Alternative titles; symbols
ORPHA: 381, 79477; DO: 0060833;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.3 | Griscelli syndrome, type 2 | 607624 | Autosomal recessive | 3 | RAB27A | 603868 |
A number sign (#) is used with this entry because of evidence that Griscelli syndrome type 2 (GS2) is caused by homozygous or compound heterozygous mutation in the RAB27A gene (603868) on chromosome 15q21.
Griscelli syndrome type 2 (GS2) is an autosomal recessive disorder characterized by pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. Patients also have immunologic abnormalities with or without neurologic impairment (summary by Menasche et al., 2000). Some GS2 patients have been reported in whom central nervous system manifestations are the first presentation (Rajadhyax et al., 2007, Masri et al., 2008; Mishra et al., 2014; Lee et al., 2017).
For a discussion of phenotypic and genetic heterogeneity of Griscelli syndrome, see Griscelli syndrome type 1 (GS1; 214450).
Griscelli et al. (1978) described 2 unrelated patients with a disorder resembling the Chediak-Higashi syndrome (CHS; 214500). Features were partial albinism, 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 rejection. Their leukocytes did not stimulate normal lymphocytes. 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. Differences from CHS were morphologic normality of polymorphonuclear leukocytes; the giant granules of CHS were not found. The morphologic characteristics of the hypopigmentation also distinguished the disorder from CHS, as well as from other pigmentary anomalies of man. Another difference was normal leukocyte specific protease activity, which is very low in CHS.
In a review, Klein et al. (1994) stated that Griscelli syndrome can be distinguished from Chediak-Higashi syndrome by pathognomonic histologic features. The prognosis is poor unless early bone marrow transplantation is carried out. They stated that since the original description, only 19 patients had been described. They reported the clinical and biologic features, therapy, and outcome in 7 cases.
In 8 Saudi Arabian kindreds, Harfi et al. (1992) described a disorder characterized by partial albinism with immunodeficiency and progressive demyelination of brain white matter, referred to as PAID syndrome. Although the authors originally considered this syndrome to be distinct from both Chediak-Higashi syndrome and Griscelli syndrome, de Saint Basile (2007) stated that 1 of the Saudi Arabian kindreds reported by Harfi et al. (1992) was found to have a mutation in the RAB27A gene.
Gogus et al. (1995) described 3 Turkish patients with Griscelli syndrome: a girl with consanguineous parents and 2 brothers who were born to another consanguineous couple. The girl and one boy had serious neurologic problems, with spasticity, rigidity, and convulsions. Despite therapy, both patients died. Hemorrhagic areas and lymphohistiocytic infiltration were found in all sections of the brain. Focal spongy degeneration was found in the cortex. Erythrophagocytosis was present in almost every organ.
Mancini et al. (1998) described a patient with Griscelli syndrome who presented with hepatosplenomegaly, hepatitis, pancytopenia, and silvery hair in the newborn period. Her parents were Hispanic and distantly related. Petechiae and hepatosplenomegaly were noted at birth, and multiple platelet and packed red blood cell transfusions were required. Bilirubin peaked at 26.5 mg/dL at 4 weeks of age. Hepatitis and pancytopenia gradually improved, necessitating only occasional transfusions for blood products. Treatment preliminary to bone marrow transplantation was initiated; however, she presented at 15 weeks of age with spasticity and seizures and it was decided that she was not a suitable candidate for transplantation.
The 16 patients with Griscelli syndrome in whom Menasche et al. (2000) identified mutations in the RAB27A gene came from consanguineous families, except a pair of brothers, whose parents originated, however, from the same village in Mauritius (603868.0003). The patients exhibited various degrees of skin hypopigmentation and a silvery-gray sheen of the hair with large pigment aggregates in hair shafts. In all of these patients, at least 1 episode of hemophagocytic syndrome had occurred, characterized by acute onset of uncontrolled lymphocyte and macrophage activation, resulting in infiltration and hemophagocytosis in multiple organs. The first episode of hemophagocytic syndrome occurred at 8 years in one, 3 years in the 2 Mauritian brothers and another patient, and before 6 months in all the others. During the course of the hemophagocytic syndrome, some of the patients presented with convulsions and/or cerebellar manifestations, thought to be the consequence of leukocyte brain infiltration.
