Indian Journal of Dermatology
E-IJDŽ - CASE REPORT
Year
: 2022  |  Volume : 67  |  Issue : 4  |  Page : 480-

Familial hypercholesterolemia presenting as cerebral ischemia and xanthoma


Yang Jingjing1, Liang Zhanhua1, Jiang Huajun2,  
1 From the Department of Neurology, First Affiliated Hospital of Dalian Medical University, Dalian, China
2 Department of Orthopaedics, First Affiliated Hospital of Dalian Medical University, Dalian, China

Correspondence Address:
Jiang Huajun
Zhongshan Road No. 222, Dalian - 116011
China

Abstract

Familial hypercholesterolemia (FH) is one of the inherited metabolic diseases, demonstrating the low-density lipoprotein receptor (LDLR) abnormality and serum cholesterol level marked elevation. FH has become an extremely high incident cause of occlusive coronary heart disease. However, even though hemorheological disorder caused by hyperlipidemia is a risk factor of ischemic cerebrovascular disease, cerebral infarction caused by FH has not been given much attention. We present a 41-year-old man with a family history of hypercholesterolemia was admitted to our hospital with dizziness, vertigo, slurred speech, and weakness in his left limbs. Head CT scan showed multiple acute cerebral infarction in the right frontal and parietal lobes. He had arcus corneae and less obvious signs of cutaneous xanthomas in the hands and knees. Molecular analysis of the LDLR gene identified heterozygous and missense mutation in exon 12 of the LDLR gene. The final diagnosis was cerebral infarction caused by FH. It is worth noting that cerebral infarction may also occur in patients with FH. Even if the most patients do not have any sign or history of cerebral ischemia, they need more attention to precise examination of the brain.



How to cite this article:
Jingjing Y, Zhanhua L, Huajun J. Familial hypercholesterolemia presenting as cerebral ischemia and xanthoma.Indian J Dermatol 2022;67:480-480


How to cite this URL:
Jingjing Y, Zhanhua L, Huajun J. Familial hypercholesterolemia presenting as cerebral ischemia and xanthoma. Indian J Dermatol [serial online] 2022 [cited 2023 Feb 9 ];67:480-480
Available from: https://www.e-ijd.org/text.asp?2022/67/4/480/360307


Full Text



 Case Description



A 41-year-old man was admitted to the hospital due to acute onset of Cerebral Infarction in March 2017. He experienced acute-onset symptoms, accompanied by dizziness, vertigo, slurred speech and weakness in his left limbs, and was transported to our emergency two days later. He had a history of hypertension about two years. He denied of smoking history and did not have history of diabetes, heart disease or cerebrovascular disease. Especially, he had family history of hyperlipidemia as well as his older sister and his son. The admission examination: Body temperature of 36°C, pulse of 80/min, respiratory rate of 18/min, blood pressure of 145/80 mmHg. On the neurological examination, he was consciousness, incomplete aphasia, and grade 4 left upper and lower limbs muscle strength. On other physical examination, he and his older sister both had arcus corneae [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. He had less obvious signs of cutaneous nodule in his hands and tendinous nodule in his knees [Figure 2]a and [Figure 2]b. He did not have skin of eyelids (xanthelesma).{Figure 1}{Figure 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 [Figure 3]a, and neck CTA demonstrated mutiple mixed arterial plaques in the bifurcation of common carotid artery. Intracranial CTA demonstrated the severe carotid stenosis was located in the initial segment of the right internal carotid artery [Figure 3]b. Chest CT scan demonstrated aortic and coronary artery calcification.{Figure 3}

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 (1.24 mmol/l), triglyceride (0.64 mmol/l), and glycated hemoglobin (5.4%) were normal. [Table 1] shows the lipid profile of the patient. Relatives of the patient with familial hypercholesterolemia (FH) were also investigated for blood lipid profile [Table 2].{Table 1}{Table 2}

Ultrasonography was performed to assess the tendinous nodule in his knees, and showed hypoechoic lesions in the anterior patellar tendon region of both knees with maximum size of 31 × 30 × 7 mm (left) and 37 × 31 × 7 mm (right). Histopathologic examination of the tendinous nodule revealed a yellowish solid tissue. On microscopy it shows multiple cholesterol crystals surrounded by granuloma formation, and infiltrated with admixture of multinuclear giant cells, foamy histiocytes, and vasoactive compounds [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d. The pathological diagnosis was xanthoma.{Figure 4}

