Griscelli Syndrome

At a glance

Griscelli Syndrome is a rare autosomal recessive disorder characterized by albinism with immunodeficiency that usually causes death by early childhood. It is characterized by partial pigmentary dilution of the skin and hair (silvery gray hair), frequent infections, neurologic abnormalities, and fatal outcome caused by uncontrolled T lymphocyte and macrophage activation. Clinical features include the presence of large clumps of pigment in hair shafts and a pathological accumulation of melanosomes in melanocytes. Two types are described: Type I with severe neurologic impairment and Type II with immunologic deficiency.

Synonyms and Classification

• Type I: Griscelli Syndrome (Elejalde Syndrome) with Neurologic Impairment; Partial Albinism and Primary Neurologic Disease without Hemophagocytic Syndrome; Cutaneous and Neurologic type of Griscelli Syndrome. It is an extremely rare autosomal recessive syndrome (only around 10 cases reported in the literature) consisting of moderate pigment dilution, profound primary neurologic defects, no immune defects, and hair with metallic silvery sheen.

• Type II: Chediak-Higashi-Like Syndrome; Partial Albinism Immunodeficiency Syndrome; PAID Syndrome.

• Type III: Griscelli Syndrome variant characterized as a disorder of melanosome transport presenting initially with hypopigmentation.

History

It is named after Claude Griscelli, professor of pediatrics at Hôpital Necker-Enfants Malades in Paris (France).

Incidence

Approximately 60 cases have been described; most reported cases are from Turkish and other Mediterranean populations. The age at diagnosis ranged from 1 month to 8 years, with a median of 17.5 months (in 20 patients).

Genetic inheritance

Autosomal recessive disorder. The responsible gene is located on 15q21.

Pathophysiology

Histopathology of Griscelli Syndrome (GS) involves prominent, mature melanosomes in skin and hair follicle melanocytes, but sparse pigmentation of adjacent keratinocytes. This leads to large, clumped melanosomes in hair shafts, resulting in hair that has a silvery-gray sheen. Type I is caused by mutation in the MyoVa (Myo5a)-gene, which is involved in melanocytic and neuronal cell vesicle transport. Type II is caused by mutations in the RAB27A gene, which encodes for a membrane-bound protein that is involved in signal transduction and similar to, or in combination with MyoVa, in the melanosome transport. Immunodeficiency often involves impaired natural killer cell activity, absent delayed-type hypersensitivity, and a poor cell proliferation response to antigenic challenges. The two genes encode for proteins, which are key effectors of intracellular vesicular transport. RAB27A seems also to be involved in the cytotoxic granule exocytosis.

Diagnosis

The single most consistent dermatological expression of albinism is the presence of silvery-gray hair. GS must be considered for any child with combined hypopigmentation and neurologic abnormalities (Type I) or what is called hemophagocytic lymphohistiocytosis, (the acute phase of severe infections may be characterized by an uncontrolled activation of macrophages and lymphocytes, which is also called the accelerated phase) (Type II). ...