Menasche et al. (2000) made a useful clinical distinction between Griscelli syndrome type 1 (214450) due to mutation in the MYO5A gene and GS2 due to mutation in the RAB27A gene. GS1 is associated with a primary neurologic impairment; immune features such as susceptibility to infections and occurrence of hemophagocytic syndrome are absent. GS2 has no primary neurologic features but is associated with an uncontrolled T lymphocyte and macrophage activation syndrome, often associated with the hemophagocytic syndrome, leading to death in the absence of bone marrow transplantation. Menasche et al. (2000) suggested that the convulsions and/or cerebral manifestations with which some of their GS2 patients with RAB27A mutations presented during the course of hemophagocytic syndrome were most likely the consequence of leukocyte brain infiltration.
Hurvitz et al. (1993) reported studies of 4 members of a highly consanguineous kindred with pigmentation and histologic findings consistent with Griscelli syndrome but without recurrent infections. These patients exhibited a range of neurologic involvement from mild cognitive delay with a convulsive disorder in one patient to a fatal degenerative course in 3 others. Anikster et al. (2002) restudied this family, a Muslim Arab kindred whose members had highly variable neurologic involvement, along with the hemophagocytic syndrome and immunologic abnormalities. This family included 4 affected children: a brother (the proband) and sister in one family, and their 2 female first cousins. All 4 individuals died in childhood, at ages 11.5 years, 10 months, 6 years, and 2 years, respectively. All had silvery hair. Skin biopsies revealed normal numbers of melanocytes containing normally sized melanin granules; Hurvitz et al. (1993) had suggested that no melanosomes were transferred to the surrounding keratinocytes. The 3 females presented with recurrent vomiting; the sister of the proband had an acute febrile illness, and 1 of her cousins presented with lethargy. All 3 deteriorated neurologically after their initial presentation, as indicated by regression of mental and physical function. The clinical course of the proband was characterized by periodic episodes of seizures, from the age of 1 year, and by mild cognitive delay. At the age of 2 years 10 months, he experienced an episode similar to the accelerated phase described by Griscelli et al. (1978) and recovered completely. He was well and had no recurrent infections and his neurologic status was stable until age 8 years. He was not monitored between the ages of 8 years and 10.5 years, after which he was repeatedly admitted to a local hospital because of prolonged fever, severe hepatosplenomegaly, and pancytopenia. His condition deteriorated, and he developed ascites, generalized edema, and jaundice and died at the age of 11.5 years.
Grandin et al. (2017) studied 7 probands from 7 consanguineous Saudi families who met the clinical criteria for a diagnosis of GS2 and were found to have a large duplication in the RAB27A gene. All had fever and hepatosplenomegaly, and all experienced at least 1 episode of hemophagocytic lymphohistiocytosis. Hemophagocytosis was documented in all 7 patients, and in the 3 patients tested, T-lymphocyte degranulation was impaired. Neurologic manifestations also occurred at some point during the course of the disease in 4 of the 7 patients.
Clinical Variability
Aksu et al. (2003) reported an 11-year-old Arab girl with Griscelli syndrome and mutation in the RAB27A gene (603868.0007). In addition to hypomelanosis, she had multiple immunologic abnormalities such as hypogammaglobulinemia and leukopenia, but no hemophagocytosis. Degenerative white matter disease was also present. Aksu et al. (2003) noted that the presence of white matter disease and the absence of hemophagocytosis in their patient were unusual for a patient with mutation in the RAB27A gene, and extended the phenotypic spectrum of Griscelli syndrome.
Rajadhyax et al. (2007) studied a girl of Asian origin with Griscelli syndrome and mutation in the RAB27 gene. She had silvery-gray hair and patchy areas of hyperpigmentation on her lower limbs; development had been unremarkable except for mild speech delay. She presented at age 32 months with drowsiness and inability to sit or stand, accompanied by neck stiffness, increased tone in the lower limbs, and extensor plantar reflexes. Head CT showed obstructive hydrocephalus with dilation of lateral and third ventricles, and MRI showed multiple contrast-enhancing lesions in the brain, mainly in the right cerebellar hemisphere, bilateral parietal and occipital lobes, and upper spinal cord. Biopsy of the cerebellar lesions showed an infiltrate of lymphocytes and histiocytes, with evidence of lymphophagocytosis, consistent with hemophagocytic lymphohistiocytosis. Electron microscopy of a hair sample showed large uneven clumps of pigment in the hair shaft.
