Griscelli Syndrome

Updated: Jan 19, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Griscelli and Prunieras [1] initially described Griscelli syndrome, or partial albinism with immunodeficiency, in 1978. Griscelli worked at Hospital Necker-Enfants Malades in Paris, France.

Griscelli syndrome is a rare autosomal recessive disorder that results in pigmentary dilution of the skin and the hair (silver hair), the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. In one variant, hepatosplenomegaly, lymphohistiocytosis, and a combined T-cell and B-cell immunodeficiency are pronounced. The associated immunodeficiency often involves impaired natural killer cell activity, absent delayed-type hypersensitivity, and a poor cell proliferation response to antigenic challenge. Occasionally, impaired lymphocyte function and an inability to produce normal levels of immunoglobulins have also been described. In another variant, neurologic signs are most prominent.

Children with Griscelli syndrome caused by a defect in the RAB27A gene develop an uncontrolled T-lymphocyte and macrophage activation syndrome known as hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH). [2, 3, 4] HS usually results in death unless the child receives a bone marrow transplant. Children with a defect in the MYO5A gene develop neurologic problems but no immunologic problems.

Takagishi and Murata [5] noted that a myosin Va mutation in rats is an animal model for the human hereditary neurological disease, Griscelli syndrome type 1. The exact role of myosin Va in Griscelli syndrome has to been defined further as Harper et al (2013) [6] demonstrated no significant functional defects in α-granule, lysosomal secretion, dense granule, Ca(2+) signalling, integrin α(IIb)β(3) activation, or spreading on fibrinogen in response to the PAR4 agonist or collagen-related peptide or in dense and α-granules numbers expressed. Thus, Harper et al conclude that myosin Va possesses no evident nonredundant role involving either the secretion of α-granules and dense granules and neither in other platelet functional responses. [6]

When analyzing cases of Griscelli syndrome, the 3 variations of it must be parsed and the apposite variant diagnosed. [7] Griscelli syndrome type 1 manifests with primary dysfunction of central nervous system. Type 2 Griscelli syndrome commonly develops HLH. Type 3 Griscelli syndrome manifests with merely partial albinism. This parsing is important as the 3 types of Griscelli syndrome have different courses. In particular, one report describes a Griscelli syndrome type I patient alive at age 21 years without no problems except motor retardation and severe mental retardation and 2 patients with Griscelli syndrome type 3, healthy at ages 21 and 24 years, manifesting merely with eye brows, eyelashes, silvery gray hair, and pigmentary dilution. [8]

Janka [9] reported that HLH occurs in (1) 3 types of familial genetic forms in which HLH is the primary and only manifestation and (2) in association with the immune deficiencies Griscelli syndrome type 2, Chediak-Higashi syndrome type 1, and X-linked lymphoproliferative syndrome, in which HLH is a sporadic event. Thus, one way of classifying Griscelli syndrome is with other diseases that are associated with HLH, such as Chediak-Higashi syndrome. [10] This finding has been reiterated in other case reports. [11]

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Pathophysiology

Griscelli syndrome is caused by mutations in 1 of 3 genes. Two of these genes are located at band 15q21: RAB27A and MYO5A. These 2 genetic defects result in both similar and distinct physical and pathologic findings. A third form of Griscelli syndrome, whose expression is restricted to the characteristic hypopigmentation of Griscelli syndrome, results from mutation in the gene that encodes melanophilin MLPH, the ortholog of the gene mutated in leaden mice. [12] It has also been shown that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern.

The first genetic defect identified in Griscelli syndrome was the gene that codes for myosin V-MYO5A. Subsequently, a second gene, the guanosine triphosphate (GTP)-binding protein RAB27A whose gene product is a reticular activating system–associated protein (RAS-associated protein), on a nearby locus, was cloned. Mutations in RAB27A have been found in all the patients with Griscelli syndrome who were analyzed and who did not have the mutated MYO5A.

Myosin Va (or Myosin 5a) is a member of the unconventional class myosin V family, and a mutation in the myosin Va gene causes pigment granule transport defects in the human form of Griscelli syndrome and in dilute mice. Slac2-a/melanophilin (leaden gene in mice) links the function of myosin Va and GTP-Rab27A present in the melanosome. [13]

The gene products of MYO5A and RAB27A are involved in the movement of melanosomes. Defects in each result in pigmentary dilution. In some body and cellular sites, MYO5A and RAB27A are expressed differently. MYO5A is expressed in the brain, whereas RAB27A is not. Defects in MYO5A cause neurologic pathology, whereas defects in RAB27A do not cause neurologic defects. Current understanding suggests that RAB27A-MLPH-MYO5A form a tripartite complex facilitating intracellular melanosome transport. [14]

Unlike Myosin Va, which is the gene product of MYO5A, the GTP-binding protein, which is the gene product of RAB27A (ie, Rab27a), appears to be involved in the control of the immune system because all patients with the RAB27A mutation develop HS, but none with the MYO5A mutation do. In addition, Rab27A-deficient T cells exhibit reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells do not.

