Familial hypercholesterolemia is an autosomal dominant disorder, clinically manifested by xanthomas, and is characterized by elevated levels of total and LDL cholesterol with normal triglycerides. We report the case of a 10 year old girl who had xanthomas and xanthelasmas with no evidence of complications. Drug therapy along with lipid lowering diet was offered.

Key Words Type II-A Familial Hypercholesterolemia.

A 10 year old girl was presented in the out patient department with multiple nodular swellings, gradually increasing in size over buttocks for 3 years and over elbows, knees and eyes for 2 years. The initial lesions were persistent, progressive and asymptomatic, and had no symptoms indicative of complications. She was a product of consanguineous marriage and was youngest amongst four healthy siblings. Her parents were asymptomatic. She had no family history of premature coronary vascular disease. There was no unexplained young death in the family.Clinical examination revealed a well grown girl with 1-3cm multiple nodular, firm, raised yellowish lesions over knees, elbow, buttocks and eyes. (Fig I).
The child was stable with pulse rate of 104/min, regular in rhythm, respiratory rate was 18/min, was afebrile with normal blood pressure and absence of cyanosis, pedal edema or clubbing. There was no involvement of palmer creases, interdigital spaces, lymphadenopathy or organomegaly. Ophthalmologic examination revealed no arcus. Systemic examination including CVS showed no abnormal sign.Hematological profile, CXR, abdominal ultrasound and ECG was normal. Serum lipid profile showed total cholesterol of 698 mg/dl & LDL cholesterol of 565mg/dl. Her blood sugar, liver function tests, urea, creatinine levels and thyroid profile was within normal range. Serum lipid profile of all the siblings and of both the parents was normal. After establishing the diagnosis of type II-A familial hypercholesterolemia, the child was put on atorvastatin 10mg/24hrs along with lipid lowering diet. The serum lipid profile showed response to therapy.

Fig I: Xanthelasma & Xanthomas

Familial hypercholesterolemia Type II - A is an autosomal dominant disorder.1 The incidence of the homozygous variant is 1/million and that of heterozygous form is 1/5001,3. There is no gender predilection. Certain populations of Finnish, Lebanese, Ashkenazi Jewish, Afrikaner, or French Canadian origins have a higher prevalence2.LDL receptor located mainly in liver are either absent or malfunctioning in this disorder due to mutations in its gene, which is located at short arm of chromosome 195. Approximately 700 mutations have been found1. Heterozygous express half the number of LDL receptors and homozygous have between 0-25%. These findings pave the way for early prenatal diagnosis6. We could not map the genetic abnormality due to the non availability of genetic diagnostic facility. Phenotypic expression of heterozygous FH, as defined by molecular analysis of genomic DNA, is evident in serum LDL-C levels already at birth, but for diagnostic purposes, blood lipid determinations carried out at 1 year of age are highly superior to those performed at birth7.Clinically, cholesterol accumulation may manifest as corneal arcus, xanthelasma, and xanthoma (tendon or tuberous). These signs in homozygous FH manifest early in childhood, even xanthomas can occur since birth. Symptoms of cardiac ischemia, peripheral vascular disease, cerebrovascular disease and aortic stenosis can also occur early in childhood. Physical signs in heterozygous form are similar but occur later and may not occur In homozygous FH. LDL level can increase until four times greater than normal, but in heterozygous form, the LDL level is not as high1,4. Some patients may have rheumatic manifestations like Achilles tendonitis, monoarthritis or even migratory polyarthritis8. Primary diseases responsible for elevated LDL such as hypothyroid, nephrotic syndrome, diabetes mellitus, storage disease, SLE, drugs and obstructive liver disease, must be excluded first1. Our patient had increased total and LDL cholesterol but was neither having rheumatic manifestations nor had any other primary disease.This disorder has been reported in different ethnic groups. A case of FH (homozygous) leading to coronary artery disease by the age of 10 year has been reported from Rawalpindi, which had xanthomatous eruptions, overt angina and was treated with coronary artery bypass grafting to the diseased vessels. This is probably the first reported case in Pakistan, suffering from coronary artery disease, so early & subjected to surgery5. There is also a case report of a 14 year old boy who presented with extensive coronary artery involvement with atheromatous plaques3. Our patient has no signs suggestive of coronary artery disease. Type II- hyperlipoproteinemia was diagnosed in a 4 year old girl who presented with tuberous xanthoma6. This presentation was atypical and was not in our case. A case of a 4 year old girl of pseudohomozygous type II hyperlipoproteinemia has been described, who presented with nodular xanthoma on both elbows and a streak like xanthoma on the interdigital area9. The first report of homozygous FH occurring together with dysbetalipoproteinemia was presented in two young boys having extensive tuberous & tendinous xanthomas, elevated cholesterol & triglycerides10. Our patient had elevated cholesterol but normal triglycerides.
The choice of lipid lowering drug depends primarily on the type of dyslipidemia. Combinations of HMG Co A inhibitors, nicotinic acid and fibrates may be used2. Recently, ezetimibe, a new drug that potently inhibits dietary and biliary cholesterol absorption at the brush border of intestine, has revolutionized the care of these patients11. A healthy diet, desirable weight, and regular exercise should be strongly encouraged. Diets should be rich in whole grains, whole fruit, legumes and other vegetables2. Plasmapharesis is the treatment of choice but it is expensive and has to be done on a biweekly basis. When all other treatment modalities have failed, a portal diversion or partial ileal bypass may help to prevent cardiovascular atherosclerotic complication in paediatric age3. Patients have been successfully treated with liver transplant but considerable risks are associated with organ transplantation and long-term immuno-suppression2. Gene therapy is experimental but may provide the answer. There is a report of five patients of homozygous FH who were treated in a somatic gene therapy protocol. After 4 months, all patients had evidence of LDL receptor transfer expression by liver biopsy. LDL cholesterol levels were decreased in two patients by 17% & 22% respectively, but LDL cholesterol levels in the other three were essentially unchanged4. The parents of all the diagnosed patients must be educated about the course of this disease. Early diagnosis and effective treatment to lower LDL levels and to treat other coronary risk factors, slows the progression of coronary atherosclerosis, and significantly reduces the risk of a cardiovascular event and mortality.

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