Familial Hypercholesterolemia and Cerebral Infarction - A Case Report

Background: Familial hypercholesterolemia has various presentations mostly including early-onset cardiovascular diseases, remarkable skin and tendon xanthomas. By comparison, Cerebral Infarction due to familial hypercholesterolemia is extremely rare. Case presentation: We present a 41-year-old man who was admitted to our hospital with dizziness, vertigo, slurred speech, weakness in his left limbs. He had family history of Hyperlipidemia in older sister . Head CT scan demonstrated multiple acute cerebral infarction in the right frontal and parietal lobes, and arterial plaques was found in the bifurcation of common carotid artery. The severe carotid stenosis was located in the initial segment of the right internal carotid artery. Histopathologic ndings were consistent with xanthoma. Especially, molecular analysis of the LDLR gene was made, which identied heterozygous missense mutation in exon 12 of the LDLR gene. The nal diagnosis of cerebral infarction associated with familial hypercholesterolemia was made. The patient was referred to a nutritionist for dietary advice, and was treated with Tab. Finally, the patient recovered well. The symptoms of brain infarct vanished and no recurrence occurred during follow-up. Conclusions: In the present case, the acute cerebral infarction most likely due as his family and arterial plaques and severe carotid stenosis was found by CTA. This case highlights the importance of the early diagnosis and treatment of hypercholesterolemia, which may help in preventing the development of cardiovascular and cerebrovascular diseases.


Background
Familial hypercholesterolemia is a genetic disorder, which due to mutation in low-density lipoprotein (LDL) receptor gene. The mutation prevents hepatic cells from removing serum LDL-cholesterol and results in hypercholesterolemia [1]. The general characterization of heterozygous FH is by elevated lowdensity lipoprotein (LDL) cholesterol and early-onset cardiovascular diseases, remarkable skin and tendon xanthomas [2]. Herein, we present a patient with familial hypercholesterolemia who presented with Cerebral Infarction. Especially, molecular analysis of the LDLR gene was made, which identi ed heterozygous missense mutation in exon 12 of the LDLR gene. Owing to its scarcity, with the consent of the patient, we herein present this case for discussing the reason for its rarity and sharing our experience of management.

Case Presentation
A 41-year-old man was admitted to the hospital due to acute onset of Cerebral Infarction in May 2017. He experienced acute-onset symptoms, accompanied also by dizziness, vertigo, slurred speech, weakness in his left limbs for 4h prior to admission. He had family history of Hyperlipidemia in older sister. On physical examination, he and his older sister both had arcus corneae (Fig. 1A,B,C,D), and less obvious signs of cutaneous xanthomas manifesting as rm, smooth, nodular thickening of the hands and knees( Fig. 2A,B).
Laboratory investigation showed total serum cholesterol level of 11.45 mmol/l and the low-density lipoprotein (LDL) 8.24 mmol/l. Levels of high-density lipoprotein (1.24mmol/l), triglyceride(0.64mmol/l) and Glycated hemoglobin (5.4%)were normal. Table 1 shows the lipid pro le of the patient. Other family members were also investigated for lipid pro le ( Table 2). Subsequent head and neck CT angiography (CTA) was performed, Head CT scan demonstrated multiple acute cerebral infarction in the right frontal and parietal lobes, and arterial plaques was found in the bifurcation of common carotid artery. The severe carotid stenosis was located in the initial segment of the right internal carotid artery. Chest CT scan demonstrated aortic and coronary artery calci cation.
A biopsy specimen (Fine-needle biopsy) removed from the nodule of the left hand. On microscopy it shows multiple cholesterol crystals surrounded by granuloma formation, and in ltrated with admixture of multinuclear giant cells, foamy histiocytes and vasoactive compounds (Fig. 3A,B,C,D).
With the consent of the patient, molecular analysis of the LDLR gene was made. Blood samples were acquired from the patient. Genomic DNA was isolated from whole blood using QIAamp DNA Mini Kit  (Table 3).
Based on the clinical, laboratory, imaging features, histologic, and molecular analysis of the LDLR gene, a diagnosis of cerebral infarction associated with familial heterozygous hypercholesterolemia was made.
The patient was referred to a nutritionist for dietary advice, and was treated with Tab. Atorvastatin 40 mg for blood lipid reduction, aspirin enteric-coated tablet 100 mg and bisulfate clopidogrel 75 mg both for resist blood platelet aggregation and thrombopoiesis. The patient recovered well. His lipid pro le 6 months later is given in Table 1. The cutaneous xanthomas have attened. The symptoms of brain infarct vanished and no recurrence occurred during follow-up.

Discussion
Familial hypercholesterolemia (FH) resulting from mutations in the low-density lipoprotein (LDL)receptor gene is associated with increased risk of premature atherosclerosis and coronary artery disease [3]. Occasionally, patients may be totally asymptomatic. Generally, this pathology is found incidentally during a routine physical examination or in the process of unrelated clinical problems [4]. In our case, hypercholesterolemia was found due to the occurrence of cerebrovascular disease.
Physical signs present in many, but not all, patients and result from cholesterol deposits affecting the corneal margins (arcus corneae), skin of eyelids (xanthelesma) and extensor tendons especially the Achilles and extensor tendons of the hands (xanthomas) [5]. In our case, we only found arcus corneae, and less obvious signs of cutaneous xanthomas.
Because xanthomas are benign lesions, a number of cases do not need surgical treatment. Frequently, ne-needle biopsy is the main choice for histologic identi cation [6]. In our case, we get the biopsy specimen by ne-needle. Microscopically, it shows multiple cholesterol crystals surrounded by granuloma formation, and in ltrated with admixture of multinuclear giant cells, foamy histiocytes and vasoactive compounds suggestive of xanthoma.
Under normal physiological conditions, the LDL receptors regulate the uptake of cholesterol but a defect in the mechanism for clearing LDL could lead to FH. The defect can result from mutations in the Low density lipoprotein receptor gene (LDLR), Apolipoprotein B-100 gene (APOB), and Proprotein convertase subtilisin/kexin type 9 gene (PCSK9) genes [7]. The LDLR gene is located on chromosome 19p13.1-13.  Tables   Table 1: Lipid pro le of the patient Table 2: Lipid pro le of the patient's family