From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R

Colony-stimulating factor 1 receptor (CSF1R) plays key roles in the development and function of the cells in the monocyte/macrophage lineage, including microglia and osteoclasts. It is well known that mono-allelic mutations of CSF1R cause hereditary diffuse leukoencephalopathy with spheroids (HDLS, OMIM # 221820), an adult-onset progressive neurodegenerative disorder. Recently, a more severe phenotypic spectrum has been identified in individuals with bi-allelic mutations of CSF1R. In addition to leukoencephalopathy of earlier onset than HDLS, the new disease shows brain malformations and skeletal dysplasia compatible with dysosteosclerosis (DOS), thus named “brain abnormalities, neurodegeneration, and dysosteosclerosis” (BANDDOS, OMIM # 618476). In addition, some individuals with bi-allelic missense mutations of CSF1R have been found to present with incomplete BANDDOS where skeletal dysplasia is absent. In this review, we summarize the monogenic disorders caused by mutations in CSF1R and their mutational spectra, and propose a dose-dependent model to explain the complex genotype–phenotype association.