Background
Griscelli syndrome (GS) 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. Three variants of Griscelli syndrome have been identified: Griscelli syndrome types 1-3. Griscelli syndrome type 2 is the most common type and has the most severe presentation, if left untreated.
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.
In Griscelli syndrome type 1, a defect in the myosin Va gene leads to the pigment dilution and neurological sequelae. Myosin Va plays a role in neurons, including development, axonal transport, dendritic spine structure, and synaptic plasticity. [2] Myosin Va has no role involving the secretion of α-granules and dense granules from lymphocytes or other platelet functional responses. [3] Griscelli syndrome type 1 is also thought to be the same entity or allelic to Elejalde syndrome, with ocular manifestations being prominent in Elejalde syndrome. [4] The exact role of myosin Va in Griscelli syndrome has yet to been defined further. Children with a defect in the MYO5A gene (Griscelli syndrome type 1) develop neurologic problems but no immunologic problems. [5]
Griscelli syndrome type 2 is caused by a defect in the RAB27A gene, which affects a melanosome-anchoring complex in melanocytes, affecting release of cytolytic granules from T cells and natural killer cells. Children with Griscelli syndrome type 2 develop an uncontrolled T-lymphocyte and macrophage activation syndrome known as hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH). [6, 7, 8] HS usually results in death unless the child receives bone marrow transplantation. In Griscelli syndrome type 2, hepatosplenomegaly, lymphohistiocytosis, and a combined T- 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. The same mutation can have varying phenotypes in different patients. [9, 10]
Griscelli syndrome type 3 manifests with the sole feature of partial albinism. Affected individuals present with pigment dilution and no systemic findings; the immune and nervous systems are intact.
When analyzing cases of Griscelli syndrome, the three variations of it must be parsed and the apposite variant diagnosed. [11]
This parsing is important as the three types of Griscelli syndrome have different courses. Griscelli syndrome type 1 manifests with primary dysfunction of the CNS. Griscelli syndrome type 2 patients commonly develop HLH, and Griscelli syndrome type 3 presents with skin dilution and no systemic findings. In particular, one report describes a Griscelli syndrome type 1 patient alive at age 21 years with motor retardation and severe intellectual disability and two patients with Griscelli syndrome type 3, healthy at ages 21 and 24 years, manifesting merely with silvery grey eyebrows, eyelashes, and hair, as well as pigmentary dilution in the skin. [12]
Griscelli syndrome type 2 can be classified with other familial causes of HLH (FHLH) such as Chédiak-Higashi syndrome type 1 (CHS1), Griscelli syndrome type 2, and X-linked lymphoproliferative (XLP) syndrome. [13, 14] This finding has been reiterated in other case reports. [15]
Pathophysiology
Griscelli syndrome (GS) is caused by mutations in one of three genes: RAB27A, MYO5A, or MLPH. Two of these genes, RAB27A and MYO5A, are located at band 15q21. These two genetic defects result in both similar and distinct physical and pathologic findings. The third form of Griscelli syndrome, whose expression is restricted to the characteristic hypopigmentation, results from mutation in the gene that encodes melanophilin, MLPH, the ortholog of the gene mutated in leaden mice. [16] Defect of MLPH is located on band 2q37.3. It has also been shown that an identical phenotype to Griscelli syndrome type 3 results from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. [17]
Deficient melanocytes of any of these genes leads to accumulation of melanosomes near the microtubule organizing center and failure to transfer to keratinocytes. Current understanding suggests that RAB27A-MLPH-MYO5A form a tripartite complex facilitating intracellular melanosome transport. [18]
The first genetic defect identified in Griscelli syndrome was the gene that codes for myosin Va (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. There is heterogenicity in genotype-phenotype in Griscelli syndrome type 2, with presentation that overlaps with Griscelli syndrome type 1. [19]
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 type 1 and in dilute mice. The gene products of MYO5A and RAB27A are involved in the movement of melanosomes. Defects in either result in pigmentary dilution.
