Original Article
  

Clinical Manifestations and Genetic Findings in Three Patients with Chediak-Higashi Syndrome: Highlighting the Splice Site Variants

Abstract

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunodeficiency, partial albinism, recurrent infections, and progressive neurologic dysfunction. Unless patients undergo successful hematopoietic cell transplantation (HCT), a majority of them die during childhood because of an accelerated phase of immune dysfunction and hemophagocytic lymphohistiocytosis (HLH). Herein, we aim to describe the laboratory diagnosis, clinical manifestations, and genetic findings in three patients with CHS.
Three patients with partial albinism associated with CHS were included in this study. Immunological screening tests were done. Leukocyte granules in peripheral blood smear (PBS) and hair shafts were examined. Subsequently, genetic analyses were performed by Whole Exome Sequencing (WES) followed by Sanger sequencing for all patients and their parents.
Initial immunology screening tests were within normal limits. Light microscopy studies of patients’ PBS showed giant granules in the leukocyte cytoplasm. Furthermore, there were evenly distributed melanin granules in the patients' hair shafts. Variant analysis of the LYST gene identified three splicing site defects: one known variant, c.7060-1G>A in intron 24, and two novel variants, c.2363+2T>C in intron 5, and c.10702-3A>G in intron 47.
Hair shaft assay and PBS are rapid and suitable tests in early diagnosis and differentiation in CHS patients. WES results revealed 2 novel splice site variants that might contribute to earlier and more accurate diagnosis. This facilitates early enrolment of CHS patients in the HCT protocol-the optimal treatment path-and enables prenatal diagnosis for affected families.

1. Bousfiha AA, Jeddane L, Picard C, et al. The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun. 2025;1(1):e20250002.
2. Talbert ML, Malicdan MCV, Introne WJ. Chediak-Higashi syndrome. Curr Opin Hematol. 2023;30(4):144-51.
3. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. J Clin Immunol. 2022;42(7):1473-507.
4. Toro C, Nicoli ER, Malicdan MCV, Leoyklang P, Gahl WA, Introne WJ. Chediak-higashi syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews. University of Washington, Seattle; 2018.
5. Morimoto M, Hosokawa Y, Tsumura H, et al. Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature. J Med Genet. 2024;61(3):212-23.
6. Koh K, Ishida Y, Takahashi Y, et al. Chédiak–Higashi syndrome presenting as a hereditary spastic paraplegia. J Hum Genet. 2022;67(2):119-21.
7. Carneiro IM, Lopes VS, Lira AL, et al. Chediak–Higashi syndrome: lessons from a single-centre case series. Allergol

Immunopathol (Madr). 2019;47(6):598-603.
8. Safavi M, Parvaneh N. Chediak Higashi syndrome with hemophagocytic lymphohistiocytosis. Fetal Pediatr Pathol. 2023;42(2):259-62.
9. Maaloul I, Talbi M, Hachicha M, Ayadi L, Gueddiche N, Elloumi M. Chediak–Higashi syndrome presenting in accelerated phase: a case report and literature review. Hematol Oncol Stem Cell Ther. 2016;9(2):71-5.
10. Gopaal N, Rajendran A, Kandasamy S, Ramadoss S, Padmanabhan R, Krishnan L. Chediak-Higashi syndrome with Epstein-Barr virus triggered hemophagocytic lymphohistiocytosis: a case report. Cureus. 2020;12(11):e11384.
11. Mathis S, Cintas P, Pautot V, et al. Motor neuronopathy in Chediak–Higashi syndrome. J Neurol Sci. 2014;344(1-2):203-7.
12. Shirazi TN, Lehky TJ, Jinnah HA, et al. The neuropsychological phenotype of Chediak-Higashi disease. Orphanet J Rare Dis. 2019;14(1):1-13.
13. Lehky TJ, Groden C, Lear B, Toro C, Introne WJ. Peripheral nervous system manifestations of Chediak‐Higashi disease. Muscle Nerve. 2017;55(3):359-65.
14. Richards S, Aziz N, Bale S, et al. 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;17(5):405-23.
15. Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35(11):1978-80.
16. Tajik S, Alizadeh Z, Fazlollahi MR, Houshmand M, Moin M, Pourpak Z. Early diagnosis of immunodeficient patients with partial albinism: the role of hair study and peripheral blood smear. Pediatr Allergy Immunol. 2024;35(11):e14264.
17. Alizadeh Z, Tajik S, Fazlollahi MR, et al. Partial albinism and immunodeficiency in patients with Hermansky-Pudlak Type II: introducing 2 novel mutations. Scand J Immunol. 2021;93(1):e12966.
18. Tajik S, Alizadeh Z, Fazlollahi MR, Houshmand M, Moin M, Pourpak Z. Molecular findings and clinical manifestations of 18 Iranian children with Griscelli syndrome type 2: two novel homozygote mutations in RAB27A gene in a patient. Scand J Immunol. 2023;97(5):e13264.
19. Aleksenko M, Ivanova A, Pechatnikova N, et al. Novel LYST variants lead to aberrant splicing in a patient with Chediak–Higashi syndrome. Genes (Basel). 2024;16(1):18.
20. Chandravathi PL, Kumar P, Kumar K, Tharini GK. Light microscopy and polarized microscopy: a dermatological tool to diagnose gray hair syndromes. Int J Trichol. 2017;9(1):38-41.
21. Sharma P, Nicoli ER, Serra-Vinardell J, Gahl WA, Malicdan MCV, Introne WJ. Chediak-Higashi syndrome: a review of the past, present, and future. Drug Discov Today Dis Models. 2020;31:31-6.
22. Ghaffari, J., S.A. Rezaee, and M. Gharagozlou, Chédiak–Higashi syndrome. Journal of Pediatrics Review, 2013. 1(2):80-7.
23. Sachdev M, Singh S, Sharma A, et al. Haploidentical stem cell transplant with post-transplant cyclophosphamide for Chediak-Higashi syndrome: a very rare case report. J Pediatr Hematol Oncol. 2021;43(7):e1030-2.
24. Helmi MM, Al-Kzayer LFY, Al-Saeed F, et al. Chédiak-Higashi syndrome with novel gene mutation. BMJ Case Rep. 2017;2017:bcr2016216628.
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Keywords
Chediak-Higashi syndrome Inborn errors of immunity LYST gene Novel variant Primary immunodeficiency Splice Site Whole exome sequencing
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How to Cite
1.
Tajik S, Molitor A, Alizadeh Z, Fazlollahi MR, Carapito R, Akbari M, Badalzadeh M, Houshmand M, Moin M, Bahram S, Pourpak Z. Clinical Manifestations and Genetic Findings in Three Patients with Chediak-Higashi Syndrome: Highlighting the Splice Site Variants. Iran J Allergy Asthma Immunol. 2026;:1-7.