Griscelli Syndrome, Type 1

A number sign (#) is used with this entry because of evidence that Griscelli syndrome with primary neurologic impairment and without immunologic impairment, referred to as type 1, is caused by homozygous mutation in the gene encoding myosin VA (MYO5A; 160777) on chromosome 15q21.

Description

Griscelli syndrome type 1 (GS1) represents hypomelanosis with a primary neurologic deficit and without immunologic impairment or manifestations of hemophagocytic syndrome (Menasche et al., 2002). Griscelli syndrome with immune impairment, or Griscelli syndrome type 2 (607624), is caused by mutation in the RAB27A gene (603868). Griscelli syndrome type 3 (609227), characterized by hypomelanosis with no immunologic or neurologic manifestations, can be caused by mutation in the melanophilin (MLPH; 606526) or MYO5A genes.

Griscelli syndrome is a rare autosomal recessive disorder that results in pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. While most patients also develop hemophagocytic syndrome, leading to death in the absence of bone marrow transplantation (Menasche et al., 2000), some show severe neurologic impairment early in life without apparent immune abnormalities. Bahadoran et al. (2003) characterized GS1 as comprising hypomelanosis and severe central nervous system dysfunction, corresponding to the 'dilute' phenotype in the mouse, and GS2 as comprising hypomelanosis and lymphohistiocytotic hemophagocytosis, corresponding to the 'ashen' phenotype in mouse.

Anikster et al. (2002), Menasche et al. (2002), Huizing et al. (2002), and Bahadoran et al. (2003, 2003) suggested that Elejalde syndrome (256710) in some patients and GS1 represent the same entity.

Clinical Features

As the original patients described by Griscelli et al. (1978) manifested signs of an immune dysfunction, these patients are discussed in the entry for GS2 (607624).

Pastural et al. (1997, 2000) described patients with Griscelli syndrome who were found to have mutations in the MYO5A gene. Both patients were referred because of hypotonia, marked motor development delay, and mental retardation, without a history of infections or 'accelerated phase' characterized by uncontrolled T lymphocyte and macrophage activation.

Duran-McKinster et al. (1999) described 7 patients thought to have Elejalde syndrome. The patients had silvery hair and profound neurologic dysfunction. Immune impairment was not found. The age of onset of neurologic signs ranged from 1 month to 11 years. The signs included severe muscular hypotonia, ocular alterations, and seizures. Mental retardation since the first months of life was noted in 4 cases. Psychomotor development was normal in 3 cases, but suddenly the patients presented with a regressive neurologic process. Four patients died between 6 months and 3 years after the onset of neurologic dysfunction. In addition to the silver-leaden hair, bronze skin developed after sun exposure. Large granules of melanin unevenly distributed in the hair shaft were observed. Duran-McKinster et al. (1999) recommended that the differential diagnosis include Chediak-Higashi syndrome (214500) and Griscelli syndrome.

Ivanovich et al. (2001) reported a 12-year-old male with Elejalde syndrome, also known as neuroectodermal melanolysosomal disease, and compared this condition with Chediak-Higashi and Griscelli syndromes. Their patient had severe developmental delay, seizure activity, exotropia, nystagmus, ataxia, and silvery gray hair and eyebrows. His skin was not hypopigmented but bronzed with diffuse freckling in sun-exposed areas. He had no history of recurrent infections and had normal immunologic studies. The authors suggested that their case may be the oldest living child with this condition reported in the literature.

Bahadoran et al. (2003) noted that 2 groups of patients with Elejalde syndrome, possibly representing separate entities, were described. In the original description patients showed the characteristic hair shaft melanin granule clumping of Griscelli syndrome, but melanosome transfer to keratinocytes appeared normal, melanocyte maturation appeared abnormal, and inclusion bodies occurred in other cell types. By contrast, the second series of Elejalde syndrome patients (Duran-McKinster et al., 1999; Ivanovich et al., 2001) had clinical and histologic features suggestive of GS1.

Thomas et al. (2009) reported 2 sisters, born of consanguineous Iraqi parents, with Griscelli syndrome type 1 confirmed by genetic analysis. Both had pigmentary abnormalities of the hair and skin. Neurologic signs included roving eye movements, seizures, hypotonia, and delayed psychomotor development with mental retardation. Both developed scoliosis and became wheelchair-bound, likely due to neurologic impairment. A maternal uncle was reportedly affected.

Molecular Genetics

Pastural et al. (1997) used linkage analysis in 3 consanguineous families and 1 nonconsanguineous family to map Griscelli syndrome to 15q21. Because of the similarities to the phenotype in the 'dilute' mouse, which is due to mutation in an unconventional myosin gene, they looked at regions of chromosomes 19, 10, and 18 known to contain genes of this type and excluded linkage to those areas. On the other hand, a peak lod score of 4.40 was obtained for a cluster of markers on chromosome 15, in a region containing the MYO5A gene. Pastural et al. (1997) demonstrated a nonsense mutation in MYO5A (160777.0002) in a Turkish patient.

Menasche et al. (2002) discussed the relationship between Griscelli syndrome type 1 and Elejalde syndrome (256710). Anikster et al. (2002) suggested that neurologic involvement in some patients with Griscelli syndrome occurred secondarily to the hemophagocytic syndrome and that patients with primary central nervous system (CNS) complications and MYO5A mutations have Elejalde syndrome. Several reports established that neurologic manifestations in patients with Griscelli syndrome caused by RAB27A (603868) (GS2) were related to lymphocyte infiltration of the CNS (Menasche et al., 2000; Pastural et al., 2000; de Saint Basile and Fischer, 2001), whereas patients with Griscelli syndrome caused by MYO5A mutations (GS1) exhibited a primary neurologic disease, potentially described as Elejalde syndrome, unrelated to the hematopoietic lineage, as observed in Myo5a mutant 'dilute' mice (de Saint Basile and Fischer, 2001; Ivanovich et al., 2001). MYO5A and RAB27A interact in the same molecular pathway, resulting in melanosome transport on actin filaments to dock at the plasma membrane. Menasche et al. (2002) suggested that patients with partial albinism and manifestations of hemophagocytic syndrome, with or without neurologic involvement, should be screened for mutation in RAB27A, and patients with partial albinism and primary neurologic disease without hemophagocytic syndrome should be screened for MYO5A mutations.