Myosin Va is an important protein in intracellular vesicle transport. This is important for fast axonal transport in nerve cells. This may explain the neurological complications seen in Griscelli syndrome type 1. Myosin Va plays a role in neurons, including development, axonal transport, dendritic spine structure, and synaptic plasticity. [6] An enzyme spermine synthetase has been noted to interact with myosin Va GTD by means of yeast two hybrid screen. Mutation in MYO5A results in reduced activity of spermine synthase; this enzyme is reduced in the X-linked disorder Snyder-Robinson intellectual disability syndrome. [20]
Desnos et al 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. [21]
In certain sites in the body, 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. A possible overcompensation by other proteins in different organs might explain the different phenotypes.
In Griscelli syndrome type 2, 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 does. 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. [18] A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome has been noted. [22]
In 2005, Neeft et al [23] 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.
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 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.
Mutations in Munc13-4 cause familial hemophagocytic lymphohistiocytosis subtype 3 (FHL3), a syndrome that resembles Griscelli syndrome type 2. Neeft et al 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. 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. [23]
In 2004, Westbroek et al [24] 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 [24] 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 [25] noted that in a Griscelli syndrome type 2 patient, CD16-mediated killing was intact and therefore RAB27A-independent, whereas NKp30-mediated killing was impaired and is therefore RAB27A-dependent. They demonstrated signaling pathways of these two receptors and phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. This shows the functional dichotomy in the killing mediated by these human NK-activating receptors. [25]
Vincent et al reported that severe Griscelli syndrome type 2 can result from a novel 47.5-kb deletion in RAB27A. [26]
The gene termed MLPH in humans, leaden (ln) in mice, is located at band 2q37 and produces a protein melanophilin. Melanophilin is involved in melanosome movement and the interaction of the gene products of RAB27A and MYO5A to form the tripartite complex (RAB27A-MLPH-MYO5A). MLPH function in organelle motility appears to be limited to skin melanocytes. [18] Slac2-a/melanophilin (leaden gene in mice) links the function of myosin Va and GTP-Rab27A present in the melanosome. [16]
A MYO-5A exon-F deletion in Griscelli syndrome type 3–like phenotype was noted in 2014. [27]
Patients with Griscelli syndrome and normal pigmentation denote RAB27A mutations, which selectively disrupt MUNC13-4 binding. [28]
Etiology
Griscelli syndrome (GS) is a genetic disorder related to mutations in MYO5A in Griscelli syndrome type 1, RAB27A in Griscelli syndrome type 2, and MLPH in Griscelli syndrome type 3. The condition is inherited as an autosomal recessive disorder. Each parent carries one defected gene. History of consanguinity is common. Mutations in any of the three genes, MYO5A, RAB27A, or MLPH, impair the normal transport of melanosomes within melanocytes.
Epidemiology
United States
Around 10 cases of Griscelli syndrome (GS) have been reported in the United States.
International
There are 150 cases of Griscelli syndrome reported to date. Most reported cases are from Turkish and Mediterranean populations. Several cases have been reported from India, [29, 30, 31, 32] as well as one from France, [33] the site of Griscelli’s initial observation. In 2004, Manglani et al and Rath et al reported several cases from India. Regardless, the disease is rare in all countries.
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 and 7 years, with the youngest occurring at 1 month. [34] Late-onset Griscelli syndrome type 2 has been described, reported in a 24-year-old female with CNS involvement and HS. [35]
Prognosis
The prognosis for long-term survival of patients with Griscelli syndrome (GS) type 2 is relatively poor. It is usually rapidly fatal within 1-4 years without aggressive treatment and bone marrow transplantation at onset of an accelerated phase. Some patients have died after transplantation, but others have had lasting remissions. The mean patient age at the time of death is 5 years.
The presence of cutaneous granulomas aids in detection of Griscelli syndrome, and it portends a poor prognosis with systemic involvement. [36]
The prognosis for Griscelli syndrome type 1 and 3 is better, although with long-term neurological sequela and disabilities in the former.
Patient Education
Parents must understand that their children need aggressive care and that they can have additional children with Griscelli syndrome (GS); there is a 25% chance for the disease to be passed to future children.
In Griscelli syndrome type 2, counselling is needed about the urgent need for a bone marrow transplantation and the complications associated with the procedure. Without bone marrow transplantation, the prognosis is dismal.
Type 1 and 3 Griscelli syndrome have no specific treatments. Symptomatic and supportive therapies are provided.
