Colony-stimulating factor 1 receptor-related disorder: Clinical variability of biallelic variants

Biallelic colony-stimulating factor 1 receptor (CSF1R) variants are a major cause of early-onset CSF1R-related disorder (CSF1R-RD), although fewer than 30 cases have been reported and genotype-phenotype correlations remain unclear. The aim of this study was to characterize the clinical, radiological, and genetic features of patients with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). Six patients with biallelic CSF1R variants underwent detailed clinical, neurological, and magnetic resonance imaging evaluation. Three siblings with a homozygous p.Gly585Val variant showed marked phenotypic variability, ranging from severe childhood-onset neurodegeneration to an asymptomatic presentation, all with white matter abnormalities. Three unrelated patients carried different biallelic CSF1R variants and presented with congenital skeletal abnormalities or early-onset neurological disease of variable severity. These cases broaden the phenotypic spectrum of biallelic CSF1R-RD and demonstrate that disease severity cannot be predicted solely by genotype, suggesting an important role for genetic or environmental modifiers.