Griscelli Syndrome

Clinical Definition, Features and Genetic Patterns

Photo courtesy of Semantic Scholar Opens in new window

Griscelli syndrome (GS) is a rare autosomal recessive disorder Opens in new window characterized by pigmentary dilution of the skin, due to abnormal melanosomal transport which result in abnormal accumulation of end-stage melanosomes in the centre of melanocytes, and by silvery grey hair, due to pigment clumping in hair shafts.

Three phenotypic spectrums (GS1: OMIM #607624 Opens in new window, GS2: OMIM #214450 Opens in new window, and GS3: OMIM #609227 Opens in new window) of the disease have been described.

While most patients also develop an hemophagocytic syndrome, characterized by uncontrolled activation of T lymphocytes and macrophages leading to death if not treated by bone marrow transplantation (OMIM #607624), some show severe primary neurological impairment early in life without apparent immune abnormalities (OMIM #214450) and other have hypomelanosis only with no immunologic or neurological manifestations (OMIM #609227).

Of recent, all three phenotypes have been grouped under the same umbrella name (i.e., Griscelli syndrome/GS) because of shared biological mechanisms, but divided into three different subtypes (GS1–GS3), as they result from defects in three separate genes, located on chromosome 15q21 and 2q37:

1. Myosin VA (MYO5A) gene, located on chromosome 15q21 (OMIM #160777), causing GS with neurological impairment without hemophagocytic syndrome or GS1 (OMIM #214450);
2. Ras-associated protein RAB27A gene, located on chromosome 15q21 (OMIM #603868), causing GS with hemophagocytic syndrome or GS2 (OMIM #60764);
3. Slac2-a/melanophilin (SLAC2A/MLPH) gene, located on chromosome 2q37 (OMIM #606526), causing GS with no immunologic or neurological involvement or GS3 (OMIM #609227).

The protein products of the three genes are functionally closely linked one to each other and interacts in the same molecular pathways, resulting in melanosome transport of actin filaments to dock at the plasma membrane (i.e., in melanosome movement).

Defects in each gene result in pigmentary dilution because of defective release of melanosome content to neighboring cells, such as keratinocytes in the skin.

In some body and cellular sites, however, MYO5A and RAB27A are expressed differently. For example, MYO5A is expressed in the brain, whereas RAB27A is not.

Defects in MYO5A cause primary neurological dysfunction, whereas defects in RAB27A do not cause neurological abnormalities (unless as secondary effects of lymphocyte infiltration of central nervous system).

Unlike myosin Va (the protein product of MYOVA), the GTP-binding protein (the protein product of RAB27A) appears to be involved in the control of the immune system thus causing the hemophagocytic syndrome.

Melanophilin (Mlph) links the function of myosin Va and the GTP-Rab27a protein in the melanosome without additional functions: this explains why expression is restricted to the characteristic hypopigmentation in the third form of GS.

In the protein complex Rab27a-Mlph-MyoVa, Mlph interacts with Rab27a through its N-terminal part (SHD) and with Myo Va through its C-terminal part (F-exon).

Series of research have shown that the GS form caused by mutations in the MYOVA gene (GS1) and the called Elejalde syndrome (OMIM #256710) are allelic or better represent the same entity.

The GS form caused by mutations Opens in new window in the Slac2-a/melanophilin (SLAC2A/MLPH) gene (GS restricted to hypopigmentation) represents the so-called silvery hair syndrome Opens in new window restricted to pigment dilution (OMIM #609227).

Clinical Manifestations

Often the first manifestation of Griscelli syndrome (GS) that is noted is silvery hair. Not long after the immunologic effects of GS caused by mutations in the Rab27A gene (GS2) are noted.

These immunologic defects resemble those of the hemophagocytic lymphohistiocytosis (HLH) and the X-linked lymphoproliferative syndrome. The neurological effects of GS caused by defects in MYOVA gene usually manifest early in life closer to birth.

