Chedíak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by a broad spectrum of clinical manifestations that include immunodeficiency, oculocutaneous albinism, bleeding tendencies, neurodevelopmental issues and progressive neurodegeneration. The syndrome was first brought to medical attention in 1943 by Cuban physician Beguez-Cesar, who described a child exhibiting abnormal giant granules in leukocytes.1 A decade later, in the early 1950s, French hematologist Moises Chedíak and Japanese physician Ototaka Higashi independently documented familial cases involving partial albinism and leukopenia, along with the hallmark feature of giant granules in leukocytes.2,3 These seminal observations led to the eponymous naming of the disorder as Chedíak-Higashi Syndrome.

The pathognomonic feature of CHS is the presence of giant granules within the cytoplasm of leukocytes, which can be readily observed on a peripheral blood smear. This finding remains the diagnostic hallmark of CHS and is critical for early recognition and diagnosis. Despite the characteristic leukocyte abnormalities, CHS is a highly variable disorder, with a wide range of clinical presentations that complicates diagnosis and management.

The clinical presentation of CHS can range from mild to severe, where severity often correlates with the type of mutation in the Lysosomal Trafficking Regulator (LYST) gene. Classic or "typical" CHS is generally associated with nonsense or frameshift mutations that result in a truncated, non-functional protein. Classical CHS typically presents in early childhood with severe immunodeficiency, recurrent infections, bleeding diathesis, and a high risk of developing hemophagocytic lymphohistiocytosis (HLH)—a life-threatening hyperinflammatory condition also referred to as the "accelerated phase" of CHS. Without prompt treatment, including hematopoietic stem cell transplantation (HSCT), the prognosis for patients with classic CHS is poor, with high mortality rates reported within the first decade of life.4 Early detection and HSCT advancements have improved mortality outcomes for patients with classical CHS. Conversely, atypical or "mild" CHS is often linked to missense mutations in the LYST gene that produce a partially functional protein. Patients with atypical CHS may present later in life with milder immunologic and hematologic abnormalities.

Regardless of the initial severity of the immune dysfunction, nearly all patients with CHS will eventually develop progressive neurological impairment5 including those that receive HSCT. Neurological symptoms in CHS may include neurodevelopmental issues in childhood in the form of variable degrees of learning difficulties and ADHD. Progressive neurodegenerative features begin in late adolescence or early adulthood and include distal lower extremity weakness with “foot drop” due to peripheral neuropathy/neuronopathy, cerebellar ataxia, parkinsonism, and progressive cognitive decline. The insidious progression of neurological manifestations has become a major determinant of long-term morbidity and mortality.

The pathogenesis of CHS is rooted in defective lysosome and lysosome-related organelle (LRO) trafficking and function. Affected cell types include immune cells, fibroblasts, melanocytes, and neurons (Fig 1A). In immune cells, particularly natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), defective lysosomal fusion and exocytosis impair the cells' ability to effectively kill pathogens and regulate immune responses. This dysfunction underlies the recurrent infections and hyperinflammatory syndromes, such as HLH, observed in patients with CHS. In melanocytes, abnormal LROs result in the partial oculocutaneous albinism characteristic of CHS. In neurons and glial cells, the lysosomal dysfunction contributes to the progressive neurodegeneration seen in affected individuals.

Despite many advances in understanding the genetic and molecular basis of this disease, recognizing CHS remains challenging due to its rarity, phenotypic variability6 and overlap with many other immune, hematological, neurological and pigmentary disorders7 such as Griscelli syndrome8,9 and Hermansky-Pudlak syndrome.10, 11, 12 Moreover, the management of CHS remains complex and multidisciplinary, involving not only HSCT for immunologic and hematologic stabilization but also symptomatic and supportive care for neurological and systemic manifestations. Current approaches are largely symptomatic, with no definitive cure available.