Rab27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis. Rab27a, a small GTPase, interfaces with multiple effectors, including Slp2-a and Myrip, all parts of the melanosome transport system. RAB27A -deficient T cells have demonstrated a normal granule content in perforin and granzymes A and B, but they showed defective granule release. RAB27B is another protein produced in cells and RAB27B and RAB27A are functionally redundant. [14] A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome has been noted. [15]

The onset of HS (accelerated phase) seems to be associated with a viral infection (eg, Epstein-Barr virus, hepatitis A virus, herpes virus 6) or sometimes a bacterial infection. When a remission is obtained, recurrent, accelerated phases with increasing severity are seen. Patients with a RAB27A mutation also have neurologic problems related to HS and a lymphohistiocytic infiltration of the CNS. These CNS problems wax and wane. The CNS problems in patients with Griscelli syndrome with mutations in MYO5A, do not wax and wane.

As stated above, another gene termed leaden (ln) in mice and MLPH in humans located at band 2q37 produces melanophilin, which is involved in melanosome movement and the interaction of the gene products of RAB27A and MYO5A.

In 2005, Neeft et al [16] noted that Griscelli syndrome type 2 is caused by the absence of functional Rab27a; the manner in which Rab27a controls secretion of lytic granule contents remains elusive.

Mutations in Munc13-4 cause familial hemophagocytic lymphohistiocytosis subtype 3 (FHL3), a syndrome that resembles Griscelli syndrome type 2

Neeft et al [16] have shown that Munc13-4 intimately interacts with Rab27a. Rab27a and Munc13-4 are intensely expressed in cytolytic T lymphocytes and mast cells. Rab27a and Munc13-4 co-localize on secretory lysosomes. The region comprising the Munc13 homology domains is needed to facilitate the localization of Munc13-4 to secretory lysosomes. They found that the Griscelli syndrome type 2 mutant Rab27aW73G strongly decreased linking to Munc13-4, whereas the FHL3 mutant (Munc13-4Delta608-611) failed to bind Rab27a.

Neeft et al [16] also showed that overexpression of Munc13-4 enhances degranulation of secretory lysosomes in mast cells. This finding demonstrates that Munc13-4 plays a positive regulatory role in secretory lysosome fusion. They went on to suggest that the secretion defects observed in Griscelli syndrome type 2 and FHL3 have a common origin and proposed that the therab27a/Munc13-4 complex is an essential regulator of secretory granule fusion with the plasma membrane in hematopoietic cells. Mutations in either Rab27a or Munc13-4 prevented the formation of this complex and abolished secretion.

In 2004, Westbroek et al [17] reported a genomic RAB27A deletion found in a 21-month-old Moroccan Griscelli syndrome patient and provided evidence that the loss of functional Rab27a in melanocytes of this Griscelli syndrome patient was partially compensated by the up-regulation of Rab27b, a homologue of Rab27a. They used real-time quantitative polymerase chain reaction and Western blot analysis to show that Rab27b mRNA and protein were expressed at low levels in normal human melanocytes. In contradistinction, a significantly up-regulated expression of these genes occurred in melanocytes derived from this boy with Griscelli syndrome.

The immunofluorescence and yeast 2-hybrid screening studies performed by Westbroek et al [17] revealed that Rab27b can form a tripartite complex on the melanosome membrane with melanophilin, a Rab27a effector, and protein products of myosin Va transcripts that contain exon F. Their data suggest the presence of up-regulated Rab27b in melanocytes of Griscelli syndrome patients. Rab27b appears capable of partially assuming the role of Rab27a. This observation explains the observation that the patient in this study reportedly had evenly pigmented skin and was able to tan.

Gazit et al [18] noted that in Griscelli syndrome, NK cytotoxicity mediated by CD16 is functional but not by NKp30.

Desnos et al [19] noted that in neurons, myosin Va manages the targeting of IP3 (inositol 1,4,5-trisphosphate)–sensitive Ca2+ stores to dendritic spines. Myosin Va also controls the transport of mRNAs in persons with Griscelli syndrome type 2.

Vincent et al reported that severe Griscelli syndrome type 2 can result from a novel 47.5-kb deletion in RAB27A. [20]

A MYO-5A exon-F deletion in Griscelli syndrome type 3–like phenotype was noted in 2014. [21]

Patients with Griscelli syndrome and normal pigmentation denote RAB27A mutations, which selectively disrupt MUNC13-4 binding. [22]

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Epidemiology

Frequency

United States

Fewer than 10 cases have been reported in the United States.

International

Most reported cases are from Turkish and Mediterranean populations; however, in 2004, Manglani et al [23] and Rath et al [24] reported several cases from India. Regardless, the disease is rare in all countries. As of January 2003, about 60 cases have been reported worldwide.

A report from India noted 7 patients with hemophagocytic lymphohistiocytosis, of which only 1 had Griscelli syndrome. [25]  A group of type 2 Griscelli syndrome patients was reported in 2015 in India. [26]  A report from France noted a 6-year-old child who presented with classic symptoms of Griscelli syndrome type 2, including hemophagocytic syndrome and severe sepsis. [27]

Race

Griscelli syndrome is a rare disease in all populations. Most cases reported are from Turkish and Mediterranean populations.

Sex

Griscelli syndrome is not a sex-linked condition; thus, males and females are affected equally.

Age

Griscelli syndrome usually manifests in persons aged 4 months to 4 years. One review reported that the onset of Griscelli syndrome ranged from 1 month to 8 years, with a mean patient age of 17.5 months. Children with mutations in MYO5A seem to manifest with symptoms earlier than those with mutations in RAB27A. In most patients, diagnosis occurs between the ages of 4 months to 7 years, with the youngest occurring at 1 month. [28]

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