Griscelli syndrome type 2

Overview

Griscelli syndrome type 2 (GS2) is a rare and severe autosomal recessive genetic disorder characterized by partial albinism and immune system dysfunction. It is one of three types of Griscelli syndrome, each involving mutations in different genes and presenting with distinct clinical features. GS2 is specifically associated with immunodeficiency and an increased risk of developing a life-threatening condition known as hemophagocytic lymphohistiocytosis (HLH), a disorder of excessive immune activation. The syndrome typically presents in infancy or early childhood and requires urgent medical attention.

Causes

Griscelli syndrome type 2 is caused by mutations in the RAB27A gene located on chromosome 15q21.3. This gene encodes a protein involved in intracellular vesicle trafficking, especially in pigment-producing melanocytes and immune cells like cytotoxic T lymphocytes and natural killer (NK) cells. A defect in RAB27A disrupts the transport of melanosomes in the skin and hair, leading to hypopigmentation, and impairs the ability of immune cells to kill infected or abnormal cells, leading to uncontrolled immune activation.

Symptoms

The main clinical features of Griscelli syndrome type 2 include:

Hypopigmentation:

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

• Light-colored skin and hair due to abnormal melanosome distribution

Immunological Dysfunction:

• Recurrent severe infections

• Fever, hepatosplenomegaly (enlarged liver and spleen)

• Hemophagocytic lymphohistiocytosis (HLH), which presents with:

  • Persistent high fever

  • Pancytopenia (low blood counts)

  • Liver dysfunction

  • Coagulopathy (clotting abnormalities)

  • Neurological symptoms (in advanced cases)

Unlike other types of Griscelli syndrome, type 2 does not usually involve significant neurological impairment unless secondary to HLH.

Diagnosis

Diagnosis of GS2 is based on clinical presentation, microscopic examination, and genetic testing:

• Microscopic analysis of hair shafts: Shows large, uneven melanin clumps under light microscopy

• Peripheral blood smear: May show evidence of HLH with cytopenias

• Bone marrow biopsy: Reveals hemophagocytosis in HLH cases

• Immunological testing: Shows impaired NK cell function and cytotoxic T cell abnormalities

• Genetic testing: Confirms mutations in the RAB27A gene

Early diagnosis is crucial due to the aggressive nature of the associated immune dysfunction.

Treatment

Treatment of Griscelli syndrome type 2 requires urgent and aggressive management of immune system dysfunction, particularly HLH:

Medical Management:

• Immunosuppressive therapy: Corticosteroids, etoposide, and cyclosporine used to treat HLH

• Supportive care: Antibiotics for infections, blood transfusions, and nutritional support

Definitive Therapy:

• Hematopoietic stem cell transplantation (HSCT): The only curative treatment, aimed at correcting the immune defect

HSCT should be considered early in the disease course to prevent irreversible organ damage from HLH.

Prognosis

The prognosis of Griscelli syndrome type 2 is poor without treatment, especially once HLH develops. Most untreated patients succumb to complications of immune dysregulation within the first few years of life. However, with early diagnosis and timely stem cell transplantation, long-term survival is possible. Lifelong follow-up and multidisciplinary care are necessary to manage complications and ensure immune system restoration post-transplant.