Masri et al. (2008) reported 3 sibs from a consanguineous Jordanian family with Griscelli syndrome and mutation in the RAB27A gene. All 3 had pale skin and silvery hair. The proband, a 6-year-old boy, presented with isolated neurologic deterioration and central nervous system infiltration. He showed no features suggesting the accelerated phase of the disease. Over the next month, his neurologic condition deteriorated, and he developed aspiration pneumonia, sepsis, and pancytopenia, resulting in his death. The proband's affected 5-year-old sister and 5-month-old brother had completely normal neurologic examinations. Hair analysis in the sister was consistent with Griscelli syndrome.
Mishra et al. (2014) reported 2 Indian brothers with Griscelli syndrome who had divergent clinical presentations and mutation in the RAB27A gene. Both sibs exhibited cutaneous hypopigmentation, and analysis of the younger sib's hair showed large melanin granules distributed irregularly along the hair shaft. The older brother, who died at age 7, presented with fever with obstructive hydrocephalus, rapidly progressive spastic quadriparesis, and papilledema. He had no organomegaly, and blood counts and bone marrow examination was normal. Brain biopsy showed nonspecific lymphocytic proliferation, and the patient was retrospectively diagnosed with GS2 with cerebral lymphohistiocytic infiltration. The 5-year-old younger brother presented with fever, pancytopenia, and hepatosplenomegaly, as well as erythema nodosum, which the authors stated had not been previously described in Griscelli syndrome. He was diagnosed with GS2 with hemophagocytic lymphohistiocytosis (HLH). Mishra et al. (2014) noted that it was unusual for 2 sibs with the same genetic mutation to present with completely diverse clinical manifestations.
Lee et al. (2017) described a 5-year-old Egyptian girl with gray hair since infancy, who presented with a recent history of difficulty in walking and speaking, as well as a decline in intellect and developmental delay. She exhibited an ataxic gait, with mild spasticity of the lower extremities. MRI showed patchy cerebral hypomyelination. There were no clinical symptoms or signs of immunodeficiency, although laboratory studies showed low CD20 and CD21 and elevated IgG.
Durandy et al. (1993) successfully undertook the prenatal diagnosis of 2 hereditary syndromes associating albinism and immune defects: Chediak-Higashi syndrome and Griscelli syndrome. Because the genes responsible for these diseases had not yet been mapped and the immune abnormalities were too subtle to be diagnosed in utero, prenatal diagnosis was made on morphologic grounds. In the case of CHS, it was based on light-microscopic examination of the hair shaft and on light- and electron-microscopic study of polymorphonuclear cells. In the Griscelli syndrome, only examination of the hair was feasible. The diagnosis was negative in 12 fetuses at risk and positive in 4.
In 4 patients with Griscelli syndrome, Pastural et al. (2000) found that the MYO5A gene was expressed, and no mutation was detected in the coding sequence of the gene, even in the alternatively spliced region for which exon-intron boundaries were characterized. Linkage analysis performed in 15 Griscelli families studied to that time confirmed the original localization to 15q21. However, fine haplotype analysis in 3 families strongly suggested the existence of a second locus for Griscelli syndrome less than 7.3 cM from the MYO5A gene.
The transmission pattern of Griscelli syndrome type 2 in the families reported by Menasche et al. (2000) was consistent with autosomal recessive inheritance.
In patients with Griscelli syndrome mapped to the non-MYO5A locus defined by Pastural et al. (2000) in the 15q21 region, Menasche et al. (2000) identified biallelic causative mutations in the RAB27A gene (see, e.g., 603868.0001-603868.0003 and 603868.0008).
