Alternative titles; symbols
SNOMEDCT: 1254946006; ORPHA: 381, 79476; DO: 0060832;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.2 | Griscelli syndrome, type 1 | 214450 | Autosomal recessive | 3 | MYO5A | 160777 |
A number sign (#) is used with this entry because of evidence that Griscelli syndrome type 1 (GS1) is caused by homozygous mutation in the gene encoding myosin VA (MYO5A; 160777) on chromosome 15q21.
Griscelli syndrome type 1 (GS1) 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. In addition to the characteristic silvery-gray appearance of hair and pigmentary defects of skin, GS1 is characterized by primary neurologic deficits that usually are apparent in early infancy and include hypotonia, developmental delay, intellectual disability, and seizures. Immune impairment is not present (summary by Abd Elmaksoud et al., 2020).
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 lymphohistiocytic 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 neuroectodermal melanolysosomal syndrome (256710) in some patients and GS1 represent the same entity.
Genetic Heterogeneity of Griscelli Syndrome
Griscelli syndrome type 2 (GS2; 607624), characterized by hypomelanosis with immunologic impairment, is caused by mutation in the RAB27A gene (603868). Griscelli syndrome type 3 (GS3; 609227), characterized by hypomelanosis with no immunologic or neurologic manifestations, is caused by mutation in the melanophilin (MLPH; 606526) gene.
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.
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.
Abd Elmaksoud et al. (2020) reported 3 patients from 2 consanguineous Egyptian families with GS1 and mutation in the MYO5A gene. All of the patients had silvery-gray hair and presented in infancy with varying neurologic and cutaneous manifestations. All were noted to lack cutaneous hypopigmentation. Seizures were reported in 1 patient, and developmental delay and hypotonia in all; one patient was able to speak only a few simple words. Abd Elmaksoud et al. (2020) noted the benefits of therapeutic support in ameliorating the severity of the phenotype; in 1 family the older affected sib had severe developmental delay, but the younger sib, in whom diagnosis and intervention occurred earlier, had mild developmental delay and improving milestones.
Clinical Variability
Menasche et al. (2003) studied a 12-year-old Turkish girl with Griscelli syndrome, previously reported by Sanal et al. (2002), who had silver-gray hair, eyebrows, and eyelashes but who developed no immune or neurologic manifestations over 8 years of follow-up. Homozygous deletion of the entire F-exon of the MYO5A gene was identified (160777.0004).
Yilmaz et al. (2014) reported a second patient with Griscelli syndrome and deletion of the MYO5A F-exon. Like the patient of Menasche et al. (2003), this patient had hypopigmentation without neurologic or immunologic manifestations.
The transmission pattern of GS1 in the families reported by Abd Elmaksoud et al. (2020) was consistent with autosomal recessive inheritance.
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 homozygous nonsense mutation in MYO5A (160777.0002) in a Turkish patient with Griscelli syndrome.
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 mutation in 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.
In a patient with Griscelli syndrome previously reported as individual P12 by Sanal et al. (2002), Menasche et al. (2003) identified a homozygous 2,439-bp deletion spanning the entire F-exon of the MYO5A gene (160777.0004), including part of the flanking 5-prime and 3-prime intronic sequences. Microscopic analysis of the patient's hair shafts revealed large clumps of pigment, a characteristic feature of Griscelli syndrome, but the patient had no immunologic or neurologic symptoms at 8 years of follow-up. Yilmaz et al. (2014) reported a second patient with a hypopigmentation-only phenotype of Griscelli syndrome who carried a homozygous deletion identical to the one reported by Menasche et al. (2003).
In 3 patients from 2 unrelated consanguineous Egyptian families who had Griscelli syndrome with developmental delay and hypotonia, Abd Elmaksoud et al. (2020) identified homozygosity for nonsense mutations in the MYO5A gene (160777.0005 and 160777.0006, respectively).
