Clinical and genetic characteristics of Griscelli syndrome type 2

Abstract

Aims: To describe the clinical features and genetic defects in Maltese children suffering from Griscelli syndrome type 2 (GS2). Methods: All children with confirmed haemophagocytic lymphohistiocytosis (HLH) and partial albinism were identified. A female infant who was suspected to have GS2, due to apparent hypopigmentation at birth and from her family history, was included in the cohort. Hair shafts were analysed by light microscopy. Mutational analysis of the RAB27A gene was carried out on DNA extracted from peripheral white blood cells except in those who were transplanted, in whom DNA was amplified from buccal cells. Results: Six children were identified with this rare autosomal recessive condition which is mainly reported in people of Mediterranean or Turkish origin. All had the characteristic silvery grey hair, eyebrows and eyelashes at presentation. Their ages ranged from 3 months- 9 years, 4 were males and 2 had already received a bone marrow transplant. At the time of testing only the 3 month old girl did not have a history of HLH; however her parents were known to be related. Light microscopy of the hair shafts showed the characteristic deposits of large clumps of melanin pigment along the length of the hair shafts. Five of the children were found to be homozygous for a 5 base pair (AAGCC) deletion at position 510-514 in exon 6. The remaining one year old girl was double heterozygous for the 510-514 deletion and for a novel mutation, del G586, in exon 6. Conclusions: The frequency of GS2 in Malta is 1.2/9000 births. The homozygous deletion 510-514 in exon 6, which leads to a frameshift and a subsequent premature stop codon, is the most common mutation in the Maltese population. We have also identified a novel G586 mutation on exon 6 which, in association with del 510-514, leads to the same phenotype. Although the prognosis of GS2 has improved with bone marrow transplantation, irreversible disabling neurological sequelae may result from histiocytic infiltration of the central nervous system. The identification of RAB27A gene mutations has now made genetic screening of extended families, and appropriate genetic counselling, possible.