Journal of Genetic Medicine

Korean Society of Medical Genetics and Genomics (대한의학유전학회)
권호 표지
DOI QR코드

DOI QR Code

Cerebrotendinous xanthomatosis in a 10-year-old male presenting with Achilles tendon xanthoma and mild intellectual disability: A case report

  • Yoon, Ji Hye (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Kim, Ka Young (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Lee, Sang-Yun (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Kim, Soo Yeon (Department of Genomic Medicine, Seoul National University Hospital) ;
  • Lee, Young Ah (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Ki, Chang-Seok (GC Genome) ;
  • Song, Junghan (Department of Laboratory Medicine, Seoul National University Bundang Hospital) ;
  • Shin, Choong Ho (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Lee, Yun Jeong (Department of Pediatrics, Seoul National University Children's Hospital)
  • Received : 2022.02.06
  • Accepted : 2022.04.07
  • Published : 2022.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Cerebrotendinous xanthomatosis (CTX) is a rare genetic disease caused by a deficiency of enzymes for the synthesis of bile acid, resulting in the accumulation of cholestanol with reduced chenodeoxycholic acid (CDCA) production and causing various symptoms such as chronic diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas in adolescence and young adulthood, and progressive neurologic dysfunction in adulthood. Because oral CDCA replacement therapy can effectively prevent disease progression, early diagnosis and treatment are critical in CTX. This study reports the case of CTX in a 10-year-old male who presented with Achilles tendon xanthoma and mild intellectual disability. Biochemical testing showed normal cholesterol and sitosterol levels but elevated cholestanol levels. Genetic testing showed compound heterozygous variants of CYP27A1, c.379C>T (p.Arg127Trp), and c.1214G>A (p.Arg405Gln), which confirmed the diagnosis of CTX. The patient had neither cataracts nor other focal neurologic deficits and showed no abnormalities on brain imaging. The patient received oral CDCA replacement therapy without any adverse effects; thereafter, the cholestanol level decreased and no disease progression was noted. The diagnostic possibility of CTX should be considered in patients with tendon xanthoma and normolipidemic conditions to prevent neurological deterioration.

Keywords

Acknowledgement

This study was supported by a grant from the SNUH Research Fund (grant no. 03-2020-0410). This study was supported by a grant from the Korean Society of Pediatric Endocrinology (grant no. 2020-01). This work was supported by grants from the Seoul National University College of Medicine (grant no. 800-20200462).

References

  1. Tsouli SG, Kiortsis DN, Argyropoulou MI, Mikhailidis DP, Elisaf MS. Pathogenesis, detection and treatment of Achilles tendon xanthomas. Eur J Clin Invest 2005;35:236-44. https://doi.org/10.1111/j.1365-2362.2005.01484.x
  2. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137-74. https://doi.org/10.1146/annurev.biochem.72.121801.161712
  3. Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis 2017;40:771-81. https://doi.org/10.1007/s10545-017-0093-8
  4. Duell PB, Salen G, Eichler FS, DeBarber AE, Connor SL, Casaday L, et al. Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis. J Clin Lipidol 2018;12:1169-78. https://doi.org/10.1016/j.jacl.2018.06.008
  5. Lee JH, Lee K, Jun SH, Song SH, Shin CH, Song J. A multiplex phytosterol assay utilizing gas chromatography-mass spectrometry for diagnosis of inherited lipid storage disorders. Ann Lab Med 2019;39:411-3. https://doi.org/10.3343/alm.2019.39.4.411
  6. Lee JH, Song DY, Jun SH, Song SH, Shin CH, Ki CS, et al. High prevalence of increased sitosterol levels in hypercholesterolemic children suggest underestimation of sitosterolemia incidence. PLoS One 2020;15:e0238079. https://doi.org/10.1371/journal.pone.0238079
  7. Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 2006;27:143-9. https://doi.org/10.1007/s10072-006-0618-7
  8. Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. https://doi.org/10.1186/s13023-014-0179-4
  9. Koyama S, Sekijima Y, Ogura M, Hori M, Matsuki K, Miida T, et al. Cerebrotendinous xanthomatosis: molecular pathogenesis, clinical spectrum, diagnosis, and disease-modifying treatments. J Atheroscler Thromb 2021;28:905-25. https://doi.org/10.5551/jat.RV17055
  10. Wong JC, Walsh K, Hayden D, Eichler FS. Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis 2018;41:647-56. https://doi.org/10.1007/s10545-018-0152-9
  11. Yoo EG. Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Ann Pediatr Endocrinol Metab 2016;21:7-14. https://doi.org/10.6065/apem.2016.21.1.7
  12. Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis 2014;37:421-9. https://doi.org/10.1007/s10545-013-9674-3
  13. De Stefano N, Dotti MT, Mortilla M, Federico A. Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis. Brain 2001;124(Pt 1):121-31. https://doi.org/10.1093/brain/124.1.121
  14. Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 1984;311:1649-52. https://doi.org/10.1056/NEJM198412273112601
  15. Stelten BML, Huidekoper HH, van de Warrenburg BPC, Brilstra EH, Hollak CEM, Haak HR, et al. Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start. Neurology 2019;92:e83-95. https://doi.org/10.1212/WNL.0000000000006731
  16. Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y. Nationwide survey on cerebrotendinous xanthomatosis in Japan. J Hum Genet 2018;63:271-80. https://doi.org/10.1038/s10038-017-0389-4
  17. von Bahr S, Movin T, Papadogiannakis N, Pikuleva I, Ronnow P, Diczfalusy U, et al. Mechanism of accumulation of cholesterol and cholestanol in tendons and the role of sterol 27-hydroxylase (CYP27A1). Arterioscler Thromb Vasc Biol 2002;22:1129-35. https://doi.org/10.1161/01.ATV.0000022600.61391.A5