Blood samples were acquired from the patient. Genomic DNA was isolated from whole blood using QIAamp DNA Mini Kit (QIAGEN) according to standard manufacturer's protocol. Qualitative and quantitative estimations were carried out on the DNA samples. Targeted next-generation sequencing (TNGS) was implemented for comprehensive genetic analysis for the known and novel mutations in hot spots within exons and exon–intron boundaries of LDLR, APOB, LDLRAP1, PCSK9, ABCG5, ABCG8, LIPA, LPL, APOA5, LIPI, USF1, APOE, LIPC, ABCA1, LCAT, APOA1, HAMP, HFE, HFE2, SLC40A1, and TFR2. We identified one suspected pathogenic variant [c.1747>T, p.(His583Tyr)], which was heterozygous and missense mutation in exon 12 of the LDLR gene [Table 3].{Table 3}

Based on the clinical, laboratory, imaging features, pathological diagnosis, and molecular analysis of the LDLR gene, the final diagnosis was FH associated with cerebral infarction.

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. His left limbs muscle strength gradually returned to normal and he was already able to walk without help before discharge. His lipid profile was clearly better 6 months later in [Table 1]. The cutaneous xanthomas have flattened. The patient was followed up for three years, the symptoms of brain infarct vanished and no recurrence occurred during follow-up.

 Discussion



FH is one of the inherited metabolic disease, demonstrating the low-density lipoprotein receptor (LDLR) abnormality and serum cholesterol level marked elevation, which is associated with high risk of atherosclerosis and coronary artery disease.[1] The features of FH is characterized by high LDL cholesterol levels, while triglycerides are generally normal and high-density lipoprotein (HDL) cholesterol either normal or reduced.[2] In our case, laboratory investigation showed total serum cholesterol level of 11.45 mmol/L and the low-density lipoprotein (LDL) 8.24 mmol/L, while levels of high-density lipoprotein (HDL) and triglyceride were normal.

FH is characterized by deposits of cholesterol in the peripheral tissues, presence of corneal margins (arcus corneae), skin of eyelids (xanthelesma), and xanthomas. The physical signs present in many, but not all.[3] In our case, we found marked arcus corneae, but cutaneous xanthomas were not obvious, however, we did not find skin of eyelids (xanthelesma). Xanthomas are important clinical marker of disordered lipid metabolism. They are nodular, firm, non-tender, subcutaneous swellings that involve the trauma-prone areas of the body, such as elbows, knees, Achilles.[4] In our case, he had less obvious signs of cutaneous nodule in his hands and tendinous nodule in his knees. Xanthomas have been separated into two groups: Group I is associated with increased serum levels of lipids because of familial hyperlipidemia and Group II has either normal or slightly increased lipid levels without any family history.[5] The patient we reported was belong to Group I.

On the other hand, FH is also characterized by deposits of cholesterol in the peripheral tissues, presence of premature, or accelerated atherosclerosis. Hemorheological disorder caused by hyperlipidemia is a risk factor of ischemic cerebrovascular disease.[6] Howerver, cerebral Infarction caused by FH has not been given much attention. The reason may be these patients early asymptomatic. Generally, the pathology is found in a routine physical examination incidentally or after the onset of clinical problems.[7] In our case, hypercholesterolemia was found due to the onset of cerebrovascular disease.

Therefore, it is worth noting that cerebral infarction may also occur in patients with FH. Even if the most patients do not have any sign or history suggesting cerebral ischemia, they need more attention and precise examination of the brain.[8] In our case, his 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. It showed that hyperviscosity is closely related to cerebral infarction, which would explain the association of cerebral infraction with FH.

FH is an inherited disorder of lipoprotein metabolism caused by abnormality of the LDL receptor, in which genetic analysis was precisely confirmed.[9] Under normal physiological conditions, the LDL receptors regulate the uptake of cholesterol and then lower cholesterol. However, any defect in the mechanism of 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.[10] The LDLR gene is located on chromosome 19p13.1–13.3 which spans 45 kb and comprises of 18 exons and 17 introns encoding a mature protein of 839 amino acids.[11] Mutations of the LDLR gene such as nucleotide substitutions, deletions and insertions, as well as rearrangements can cause FH. The previous report in Asia have identified a novel mutation at position c. 2132 in exon 14 translating the wild-type amino acid cysteine (711C) to a nonsynonymous missense tyrosine (711Y).[12] In our case, we identified the mutation at position c. 1747C>T in exon 12 for His583Tyr. However, up to now, we can't be certain that any significance of this missense variant being associated with phenotypic characteristics.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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