Abd Elmaksoud, M. S., Gomaa, N. S., Azouz, H. G., On, C. N. V., Ho, C. T., Omar, T. E., McGrath, J. A., Onoufriadis, A. Genetic analysis in three Egyptian patients with Griscelli syndrome type 1 reveals new nonsense mutations in MYO5A. Clin. Exp. Derm. 45: 789-792, 2020. [PubMed: 32275080] [Full Text: https://doi.org/10.1111/ced.14220]
Anikster, Y., Huizing, M., Anderson, P. D., Fitzpatrick, D. L., Klar, A., Gross-Kieselstein, E., Berkun, Y., Shazberg, G., Gahl, W. A., Hurvitz, H. Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. Am. J. Hum. Genet. 71: 407-414, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 1007 only, 2002. [PubMed: 12058346] [Full Text: https://doi.org/10.1086/341606]
Bahadoran, P., Ballotti, R., Ortonne, J.-P. Hypomelanosis, immunity, central nervous system: no more 'and,' not the end. Am. J. Med. Genet. 116A: 334-337, 2003. [PubMed: 12522786] [Full Text: https://doi.org/10.1002/ajmg.a.10066]
Bahadoran, P., Ortonne, J.-P., Ballotti, R., de Saint-Basile, G. Comment on Elejalde syndrome and relationship with Griscelli syndrome. Am. J. Med. Genet. 116A: 408-409, 2003. [PubMed: 12522801] [Full Text: https://doi.org/10.1002/ajmg.a.10065]
de Saint Basile, G., Fischer, A. The role of cytotoxicity in lymphocyte homeostasis. Curr. Opin. Immun. 13: 549-554, 2001. [PubMed: 11544002] [Full Text: https://doi.org/10.1016/s0952-7915(00)00257-0]
Griscelli, C., Durandy, A., Guy-Grand, D., Daguillard, F., Herzog, C., Prunieras, M. A syndrome associating partial albinism and immunodeficiency. Am. J. Med. 65: 691-702, 1978. [PubMed: 707528] [Full Text: https://doi.org/10.1016/0002-9343(78)90858-6]
Huizing, M., Anikster, Y., Gahl, W. A. Reply to Menasche et al. (Letter) Am. J. Hum. Genet. 71: 1238 only, 2002.
Ivanovich, J., Mallory, S., Storer, T., Ciske, D., Hing, A. 12-year-old male with Elejalde syndrome (neuroectodermal melanolysosomal disease). Am. J. Med. Genet. 98: 313-316, 2001. [PubMed: 11170073] [Full Text: https://doi.org/10.1002/1096-8628(20010201)98:4<313::aid-ajmg1098>3.0.co;2-p]
Menasche, G., Fischer, A., de Saint Basile, G. Griscelli syndrome types 1 and 2. Am. J. Hum. Genet. 71: 1237-1238, 2002. [PubMed: 12452176] [Full Text: https://doi.org/10.1086/344140]
Menasche, G., Ho, C. H., Sanal, O., Feldmann, J., Tezcan, I., Ersoy, F., Houdusse, A., Fischer, A., de Saint Basile, G. Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1). J. Clin. Invest. 112: 450-456, 2003. Note: Erratum: J. Clin. Invest. 115: 1100 only, 2005. [PubMed: 12897212] [Full Text: https://doi.org/10.1172/JCI18264]
Menasche, G., Pastural, E., Feldmann, J., Certain, S., Ersoy, F., Dupuis, S., Wulffraat, N., Bianchi, D., Fischer, A., Le Deist, F., de Saint Basile, G. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nature Genet. 25: 173-176, 2000. [PubMed: 10835631] [Full Text: https://doi.org/10.1038/76024]
Pastural, E., Barrat, F. J., Dufourcq-Lagelouse, R., Certain, S., Sanal, O., Jabado, N., Seger, R., Griscelli, C., Fischer, A., de Saint Basile, G. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nature Genet. 16: 289-292, 1997. Note: Erratum: Nature Genet. 23: 373 only, 1999. [PubMed: 9207796] [Full Text: https://doi.org/10.1038/ng0797-289]
Pastural, E., Ersoy, F., Yalman, N., Wulffraat, N., Grillo, E., Ozkinay, F., Tezcan, I., Gedikoglu, G., Philippe, N., Fischer, A., de Saint Basile, G. Two genes are responsible for Griscelli syndrome at the same 15q21 locus. Genomics 63: 299-306, 2000. [PubMed: 10704277] [Full Text: https://doi.org/10.1006/geno.1999.6081]
Sanal, O., Ersoy, F., Tezcan, I., Metin, A., Yel, L., Menasche, G., Gurgey, A., Berkel, I., de Saint Basile, G. Griscelli disease: genotype-phenotype correlation in an array of clinical heterogeneity. J. Clin. Immun. 22: 237-243, 2002. [PubMed: 12148598] [Full Text: https://doi.org/10.1023/a:1016045026204]
Thomas, E. R., Walker, L. J., Pullamperuma, S., Cooper, B., Brueton, L. A., de Saint Basile, G., Suri, M., Brady, A. F. Griscelli syndrome type 1: a report of two cases and review of the literature. Clin. Dysmorph. 18: 145-148, 2009. [PubMed: 19318926] [Full Text: https://doi.org/10.1097/MCD.0b013e328317b870]
Yilmaz, M., Cagdas, D., Grandin, V., Altintas, D. U., Tezcan, I., de Saint Basile, G., Sanal, O. Griscelli syndrome type 3-like phenotype with MYO-5A exon-F deletion. Pediat. Allergy Immun. 25: 817-819, 2014. [PubMed: 25283056] [Full Text: https://doi.org/10.1111/pai.12285]