Sitosterolemia: clinical, biochemical and molecular characteristics in a 3 years old boy with marked hypercholesterolemia
Authors:
M. Floriánková 1; Z. Urbanová 1; Š. Bláhová 1; M. Pencová 1; J. Hyánek 2; L. Tichý 3; L. Fajkusová 3; T. Freiberger 4; T. Honzík 1
Authors‘ workplace:
Klinika dětského a dorostového lékařství 1. LF UK a VFN, Praha
1; Oddělení klinické biochemie, hematologie a imunologie, Nemocnice Na Homolce, Praha
2; Centrum molekulární biologie a genové terapie, FN Brno
3; Centrum kardiovaskulární a transplantační chirurgie, Brno
4
Published in:
Čes-slov Pediat 2017; 72 (8): 495-503.
Category:
Case Report
Overview
Background:
Sitosterolemia is a rare, autosomal recessive inherited disorder of lipid metabolism, associated with an abnormal transport of plant sterols in a small intestine and a liver due to malfunction of a transport protein ABCG5/ABCG8. Disorder is associated with significant hyperphytosterolemia and also with hypercholesterolemia in most pediatric patients, tuberous and tendinous xanthomas, hemolytic anemia, macrothrombocytopenia, abnormal bleeding, splenomegaly, premature atherosclerosis, arthritis, failure to thrive and hepatopathy. A rare finding of normocholesterolemia and normal levels of phytosterols in breastfed infants might result in a delay in diagnosis. Patients with sitosterolemia respond well to a low cholesterol and a low plant sterol diet in combination with ezetimibe therapy. Here, we report clinical, biochemical and molecular genetic data of a boy with sitosterolemia.
Case report:
3 years old boy has been monitored since 7 months of age for hypercholesterolemia (16–25.6 mmol/l), found accidentally. Family history was negative. Since one year of age a failure to thrive was documented, weight/lenght ratio dropped from 75th to 8.8th percentile. At the age of 20 months laboratory tests showed significantly increased levels of serum sitosterol (13 times above normal level) and campesterol (4 times above normal level). Molecular genetic analysis revealed compouned heterozygosity for a previously described pathogenic mutation p.Arg446* and another, up to now unpublished, probably pathogenic variant p.Arg419Cys in the ABCG5 gene. Both parents were confirmed as healthy mutation carriers.
Conclusion:
We presented the first Czech patient with sitosterolemia carrying mutations in ABCG5. Patient is on a low-cholesterol and a low-plant sterol diet and ezetimibe therapy. During 16 months of therapy, level of total cholesterol and also of LDL cholesterol almost normalized and serum concentration of plant sterols decreased significantly. Therefore, sitosterolemia should be considered in the differential diagnosis of severe hypercholesterolemia in children.
Key words:
sitosterolemia, phytosterolemia, hypercholesterolemia, ABCG5, non-cholesterol sterols, failure to thrive
Sources
1. Nghiem-Rao TH, Patel SB. Investigating sitosterolemia to understand lipid physiology. Clin Lipidol 2013; 8 (6): 649–658.
2. Yoo EG. Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Ann Pediatr Endocrinol Metab 2016; 21: 7–14.
3. Lee MH, Lu K, Hazard S, Yu H, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 2001 Jan; 27 (1): 79–83.
4. Dikkers A, de Boer JF, Groen AK, et al. Hepatic ABCG5/G8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage-to-feces RCT. Atherosclerosis 2015; 243: 402–406.
5. Merkens LS, Myrie SB, Steiner RD, et al. Sitosterolemia. Gene Reviews. NCBI Bookshelf online [http://www.ncbi.nim.nih.goc/books//NBK131810/] cit. 3. 5. 2017.
6. Park JH, In Hyuk Ch, Dong Hyun K, et al. Sitosterolemia presenting with severe hypercholesterolemia and intertriginous xanthomas in a breastfed infant: Case report and brief review. J Clin Endocrinol Metab 2014 May; 99 (5): 1512–1518.
