eMedicine Specialties > Dermatology > Diseases of Pigmentation
Griscelli Syndrome
Updated: Feb 1, 2008
Introduction
Background
Griscelli and Prunieras1 initially described Griscelli syndrome (GS), or partial albinism with immunodeficiency, in 1978. Griscelli worked at Hospital Necker-Enfants Malades in Paris, France.
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. 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 GS 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 Murata5 noted that a myosin Va mutation in rats is an animal model for the human hereditary neurological disease, GS type 1.
Janka6 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 GS type 2 (GS2), Chediak-Higashi syndrome type 1, and X-linked lymphoproliferative syndrome, in which HLH is a sporadic event. Thus one way of classifying GS is with other diseases that are associated with hemophagocytic lymphohistiocytosis such as Chediak Higashi syndrome.7
Pathophysiology
GS 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 GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin MLPH, the ortholog of the gene mutated in leaden mice.8 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 GS 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 GS 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 GS and in dilute mice. Slac2-a/melanophilin (leaden gene in mice) links the function of myosin Va and GTP-Rab27A present in the melanosome.9
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.
Unlike Myosin Va, which is the gene product of RAB27A, 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. Specifically, RAB27A -deficient T cells had a normal granule content in perforin and granzymes A and B, but they showed defective granule release.
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 GS 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 al10 noted that GS2 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 GS2
Neeft et al10 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 GS2 mutant Rab27aW73G strongly decreased linking to Munc13-4, whereas the FHL3 mutant (Munc13-4Delta608-611) failed to bind Rab27a.
Neeft et al10 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 GS2 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 al11 reported a genomic RAB27A deletion found in a 21-month-old Moroccan GS patient and provided evidence that the loss of functional Rab27a in melanocytes of this GS 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 GS.
The immunofluorescence and yeast 2-hybrid screening studies performed by Westbroek et al11 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 GS 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 al12 noted that in GS, NK cytotoxicity mediated by CD16 is functional but not by NKp30.
Desnos et al13 noted that in neurons, myosin Va manages the targeting of IP3 (inositol 1,4,5-trisphosphate) – sensitive Ca2+ stores to dendritic spines. MyosinVa also controls the transport of mRNAs in persons with GS2.
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 al14 and Rath et al15 reported several cases from India. Regardless, the disease is rare in all countries. As of January 2003, about 60 cases have been reported worldwide.
Mortality/Morbidity
Without bone marrow transplantation, GS results in death. The mean patient age at the time of death is 5 years.
Race
GS is a rare disease in all populations. Most cases reported are from Turkish and Mediterranean populations.
Sex
GS is not a sex-linked condition; thus, males and females are affected equally.
Age
GS usually manifests in persons aged 4 months to 4 years. One review reported that the onset of GS 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.
Clinical
History
Often, the first manifestation of GS that is noted is silver hair. The differential diagnosis of the disease in a patient presenting with silvery hair includes primarily GS, Chediak-Higashi syndrome, and Elejalde syndrome. Not long after, the immunologic effects of GS caused by mutations in RAB27A are noted. The immunologic defects of GS resemble those of HLH syndrome and the X-linked lymphoproliferative syndrome. Although Hermansky-Pudlak disease is a form of albinism, it does not present with silver hair or immunologic findings like GS.16,17
The neurologic effects of GS caused by defects in MYO5A usually manifest early in life and even close to birth.
- Severe neurologic manifestations in GS are associated with defects in the MYO5A gene. Severe neurologic symptoms are noticeable at birth without any sign of an accelerated phase. CNS disorder is stable and never regresses with time. The symptoms consist of the following:
- Obstructive hydrocephalus without hematological abnormalities or organomegaly18
- Bilateral basal ganglia involvement19
- Hypotonia
- Absence of coordinated voluntary movements
- Bulbar poliomyelitis
- Encephalopathy
- Hemiparesis
- Peripheral facial palsy
- Spasticity
- Seizures
- Psychomotor retardation
- Severe retarded psychomotor development similar to that observed in Elejalde syndrome
- GS caused by the RAB27A mutation can also cause neurologic manifestations in association with HS (accelerated phase). Neurologic problems may be the first sign of HS (accelerated phase). Neurologic manifestations occurring in patients with GS caused by the RAB27A mutation are related to lymphocyte infiltration of the CNS. These problems are not as severe as those found in GS caused by MYO5A mutations.
- The symptoms include hyperreflexia, seizures, signs of intracranial hypertension (eg, vomiting, altered consciousness), regression of developmental milestones, hypertonia, nystagmus, and ataxia.
- Psychomotor development is normal at onset, and regression of CNS signs, at least in part, can be observed during remission, although some sequelae may be irreversible.
- At birth, nonspecific findings can occur that include petechiae and hepatosplenomegaly.
- A history of severe infections associated with the occurrence of acute phases of uncontrolled lymphocyte and macrophage activation, so-called HS (accelerated phase), can be present in patients with mutations in RAB27A. These infections are not present in patients with mutations in MYO5A.
- In 2003, Dinakar et al20 reported on a 6-year-old girl with GS. The patient experienced perpetual infections, seizures, regression of milestones, silvery hair, and organomegaly. Her brain was affected with unusual features of a Dandy-Walker cyst, and her blood and bone marrow were also affected, manifesting hypergammaglobulinemia.
Physical
Mutations in both MYO5A and RAB27A cause pigmentary dilution and other internal organ abnormalities.
- Skin manifestations of both GS variants include granulomatous skin lesions, partial albinism, and generalized lymphadenopathy. The appearance of the hair has been variably described as silvery gray, silvery, grayish golden, or dusty. The skin is usually pale, but the albinism is not complete.
- Liver manifestations include hepatosplenomegaly and jaundice as a result of hepatitis.
- Patients can present with pallor as a result pancytopenia.
- Neurologic impairments can occur as a result of CNS lymphohistiocytic infiltration with erythrophagocytosis. Upon physical examination, especially in children with mutations in MYO5A, hemiparesis, peripheral facial palsy, spasticity, seizures, psychomotor retardation, and severe retarded psychomotor development may be noted.
- Ocular defects can occur in GS. Partial ocular albinism has been observed in some patients with GS, but retinal degeneration has not been reported in this disorder.21
- Akcakus et al22 noted GS in an infant associated with asymmetric crying facies.
- Kharkar et al23 described a phenotype of GS with circumscribed pigment loss.
- Rajadhyax et al18 noted obstructive hydrocephalus without hematological abnormalities or organomegaly in a patients with GS.
Causes
GS is a genetic disorder related to mutations in MYO5A and RAB27A (see Pathophysiology).
More on Griscelli Syndrome |
 Overview: Griscelli Syndrome |
| Differential Diagnoses & Workup: Griscelli Syndrome |
| Treatment & Medication: Griscelli Syndrome |
| Follow-up: Griscelli Syndrome |
| References |
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References
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Further Reading
Keywords
GS, MIM 214450, partial albinism with immunodeficiency, Griscelli-Prunieras syndrome, Griscelli-Prunieras variant, Griscelli's disease, Griscelli disease
