Griscelli syndrome is a rare autosomal recessive disorder in which patients present with silvery hair and dilution of skin pigment due to an inherited defect in pigment distribution within their melanocytes. Three subtypes of Griscelli syndrome exist – GS1, GS2, and GS3 – which differ by clinical picture and associated genetic mutations.

GS1 is caused by a variant in MYO5A, a gene that encodes myosin Va. Because myosin Va is involved in neuron development in addition to pigment distribution within melanocytes, patients with GS1 present with neurologic deficits in infancy such as seizures, hypotonia, ataxia, psychomotor retardation, and cognitive and developmental impairment. Patients who also experience ophthalmologic symptoms (ie nystagmus, diplopia, and retinal changes) were originally thought to have a distinct disorder called Elejalde syndrome. However, current literature suggests that Elejalde syndrome is a rare form of GS1.

GS2 is the most commonly reported subtype of Griscelli syndrome and results from a variant in the RAB27A gene. RAB27A supports both pigment distribution in melanocytes and the immune system. Without a normally functioning RAB27A, patients with GS2 experience defective humoral and cell-mediated immunity, which predisposes them to infections. Furthermore, patients have dysfunctional cytotoxic degranulation, which can lead to hemophagocytic lymphohistiocytosis (HLH), in which T-cells and macrophages are perpetually overactivated. This overactivation can cause lymphohistiocytic infiltration into organs, including the central nervous system, where it manifests as neurologic symptoms such as seizures, altered consciousness, cerebellar symptoms, and hearing, sight, motor, and language impairment. Other signs of HLH include fever, cytopenias, splenomegaly, and hemophagocytosis. Patients with GS2 may also present with granulomatous skin nodules due to overactive T-cells and macrophages. Abnormal lipid metabolism, pulmonary lymphomatoid granulomatosis, and hepatosplenomegaly may also be seen.

The third subtype, GS3, is due to a variant in MLPH, which encodes melanophilin. Patients with GS3 have only the cutaneous findings of Griscelli syndrome, including skin, hair, and occasionally iris hypopigmentation.