Online Mendelian Inheritance in Man (OMIM) (original) (raw)

# 609227

GRISCELLI SYNDROME, TYPE 3; GS3

SNOMEDCT: 1254947002; ORPHA: 381, 79478; DO: 0060834;

Phenotype-Gene Relationships

TEXT

A number sign (#) is used with this entry because of evidence that Griscelli syndrome type 3 (GS3) is caused by homozygous mutation in the melanophilin gene (MLPH; 606526) on chromosome 2q37.

Description

Griscelli syndrome type 3 (GS3) is a rare autosomal recessive disorder that results in a characteristic pigmentary dilution of the skin and hair, which shows a silvery-gray sheen associated with large clumps of pigment in hair shafts and an abnormal accumulation of end-stage melanosomes in the center of melanocytes. There are no immunologic or neurologic manifestations (summary by Menasche et al., 2003).

For a discussion of phenotypic and genetic heterogeneity in Griscelli syndrome, see GS1 (214450).

Clinical Features

Sanal et al. (2002) reported a 15-year-old Turkish boy (P13), born of first-cousin parents, who presented at age 10 with silver-gray hair, eyebrows, and eyelashes who had large clumps of pigment, typical of Griscelli syndrome, on microscopic analysis of hair shafts. The patient had no evidence of hemophagocytic syndrome, hepatosplenomegaly, or lymphadenopathy. Cagdas et al. (2012) provided follow-up on patient P13 at 24 years old, still exhibiting only pigmentary dilution.

Westbroek et al. (2011) studied 3 highly consanguineous Arab pedigrees with Griscelli syndrome and mutation in the MLPH gene. The 7 affected individuals exhibited abnormal pigmentation compared to other family members, including lightly pigmented skin and silvery-gray hair, eyebrows, and eyelashes. Microscopic analysis of patient hair showed irregularly distributed pigment clumps. No other clinical manifestations were present in 5 of the patients; 2 patients from the multiply consanguineous pedigree 2 had additional clinical anomalies including psychomotor retardation in one and marfanoid features in the other. Light microscopy of patient hair showed the typical cellular phenotype of Griscelli syndrome, with perinuclear accumulation of melanosomes and dendrites and dendritic tips that were devoid of pigment. In addition, immunofluorescence confocal microscopy using a melanosome-specific marker revealed perinuclear accumulation, with no pigment observed in dendrites or dendritic tips.

Cagdas et al. (2012) reported 2 unrelated Turkish children with Griscelli syndrome and mutation in the MLPH gene. A 9-year-old girl (patient 3) and an 11-year-old boy (patient 4) had silvery-gray hair, eyebrows, and eyelashes, with an otherwise normal physical examination. Light microscopy of hair shafts showed large clumps of pigment in both patients. No problems had developed over 4 years and 2 years of follow-up, respectively.

Nouriel et al. (2015) described a 3-year-old Arab boy with Griscelli syndrome and mutation in the MLPH gene. He had congenital gray hair and lighter skin color, whereas his parents and 5 of his sibs had black hair and dark skin; an 18-year-old brother was reported to have fair skin and silvery-gray hair. The proband was also born with hypoplastic left heart syndrome; family history revealed that another brother had died of unspecified congenital heart defects at age 2 years, but he had normal pigmentation. Because the affected older brother had hypopigmentation but no heart disease, the authors concluded that the proband's heart defect was unlikely to be associated with his diagnosis of Griscelli syndrome. The proband's mother reported that he had no history of neurologic or immunologic symptoms or diagnoses. Dermatologic examination showed generalized fair skin pigmentation, with silvery-gray hair, eyebrows, and eyelashes. Hair microscopy showed a normal cuticular pattern with abnormal discrete conglomerations of melanin pigment irregularly clustered throughout the interior portion of the shaft. Upon review of published cases, the authors noted that the average age at diagnosis was about 10 years, and suggested that GS3 may be underdiagnosed because it is not associated with illness requiring medical attention.

Kassem Youssef et al. (2018) reported a 31-year-old Algerian woman, born of consanguineous parents, with Griscelli syndrome and mutation in the MLPH gene. She had gray-white scalp and body hair, eyebrows, and eyelashes from early childhood, and her skin color was lighter than that of her sibs. At around 12 years of age, she also developed multiple hyperpigmented lesions on sun-exposed skin. She was approximately 32 weeks pregnant at the time of examination, and had a personal and familial history of multiple miscarriages. Microscopic examination of her hair showed irregular clumps of melanin along the hair shaft.

Dagnewu et al. (2020) reported 2 Ethiopian sisters, aged 15 and 16 years, with abnormal pigmentation of the skin and hair. Their hair was silvery gray and skin findings included macular patchy hypopigmentation of the arms and trunk. Microscopic analysis of the hair showed irregularly distributed pigmented clumps at the hair shaft. Neither sister had any neurologic or immunologic abnormalities.