7. Escolà-Gil JC, Quesada H, Julve J, et al. Sitosterolemia: Diagnosis, investigation, and management. Curr Atheroscler Rep 2014; 16: 424.
8. Krásničanová H, Lesný P. Kompendium pediatrické auxologie 2005. 1. vyd. Praha: Mladá fronta, 2013 (CD-ROM).
9. Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May; 17 (5): 405–424.
10. Hyanek J, Pehal F, Dubska L, et al. Lathosterol and noncholesterol sterols in routine use for the differentiation and monitoring of dietary and drug induced treatment of hypercholesterolemias in children and adolescents. J Nutr Ther 2014; 3: 1–12.
11. Wang J, Joy T, Mymin D, et al. Phenotypic heterogenity of sitosterolemia. J Lipid Res 2004; 45: 2361–2367.
12. Fausto AGC, García JRG, Madero LEWL, et al. Two novel mutations in the ABCG5 gene, c.144 -1G.A and c.1523 delC, in a Mexican family with sitosterolemia. J Clin Lipidol 2016; 10: 204–208.
13. Beaty TH, Kwiterowich PO Jr, Khoury MJ, et al. Genetic analysis of plasma sitosterol, apoprotein B and lipoproteins in a large Amish pedigree with sitosterolemia. Am J Hum Genet 1986; 38: 492–504.
14. Sehayek E, Yu HJ, von Bergmann K, et al. Phytosterolemia on the island of Kosrae: founder effect for a novel ABCG8 mutation results in high carreer rate and increased plasma plant sterol levels. J Lipid Res 2004; 45: 1608–1613.
15. Mannucci L, Guardamagna O, Bertucci P. et al. Beta-sitosterolemia: a new nonsense mutation in the ABCG5 gene. Eur J Clin Invest 2007; 37: 997–1000.
16. Niu D-M, Kah-Wai CH, Ju-Hui H, et al. Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. J Inherit Metab Dis 2010; 33: 437–443.
17. Melenotte C, Carri A, Serratrice J, et al. Sitosterolemia: A new station in a Mediterranean patient. J Clin Lipidol 2014; 8: 451–454.
18. Miettinen TA. Phytosterolemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Eur J Clin Invest 1980; 10: 27–35.
19. Togo M, Hashimoto Y, Iso-O N, et al. Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases. Clin Chim Acta 2009; 401: 165–169.
20. Liebeskin A, Wilson DP. Sitosterolemia in the Pediatric Population. NCBI Endotext [https://www.ncbi.nlm.nih.gov/books/NBK395586] cit. 6. 6. 2017.
21. Kwiterovich PO Jr, Bachorik PS, Smith HH, et al. Hyperapolipoproteinemia in two families with xanthomas and phyto-sterolemia. Lancet 1981; 1: 466–469.
22. Chong JX, Ouwenga R, Anderson RL, et al. A population-based study of autosomal-recessive disease-cusing mutations in a founder population. Am J Hum Genet 2012; 91: 608–620.
23. Rios J, Stein E, Shendure J, et al. Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum Mol Genet 2010; 19: 4313–4318.
24. Nguyen LB, Shefer S, Salen G, et al. A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. J Clin Invest 1990 Sep; 86 (3): 923–931.
25. Patel SB, Honda A, Salen G. Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. J Lipid Res 1998; 39: 1055–1061.
26. Rees DC, Iolascon A, Carella M, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 2005; 130 (2): 297–309.
27. Falet H. Sitosterolemia: platelets on high-sterol diet. Blood 2013; 122 (1): 100–108.
28. Kanaji T, Kanaji S, Montgomery RR, et al. Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia. Blood 2013; 122 (15): 2732–2742.
29. Lu K, Lee M-H, Hazard S, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8 respectively. Am J Hum Genet 2001; 69: 278–290.
