Chedíak-Higashi Syndrome: Hair-to-toe spectrum

Sunny Greene¹, Ariane Soldatos², Camilo Toro³, Wadih M Zein⁴, Joseph Snow⁵, Tanya J Lehky⁶, May Christine V Malicdan⁷, Wendy J Introne⁸

Affiliations

¹ Department of Medical Education, University of Miami, Miller School of Medicine, Miami, FL, USA.
² National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
³ National Institutes of Health Undiagnosed Disease Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Ophthalmic Clinical Genetics Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁶ EMG Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁷ National Institutes of Health Undiagnosed Disease Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: wintrone@nhgri.nih.gov.

PMID: 39622608
PMCID: PMC11730025 (available on 2025-12-01)
DOI: 10.1016/j.spen.2024.101168

Review

Chedíak-Higashi Syndrome: Hair-to-toe spectrum

Sunny Greene et al. Semin Pediatr Neurol. 2024 Dec.

. 2024 Dec:52:101168.

doi: 10.1016/j.spen.2024.101168. Epub 2024 Nov 8.

Authors

Sunny Greene¹, Ariane Soldatos², Camilo Toro³, Wadih M Zein⁴, Joseph Snow⁵, Tanya J Lehky⁶, May Christine V Malicdan⁷, Wendy J Introne⁸

Affiliations

¹ Department of Medical Education, University of Miami, Miller School of Medicine, Miami, FL, USA.
² National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
³ National Institutes of Health Undiagnosed Disease Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Ophthalmic Clinical Genetics Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁶ EMG Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁷ National Institutes of Health Undiagnosed Disease Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: wintrone@nhgri.nih.gov.

PMID: 39622608
PMCID: PMC11730025 (available on 2025-12-01)
DOI: 10.1016/j.spen.2024.101168

Abstract

Chedíak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the Lysosomal Trafficking Regulator (LYST) gene, leading to defective lysosomal function in immune cells, melanocytes, and neurons. Clinically, CHS is characterized by a spectrum of symptoms, including immunodeficiency, partial oculocutaneous albinism, bleeding tendencies, neurodevelopmental deficits and progressive neurodegenerative symptoms. The severity of CHS correlates with the type of LYST mutation: the classic form, linked to nonsense or frameshift mutations, presents early in childhood with severe immune dysfunction, recurrent infections, and a high risk of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory state. Without timely treatment, including hematopoietic stem cell transplantation (HSCT), prognosis is poor, with high mortality in early life. Atypical forms, associated with missense mutations, manifest later with milder immunologic symptoms but inevitably progress to neurological impairment, including cognitive decline and motor dysfunction. Diagnosing CHS is complex due to its rarity, phenotypic variability, and overlap with other disorders. A thorough approach, incorporating clinical evaluation, peripheral blood smear for giant granules in leukocytes, and genetic testing for LYST mutations, is crucial for accurate diagnosis. Management of CHS requires a multidisciplinary approach, focusing on HSCT for immunologic and hematologic stabilization and symptomatic and supportive care for neurological symptoms. Even those patients who undergo stabilizing HSCT eventually develop neurological difficulties. This review provides an in-depth exploration of CHS, covering its epidemiology, clinical presentation, molecular genetics, diagnostic challenges, and current management strategies, while emphasizing the necessity of a comprehensive, multidisciplinary approach to improve patient outcomes.

Keywords: CHS; Chediak-Higashi syndrome; LYST; Lysosomal disorder; Neurocutaneous; Neurodegenerative.

Published by Elsevier Inc.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

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Chedíak-Higashi Syndrome: Hair-to-toe spectrum

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Chedíak-Higashi Syndrome: Hair-to-toe spectrum

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