 boys, low-density lipoprotein cholesterol (LDL-C) levels were greater than or equal to the age-, sex-, race-specific 90th percentile, and in three of these nine children, there was at least one additional first degree relative also having a primary top decile LDL-C level, consistent with the presumptive diagnosis of familial hypercholesterolemia. The finding of more than three times as many boys with migraine headache having top decile LDL-C than expected (9 v 2.6) was significant (chi 2 = 17.5, P less than .01). Also, there were six boys having bottom decile levels of high-density lipoprotein cholesterol (HDL-C); all six came from kindreds with at least one first degree relative also having bottom decile HDL-C.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypercholesterolemia and hyper-alpha-lipoproteinemia in schoolchildren.

Elevated levels of high-density lipoprotein cholesterol (C-HDL) can explain apparent hypercholesterolemia in some children, and high C-HDL levels may aggregate in families. In this study, 17 kindreds were identified by virture of hypercholesterolemic proband children whose hypercholesterolemia was accounted for the elevated C-HDL levels Family lipod and lipoprotein sampling revealed three-generation vertical appearance of elevated C-HDL level in two kindreds, and two-generation vertical appearance in eight additional kindreds. Since CHDL level is inversely associated with coronary heart disease in adults, it is important to quantitate C-HDL and low-density lipoprotein cholesterol (C-LDL) in hypercholesterolemic children and to identify those with putatively reduced risk (elevated C-HDL level) or increased risk (elevated C-LDL level).     

Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter,randomized, placebo-controlled trial

OBJECTIVE: To determine the safety and efficacy of atorvastatin (10 to 20 mg) in children and adolescents with familial hypercholesterolemia or severe hypercholesterolemia. STUDY DESIGN: Subjects (n=187) were randomly assigned to 26 weeks of treatment with atorvastatin (10 mg) or placebo. Dosage was increased to 20 mg if LDL cholesterol (LDL-C) levels remained >3.4 mmol/L (130 mg/dL) at week 4. At week 26, subjects received 10 mg of atorvastatin for an additional 26 weeks. Efficacy variables included percent changes in LDL-C, total cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B from baseline to week 26. RESULTS: Atorvastatin caused a highly significant reduction in LDL-C compared with placebo (-40% vs -0.4%, respectively; P<.001). Percent changes at week 26 also significantly favored atorvastatin for total cholesterol (-32% vs -1.5%; P<.001), triglycerides (-12% vs +1.0%; P=0.03), and apolipoprotein B (-34% vs +0.7%; P<.001), with a significantly greater increase in HDL cholesterol with atorvastatin compared with placebo (+2.8% vs -1.8%; P=.02). Atorvastatin was as well-tolerated as placebo. CONCLUSIONS: Treatment with atorvastatin for 12 months was effective and safe for pediatric subjects with known familial hypercholesterolemia or severe hypercholesterolemia.     

Plant stanols do not restore endothelial function in pre-pubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels

OBJECTIVE: To examine the effect of plant stanols on lipids and endothelial function in pre-pubertal children with familial hypercholesterolemia (FH). STUDY DESIGN: Children with FH (n=42), aged 7-12 years, were enrolled in a double-blind crossover trial, in which they consumed 500 mL of a low-fat yogurt enriched with 2.0 g of plant stanols and 500 mL of a low-fat placebo yogurt for 4 weeks, separated by a 6-week washout period. Lipid profiles and endothelial function were assessed after both consumption periods. Endothelial function was measured as flow-mediated dilation (FMD) of the brachial artery. RESULTS: This daily intake of 2.0 g of stanols significantly decreased the levels of total cholesterol (TC) by 7.5% and low-density lipoprotein cholesterol (LDL-C) by 9.2% as compared with placebo. High-density lipoprotein cholesterol and triglyceride levels remained unaltered. The reduction of LDL-C levels did not improve FMD, which was 10.5%+/-5.1% after plant stanol consumption and 10.6%+/-5.0% after placebo consumption, respectively (P=.852). CONCLUSION: This study demonstrates that plant stanols reduce LDL-C levels in children with FH without improving endothelial function.     

Cholesterol and carotid artery wall in children and adolescents with familial hypercholesterolaemia: a controlled study by ultrasound

The carotid artery wall was studied with ultrasound in 23 children and adolescents with familial hypercholesterolaemia and in 23 age-matched healthy controls. The study revealed changes in the carotid artery wall related both to familial hypercholesterolaemia and to age. In the control subjects, the carotid artery wall became stiffer with age. In the patients with hypercholesterolaemia, no clear age-dependence was found, but wall stiffness correlated with total and low-density lipoprotein cholesterol. The intimal-medial wall thickness was associated with serum total cholesterol, low-density lipoprotein and triglyceride concentrations, and correlated inversely with the ratio of high-density lipoprotein to total cholesterol. Carotid artery wall properties seem to be associated with the degree of hypercholesterolaemia and the high-density lipoprotein-to-total cholesterol ratio even in children. In childhood and adolescence it is already possible, with ultrasound, to detect changes in the arterial wall related both to familial hypercholesterolaemia and to age.