Compound heterozygous variants in the ABCG5 gene in a Korean boy with sitosterolemia

Article information

Ann Pediatr Endocrinol Metab. 2024;29(5):344-346
Publication date (electronic) : 2024 October 31
doi : https://doi.org/10.6065/apem.2348030.015
1Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Address for correspondence: Sung Yoon Cho Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 115, Irwon-ro, Gangnam-gu, Seoul 06355, Korea Email: nadri1217@naver.com
Received 2024 February 14; Revised 2024 June 5; Accepted 2024 June 28.

Highlights

· This case describe a 6-year-old boy diagnosed with sitosterolemia through whole exome sequencing. A plant sterol-restricted diet and cholestyramine normalized his cholesterol levels and reduced xanthomas, highlighting the importance of genetic testing in persistent xanthomas despite statin therapy.

To the editor,

Sitosterolemia (OMIM #210250 and #618666) is an autosomal recessive disease affecting lipid metabolism, characterized by increased absorption of plant sterols and decreased biliary excretion of cholesterol [1]. Homozygous or compound heterozygous mutations in either ABCG5 [NM_022436.2] or ABCG8 [NM_022437.2] result in increased absorption and reduced biliary elimination of plant sterols, leading to elevated plasma sterol levels [2]. Patients with sitosterolemia present with a wide spectrum of clinical manifestations, including asymptomatic cases, xanthomas, hypercholesterolemia, premature cardiovascular disease, hematological symptoms, arthritis, and arthralgia [2]. This study presents the case of a young Korean boy with sitosterolemia, highlighting the use of genetic testing and plasma plant sterol measurements in accurate diagnosis.

A 6-year-old boy visited Samsung Medical Center because of multiple xanthomatous lesions on his elbows, ankles, hips, and behind the knees. The patient was the second son born to nonconsanguineous, healthy Korean parents and was delivered at term. The family history revealed no significant genetic disorders, and the parents and sibling exhibited no signs of xanthomas or hypercholesterolemia. The patient had developed xanthomas on his elbow when he was 5 years old, and they had worsened with age. The largest xanthoma on the right elbow was approximately 2×5 cm in size (Fig. 1). Hepatosplenomegaly or lymph node enlargement was not observed. Blood tests revealed a total cholesterol of 546 mg/dL (normal range, 0–170 mg/dL), triglycerides (TG) of 130 g/dL (normal range, 0–75 g/dL), high-density lipoprotein cholesterol (HDL-C) of 56 mg/dL (normal range > 45 g/dL), low-density lipoprotein cholesterol (LDL-C) of 472 mg/dL (normal range, 0–110 mg/dL), and blood cell morphology indicating normocytic and hypochromic anemia with polychromasia [3]. Pathological examination revealed a xanthomatous lesion based on the identification of large foam cells, suggesting xanthoma associated with hypercholesterolemia.

Fig. 1.

Xanthomas present in the patient. (A) The largest xanthoma was observed on the patient's right elbow and had developed at 5 years of age. (B) Multiple xanthomas were observed on both buttocks .

After 4 months of atorvastatin (10 mg/day), LDL-C dropped from 472 to 168 mg/dL, but the xanthoma remained unchanged. Whole-exome sequencing identified compound heterozygous variants c.1673_1677del (p.Pro558Glnfs14) and c.1217G>A (p.Arg406Gln) in the ABCG5 gene. The pathogenicity of these mutations was evaluated according to the guidelines established by the American College of Medical Genetics. The variant c.1673_1677del (p.Pro558Glnfs14) met the criteria for PVS1 and PM2, leading to its classification as likely pathogenic. The variant c.1217G>A (p.Arg406Gln) met the criteria for PM1, PM2, and BP4, resulting in its classification of uncertain significance [4]. The patient's mother harbored the c.1217G>A variant, while the father had c.1673_1677del in ABCG5. Notably the c.1673_1677del (p.Pro558Glnfs*14) variant has been frequently observed in recent Japanese cases [5]. The c.1217G>A (p.Arg406Gln) variant has been identified in at least two heterozygous sitosterolemia patients, indicating a possible association with the condition [6,7].

Ezetimibe is the first-line medication for sitosterolemia. However, there is no evidence for its long-term use in children under the age of 10 years. Therefore, cholestyramine, a cholesterol absorption inhibitor, was initiated. During meals, 4 g of cholestytramine mixed with water or a nonsparkling beverage was recommended.

After 4 months of plant-based fat restriction and cholestyramine intake, sitosterol decreased from 21.42 to 18.8 mg/dL (normal≤1.48 mg/dL), campesterol from 11.86 to 6.69 mg/dL (normal≤1.88 mg/dL), and cholestenol from 3.55 to 0.43 mg/dL (normal≤1.68 mg/dL). Lipid profile values also changed: total cholesterol from 240 to 150 mg/dL, TG from 79 to 45 mg/dL, HDL-C from 66 to 94 mg/dL, and LDL-C from 168 to 55 mg/dL. Lesions in both elbows decreased in size by approximately half.

A low-plant-sterol diet along with the administration of cholestyramine led to a marked improvement in the patient's condition and remedied the xanthomas within 1 year. Xanthomas are common in pediatric sitosterolemia [8] and can be misdiagnosed as familial hypercholesterolemia (FH) [9]. Absence of family history of hypercholesterolemia in patients with xanthomas raises the possibility of sitosterolemia. Tendon xanthomas in sitosterolemia are more severe compared to those found in FH. In infants, the presence of hypercholesterolemia and xanthomas may also raise suspicion of sitosterolemia [10]. Common laborator y techniques may not consistently differentiate between plant sterols and cholesterol. Therefore, a plant sterol analysis is required for accurate measurement of sitosterolemia. Testing for sitosterolemia may also be required if patients have xanthoma but normal cholesterol levels, if statins are ineffective in controlling lipid profiles and xanthomatous lesions, or if patients present with macrothrombocytopenia and unexplained hemolytic anemia. Genetic testing for ABCG5 and ABCG8 plays a crucial role in the accurate and early diagnosis of sitosterolemia when plant sterol analyses cannot be performed. Correct diagnosis is important for avoiding unnecessary and ineffective therapies. In sitosterolemia, the prognosis can be improved by proper management, such as restriction of plant sterol intake and administration of a cholesterol absorption inhibitor, as observed in our patient.

Notes

Conflicts of interest

No potential conflicts of interest relevant to this article were reported.

Funding

This study was supported by the Samsung Medical Center Grant #2021R1G1A1092117.

Ethical statement

Written informed consent was obtained from the patient and both parents.

References

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Article information Continued

Fig. 1.

Xanthomas present in the patient. (A) The largest xanthoma was observed on the patient's right elbow and had developed at 5 years of age. (B) Multiple xanthomas were observed on both buttocks .