Griscelli syndrome

Griscelli syndrome is a rare autosomal‑recessive disorder that causes unusually light skin and hair, with three genetic types that differ by neurological involvement, immune dysfunction, or isolated pigment loss.

Overview

Griscelli syndrome is an inherited condition characterized by hypopigmented skin and light silvery‑gray hair that appears in infancy. Three types have been identified, each distinguished by its genetic cause and pattern of clinical signs.

Types & Symptoms

Type 1

• Severe neurological problems: delayed development, intellectual disability, seizures, hypotonia, and eye/vision abnormalities.
• Hypopigmented skin and hair.
• Often considered synonymous with Elejalde disease.

Type 2

• Immune system abnormalities leading to recurrent infections.
• Development of hemophagocytic lymphohistiocytosis (HLH), a life‑threatening over‑activation of T‑lymphocytes and macrophages.
• Hypopigmented skin and hair.
• No neurological abnormalities.

Type 3

• Isolated hypopigmentation of skin and hair.
• No neurological or immune system problems.

Causes & Pathophysiology

The three types result from mutations in different genes:

• Type 1 – MYO5A gene
• Type 2 – RAB27A gene
• Type 3 – MLPH gene

The proteins encoded by these genes are expressed in melanocytes, the pigment‑producing cells. They cooperate to transport melanosomes—organelles that synthesize melanin—from the cell center to the periphery, where melanin is transferred to surrounding cells for normal pigmentation.

Mutations disrupt melanosome transport, causing melanosomes to cluster centrally and trap melanin, which produces the characteristic light skin and hair. Microscopic examination of hair shafts reveals these pigment clumps, a hallmark of the disorder.

Beyond melanosome transport, MYO5A and RAB27A have additional roles:

• MYO5A protein moves materials within neurons, essential for normal brain function; its loss underlies the neurological deficits of type 1.
• RAB27A protein functions in immune cells to release cytotoxic compounds; its loss leads to the immune dysregulation seen in type 2.

Inheritance

Griscelli syndrome follows an autosomal recessive pattern. Both copies of the relevant gene must carry mutations for the disease to manifest. Parents of an affected individual are typically carriers of a single mutated allele and do not show symptoms.

Other Names

• GS
• Hypopigmentation immunodeficiency disease
• Partial albinism with immunodeficiency

Genetic Testing & Resources

Genetic Testing Information

• Genetic Testing Registry: Griscelli syndrome type 1
• Genetic Testing Registry: Griscelli syndrome type 2
• Genetic Testing Registry: Griscelli syndrome type 3

Patient Support and Advocacy

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Scientific Articles (selected)

• Anikster Y, et al. Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. Am J Hum Genet. 2002.
• Bizario JC, et al. Griscelli syndrome: characterization of a new mutation and rescue of T‑cytotoxic activity by retroviral transfer of RAB27A gene. J Clin Immunol. 2004.
• Cagdas D, et al. Griscelli syndrome types 1 and 3: analysis of four new cases and long‑term evaluation. Eur J Pediatr. 2012.
• Menasche G, et al. Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F‑exon deletion (GS1). J Clin Invest. 2003.
• Menasche G, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000.
• Pastural E, et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin‑Va gene. Nat Genet. 1997.
• Van Gele M, et al. Griscelli syndrome: a model system to study vesicular trafficking. Pigment Cell Melanoma Res. 2009.

Genes Associated with Griscelli syndrome

• MLPH
• MYO5A
• RAB27A