Mutations in both MYO5A and RAB27A genes cause pigmentary dilution and other internal organ abnormalities. Skin manifestations of both GS1 and GS2 include granulomatous skin lesions, partial albinism, and generalized lymphadenopathy.

The skin is usually pale, but the hypopigmentation is not complete. Liver manifestations include hepatosplenomegaly and jaundice as a result of hepatitis.

Patients can present with pallor as a result of pancytopenia. Partial ocular hypopigmentation has been observed in some patients but retinal degeneration has not been reported.

The following pages are designed to describe the main clinical features, the pathogenesis and molecular genetic aspects according to the three different subtypes.

Incidence and Prevalence

Griscelli syndrome is a rare disease in all populations. Male and female are equally affected. Most reported cases are from Turkish and Mediterranean populations; however, in 2004, Manglani et al. (20045) and Rath et al. (2004) reported several cases from India.

It is rare in the US with fewer than 10 cases reported. The largest series of patients with GS1 (Griscelli/Elejalde syndrome) have been reported in Mexico.

Historical Perspective and Eponyms

Historically, Griscelli and co-workers who worked at the Hospital Necker pour les enfants maladies in Paris, France, and his colleague Siccardi first described a condition characterized partial albinism Opens in new window, frequent pyogenic infections and acute episodes of fever, neutropenia and thrombocytopenia.

The pigmentary dilution was characterized by large clumps of pigment in the hair shafts and an accumulation of melanosomes in melanocytes.

Despite an adequate number of T and B lymphocytes, the patients were hypogammaglobulinemic, deficient in antibody production, and incapable of delayed skin hypersensitivity and skin graft reaction. Their leukocytes did not stimulate normal leukocytes.

A defect of helper T-cells was postulated. One patient was an 11-year-old North African girl with unrelated parents with a brother and sister with silvery hair who had died at 30 and 18 months of age, respectively.

The morphological normality of polymorphonuclear leukocytes and lack of giant granules distinguished the disorder from Chediak-Higashi syndrome Opens in new window.

The morphologic characteristics of hypopigmentation also distinguished the disorder from Chediak-Higashi syndrome, as well as from other pigmentary anomalies. These original cases fit with the GS2 phenotype Opens in new window.

Diagnosis

As silver hair syndrome present four different clinical and genetic patterns, in view of the restricted or failure of current therapeutic measures, a correct diagnosis is mandatory to offer a correct genetic counseling Opens in new window to the families with affected children.

Skin biopsy and light microscopic examination in all the three forms of GS reveals the same pattern. Light microscopy of the hair reveals a different distribution of melanin in small and large clumps irregularly arranged along the hair shaft.

MYOVA and RAB27A interact in the same molecular pathway, resulting in melanosome transport.

Menasche et al. (2002) suggested that patients with partial (albinos-like) hypopigmentation and manifestations of hemophagocytic syndrome, with or without neurological involvement, should be screened for mutations in RAB27A, and patients with partial (albinos-like) hypopigmentation and primary neurological disease without hemophagocytic syndrome should be screened for MYO5A mutations.

Characteristic laboratory features in GS2 include pancytopenia, hypofibrinogenemia, and hypoproteinemia.

Therapeutics

Medical treatment for patients with GS is difficult. For patients with defects in RAB27A (GS2) Opens in new window, antibiotics and antiviral agents are used with mixed effects. Similarly medications may not control the neurological signs/symptoms of the disease.

In GS related to MYO5A mutations (GS1) Opens in new window, no specific treatment exists because the defect is in the brain rather than in the blood cells as in cases caused by mutations in the RAB27A mutations (GS2) Opens in new window. The severe neurological impairment and retarded psychomotor development do not improve with time.

Only allogenetic bone marrow transplantation is the treatment of choice in the early period of the disease.

In preparation for a transplant, particularly in patients with GS caused by mutations in RAB27A (GS2), various immunosuppressive regimes have been used to attenuate the accelerated phase.

Even a low number of donor cells in the patient’s bone marrow can be sufficient to control symptoms of GS cases caused by mutations of the RAB27A gene (GS2).