Griscelli disease: genotype-phenotype correlation in an array of clinical heterogeneity

Griscelli disease is a rare autosomal recessive disorder characterized by diffuse pigmentary dilution and occurrence of acute phases of uncontrolled lymphocyte and macrophage activation, so-called "hemophagocytic syndrome" (HS) that leads to death. Recently, two closely linked genes located on human 15q21 region have been found to be responsible for the disease. We present clinical and laboratory findings of 13 unrelated patients with Griscelli disease as well as mutation analyses in an effort to define a genotype-phenotype correlation. Eight patients who showed RAB27A mutations presented with HS. In contrast, two patients who primarily presented with a neurological impairment in the absence of infection susceptibility or HS were found to have homozygous MYO5A mutations. No mutation in RAB27A could be detected in the other three patients. One of the latter developed HS at a rather late age, while the other two are free of HS at 12 and 15 years of age. Griscelli disease presents with a heterogeneous clinical picture that seems to reflect the involved gene defect. This genotype-phenotype correlation suggests that the natural course of the disease and outcome is dictated by the site and type of the genetic mutation.