Inheritance

The transmission pattern of GS3 in the families reported by Sanal et al. (2002) and Westbroek et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 16-year-old Turkish boy (patient PA) who exhibited hypopigmentation without immunologic or neurologic manifestations, who was originally reported by Sanal et al. (2002) as patient P13 and in whom no mutation was found in the RAB27A (603868) or MYO5A (160777) genes, Menasche et al. (2003) identified homozygosity for a missense mutation in the MLPH gene (R35W; 606526.0001). Menasche et al. (2003) noted that this patient developed no manifestations other than a pigmentary disorder over 6 years of follow-up. In another patient (PB) reported by Sanal et al. (2002) (P12) with a similar phenotype, Menasche et al. (2003) detected homozygous deletion of the F-exon of the MYO5A gene; see 160777.0004 and GS1 (214450).

In 7 affected individuals from 3 distinct consanguineous Arab families with hypopigmentation but no immunologic or neurologic manifestations, Westbroek et al. (2011) sequenced the MLPH gene and identified homozygosity for the previously reported R35W mutation. The variant segregated fully with disease in all 3 families. Noting that patients with mutations in the F-exon of the MYO5A gene show a similar phenotype (see GS1, 214450), the authors sequenced all affected individuals for that exon and flanking intronic sequence but found no changes, supporting the pathogenicity of the R35W mutation in MLPH.

In a 9-year-old Turkish girl (patient 3) and an unrelated 11-year-old Turkish boy (patient 4) with hypopigmentation, both born of consanguineous parents, Cagdas et al. (2012) identified homozygosity for mutations in the MLPH gene: the girl was homozygous for the recurrent R35W mutation, whereas the boy was homozygous for a nonsense mutation (E98X; 606526.0002). Neither child had immunologic or neurologic manifestations.

In a 3-year-old Arab boy with hypopigmentation but no neurologic or immunologic manifestations, Nouriel et al. (2015) identified homozygosity for the R35W mutation in the MLPH gene. Although his parents denied consanguinity, both were Muslim Arabs from the Hebron area; the authors noted that this was the same area of residence as the 7 affected individuals reported by Westbroek et al. (2011), suggesting a likely founder effect.

In a 31-year-old Algerian woman with hypopigmentation of hair and skin, Kassem Youssef et al. (2018) identified homozygosity for the recurrent R35W mutation in the MLPH gene.

In 2 Ethiopian sisters with GS3, Dagnewu et al. (2020) identified a homozygous missense mutation (R35Q; 606526.0003) in the MLPH gene. The mutation was identified by Sanger sequencing of the gene.

REFERENCES

1. Cagdas, D., Ozgur, T. T., Asal, G. T., Tezcan, I., Metin, A., Lambert, N., de Saint Basile, G., Sanal, O.Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients. Europ. J. Pediat. 171: 1527-1531, 2012. [PubMed: 22711375] [Full Text: https://doi.org/10.1007/s00431-012-1765-x\]
2. Dagnewu, K. Y., Ayele, A., Liu, L., Pramanik, R., Onoufriadis, A., Abebe, E., McGrath, J. A.Griscelli syndrome type 3 in Ethiopian sisters resulting from a homozygous missense mutation in MLPH. (Letter) Int. J. Derm. 59: e55-e57, 2020. [PubMed: 31721180] [Full Text: https://doi.org/10.1111/ijd.14724\]
3. Kassem Youssef, H., Ramstein, C., Ginglinger, E., Chouta Ngaha, F., Nojavan, H., Michel, C.Syndrome de Griscelli de type 3 : un nouveau cas. Ann. Derm. Venereol. 145: 785-789, 2018. [PubMed: 30389201] [Full Text: https://doi.org/10.1016/j.annder.2018.07.030\]
4. 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\]
5. Nouriel, A., Zisquit, J., Helfand, A. M., Anikster, Y., Greenberger, S.Griscelli syndrome type 3: two new cases and review of the literature. Pediat. Derm. 32: e245-e248, 2015. [PubMed: 26337734] [Full Text: https://doi.org/10.1111/pde.12663\]
6. 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\]
7. Westbroek, W., Klar, A., Cullinane, A. R., Ziegler, S. G., Hurvitz, H., Ganem, A., Wilson, K., Dorward, H., Huizing, M., Tamimi, H., Vainshtein, I., Berkun, Y., Lavie, M., Gahl, W. A., Anikster, Y.Cellular and clinical report of new Griscelli syndrome type III cases. Pigment Cell Melanoma Res. 25: 47-56, 2011. [PubMed: 21883982] [Full Text: https://doi.org/10.1111/j.1755-148X.2011.00901.x\]

Contributors:

Hilary J. Vernon - updated : 05/25/2023
Marla J. F. O'Neill - updated : 05/23/2022

Creation Date:

Marla J. F. O'Neill : 3/1/2005

Edit History:

carol : 09/12/2024
carol : 05/25/2023
alopez : 05/23/2022
carol : 05/19/2022
alopez : 05/18/2022
alopez : 06/24/2005
alopez : 3/2/2005
alopez : 3/1/2005