30. Wang G, Wang Z, Liang J, et al. A phytosterolemia patient presenting exclusively with macrothrombocytopenia and stomatocytic hemolysis. Acta Haematol 2011; 126 (2): 95–98.
31. Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol 2001b; 12 (2): 141–149.
32. Ballantyne CM. Clinical Lipidology: A Companion to Braunwald´s Heart Disease. 2nd ed. Elsevier Inc. 2015: 1–568.
33. Salen G, von Bergmann K, Lütjohann D, et al. Ezetimibe effectively reduces plasma plant sterols in patiens with sitosterolemia. Circulation 2004 Mar 2; 109 (8): 966–971.
34. Davis HR Jr, Zhu LJ, Hoos LM, et al. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J Biol Chem 2004 Aug 6; 279 (32): 33586–33592.
35. Salen G, Starc T, Sisk CM, et al. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemiaand xanthomatosis. Gastroenterology 2006 May; 130 (6): 1853–1857.
36. Nguyen LB, Shefer S, Salen G, et al. The effect of abnormal plasma and cellular sterol content and composition on low density lipoprotein uptake and degradation by monocytes and lymphocytes in sitosterolemia with xanthomatosis. Metabolism 1988 Apr; 37 (4): 346–351.
37. Zhaoyue W, Lijuan C, Yanhua S, et al. Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. Am J Hematol 2014 Mar; 89 (3): 320–324.
38. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290 (5497): 1771–1775.
39. Bhattacharya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sister. J Clin Invest 1974; 53: 1033–1043.
40. Hubacek JA, Berge KH, Cohen JC, et al. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat 2001 Oct; 18 (4): 359–360.
41. Katayama T, Satoh T, Yagi T, et al. 19-year-old man with myocardial infarction and sitosterolemia. Intern Med 2003; 42: 591–594.
42. Kaya Z, Niu D-M, Yorulmaz A, et al. A Novel mutation of ABCG5 gene in a Turkish boy with phytosterolemia presenting with macrothrombocytopenia and stomatocytosis. Pediatr Blood Cancer 2014; 61: 1457–1459.
43. Keller S, Prechtl D, Aslanidis CH, et al. Increased plasma plant sterol concentrations and a heterozygous amino acid exchange in ATP binding cassette transporter ABCG5: A case report. Eur J Med Genet 2011; 54: e458–e460.
44. Ono S, Matsuda J, Siato A, et al. Case report: A case of sitosterolemia due to compound heterozygous mutations in ABCG5: clinical features and treatment outcomes obtained with colestimide and ezetimibe. Clin Pediatr Endocrinol 2017; 26 (1): 17–23.
45. Renner C, Connor WE, Steiner RD, et al. Sitosterolemia presenting as pseudohomozygous familiar hypercholesterolemia. Clin Med Res 2016 Jun; 14 (2): 103–108.
46. Tada H, Kawashiri M, Noguchi T, et al. A novel method for determining functional LDL receptor activity in familial hypercholesterolemia: application of the CD3/CD28 assay in lymphocytes. Clin Chim Acta 2009; 400: 42–47.
47. Webb TN, Ramratnam M, Evans RW, et al. Atherosclerotic renal artery stenosis as a cause of hypertension in an adolescent patient. Pediatr Nephrol 2014; 29: 1457–1460.
48. Neff AT. Sitosterolemia´s stomatocytosis and macrothrombocytopenia. Blood 2012 Nov; 120: 4283.
49. Yamamoto T, Matsuda J, Dateki S, et al. Numerous intertriginous xanthomas in infant: A diagnostic clue for sitosterolemia. J Dermatol 2016; 43: 1340–1344.
Labels
Neonatology Paediatrics General practitioner for children and adolescentsArticle was published in
Czech-Slovak Pediatrics
2017 Issue 8
Most read in this issue
- Thalassemias
- Brain abscess – a rare but a serious infection in childhood
- Chronic otitis media in childhood
- Thalassemias and hemoglobin variants in children