Griscelli syndrome

Overview

Griscelli syndrome is a group of rare, autosomal recessive genetic disorders characterized by partial albinism (light-colored skin and silvery-gray hair) and, depending on the type, may involve severe immune or neurological dysfunction. The condition is divided into three subtypes: Griscelli syndrome type 1, type 2, and type 3, each caused by mutations in different genes and associated with distinct clinical features. While type 3 involves only pigmentary changes, types 1 and 2 are associated with life-threatening complications such as neurological impairment and immune system dysfunction, respectively.

Causes

Griscelli syndrome is caused by mutations in genes involved in melanosome (pigment granule) transport within melanocytes. These include:

• Type 1: Mutation in the MYO5A gene (myosin VA), affecting neurological function and pigmentation

• Type 2: Mutation in the RAB27A gene, leading to immune system defects and hemophagocytic lymphohistiocytosis (HLH)

• Type 3: Mutation in the MLPH gene (melanophilin), causing only pigmentary abnormalities

The disorder is inherited in an autosomal recessive pattern, meaning an affected child must inherit two mutated copies of the gene—one from each parent.

Symptoms

The symptoms of Griscelli syndrome vary by type:

Common Features (All Types):

• Silvery-gray hair, especially on the scalp, eyelashes, and eyebrows

• Light-colored skin (partial albinism)

Type 1 (Neurological Type):

• Severe developmental delays

• Hypotonia (low muscle tone)

• Seizures

• Progressive neurodegeneration

Type 2 (Immunological Type):

• Recurrent, severe infections

• Hemophagocytic lymphohistiocytosis (HLH): fever, enlarged liver and spleen, pancytopenia

• Life-threatening immune activation

Type 3 (Pigmentary Only):

• No neurological or immune involvement

• Normal development and immune function

Diagnosis

Diagnosis of Griscelli syndrome involves a combination of clinical evaluation, microscopy, and genetic testing:

• Clinical observation: Presence of silvery-gray hair and light skin

• Hair shaft microscopy: Shows unevenly distributed melanin clumps

• Genetic testing: Confirms mutations in MYO5A, RAB27A, or MLPH genes

• Neurological evaluation: For type 1 suspicion

• Immunological testing: For signs of immune dysfunction in type 2

• Bone marrow biopsy: May show hemophagocytosis in type 2 cases with HLH

Treatment

Treatment depends on the specific type of Griscelli syndrome and the associated complications:

Type 1:

• No curative treatment

• Supportive care for neurological symptoms

• Antiepileptic medications and physical therapy

Type 2:

• Urgent treatment of HLH with immunosuppressive drugs (e.g., steroids, etoposide, cyclosporine)

• Hematopoietic stem cell transplantation (HSCT): The only curative treatment

Type 3:

• No medical treatment necessary

• Cosmetic or supportive care (e.g., sun protection, hair management)

Prognosis

The prognosis of Griscelli syndrome varies by type:

• Type 1: Poor prognosis due to progressive neurodegeneration; most patients die in early childhood

• Type 2: Fatal if untreated due to HLH, but outcomes can improve significantly with early HSCT

• Type 3: Excellent prognosis; individuals live normal lives with only cosmetic pigmentation differences

Early diagnosis and appropriate genetic counseling are essential for management and family planning in affected families.