Anikster et al. (2002) performed mutation analysis of the MYO5A and RAB27A genes in the family originally described by Hurvitz et al. (1993). The patients had normal MYO5A genes but exhibited a homozygous 67.5-kb deletion (603868.0004) that eliminated RAB27A mRNA and immunocytofluorescence-detectable protein. The RAB27A and MYO5A genes are less than 1.6 cM from each other on 15q21. Furthermore, their gene products interact and function in vesicle trafficking. Anikster et al. (2002) proposed that all patients with RAB27A mutations have Griscelli syndrome and that neurologic complications in these individuals occur secondarily to lymphocytic and histiocytic infiltration of the brain (Gogus et al., 1995). They further proposed that patients with MYO5A mutations have Elejalde syndrome, also known as neuroectodermal melanolysosomal disease (256710), a condition characterized by mild hypopigmentation and severe, primary neurologic abnormalities. Menasche et al. (2002), Huizing et al. (2002), and Bahadoran et al. (2003, 2003) also suggested the identity of Elejalde syndrome, at least in some patients, and Griscelli syndrome type 1.
In an 11-year-old Arab girl who had Griscelli syndrome with multiple immunologic abnormalities and degenerative white matter disease but no hemophagocytosis, Aksu et al. (2003) identified homozygosity for a 2-bp deletion in the RAB27A gene (603868.0007).
In a 4-year-old Brazilian boy with Griscelli syndrome, Bizario et al. (2004) identified compound heterozygosity for a previously reported splice site mutation (603868.0008) and a nonsense mutation (Q118X; 603868.0009) in the RAB27A gene. Using retroviral vector-mediated gene transfer of RAB27A into CD8+ T cells from the proband, the authors demonstrated rescue of the cytotoxic function of the patient's mutant cells, and concluded that RAB27A GTPase plays an essential role in lytic granule release.
In a girl of Asian origin with Griscelli syndrome and obstructive hydrocephalus, without hematologic abnormalities or organomegaly, Rajadhyax et al. (2007) identified homozygosity for a nonsense mutation (R200X; 603868.0011) in the RAB27A gene.
In 3 sibs from a consanguineous Jordanian family with Griscelli syndrome, Masri et al. (2008) identified homozygosity for a missense mutation (K134E; 603868.0012) in the RAB27A gene. Their first-cousin parents and an unaffected sister were heterozygous for the mutation. The proband presented at age 6 years with isolated neurologic deterioration; his affected 5-year-old sister and 5-month-old brother had normal neurologic examinations.
In 2 Indian brothers with Griscelli syndrome and diverse clinical presentations, one neurologic and the other hematologic, Mishra et al. (2014) identified homozygosity for a missense mutation (F46I; 603868.0013) in the RAB27A gene, for which their unaffected parents were heterozygous.
In a 5-year-old Egyptian girl with Griscelli syndrome and a primarily neurologic presentation, who was negative for mutation in the MYO5A gene, Lee et al. (2017) sequenced RAB27A and identified a homozygous splice site mutation (603868.0014). Her parents, who came from the same region in northern Egypt, and her 2 healthy brothers were heterozygous for the mutation, which was not found in public variant databases. The authors noted that, like some previously reported cases (Rajadhyax et al., 2007, Masri et al., 2008; Mishra et al., 2014), this patient did not fit the paradigm of genotype-phenotype correlation in which GS1 is associated with primarily neurologic involvement, and GS2 with immunologic abnormalities.
In 7 probands from consanguineous Saudi families with GS2, who shared a founder haplotype of 4 microsatellite markers around the RAB27A gene, Grandin et al. (2017) sequenced RAB27A but did not detect a mutation. Copy number variation (CNV) analysis of genomic sequencing data revealed a 2-fold increase in the reads for exons 2 to 5 of RAB27A generated from the patients compared to controls. Further analysis demonstrated that all 7 patients were homozygous for an approximately 38-kb duplicated region comprising RAB27A exons 2 to 5 (603868.0015), inserted in tandem and directly oriented, after exon 5 of the first gene copy. The unaffected parents and 2 unaffected sibs were heterozygous for the duplication. Screening for the duplication in 6 additional probands with unsolved GS2 from 5 different ethnic groups did not detect the duplication, suggesting that this specific duplication originates from a common ancestor.
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