CSF1R – Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS)

CSF1R encodes the receptor tyrosine kinase for macrophage colony‐stimulating factor-1, critical for microglial and osteoclast development. While heterozygous CSF1R mutations cause adult-onset leukoencephalopathy with spheroids (ALSP) in an autosomal dominant manner, biallelic pathogenic variants underlie the autosomal recessive syndrome brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS).

Autosomal recessive inheritance of BANDDOS is supported by eight probands across three unrelated families (PMID:37431483; PMID:38934054; PMID:33749994), with segregation of heterozygous carriers who remain asymptomatic (PMID:37431483).

Biallelic variants reported include a homozygous missense in exon 19, c.2498C>T (p.Thr833Met), a hypomorphic intronic deletion c.1969+115_1969+116del affecting splicing, and a canonical splice-site change adjacent to exon 21. All alter the protein tyrosine kinase (PTK) domain, consistent with loss-of-function.

Clinically, affected individuals present in infancy or early childhood with global developmental delay, therapy-resistant epilepsy, dysmorphic facial features, and increased bone mineral density. Neuroimaging shows developmental brain anomalies, multifocal white matter abnormalities, and calcifications, while skeletal surveys reveal variable osteosclerosis.

In silico modeling predicts deleterious effects on CSF1R structure and function; however, direct functional assays on BANDDOS-associated variants are lacking, and no animal models have yet recapitulated the full human phenotype.

Integration of genetic and preliminary computational data supports a loss-of-function mechanism for CSF1R in BANDDOS, distinct from the dominant-negative or haploinsufficiency seen in ALSP. Genetic testing for CSF1R should be considered in early-onset neurodegenerative syndromes with skeletal dysplasia for accurate diagnosis, prognostication, and family counseling.

Key Take-home: Biallelic CSF1R variants cause an autosomal recessive syndrome of early-onset brain malformations, neurodegeneration, and dysosteosclerosis, warranting CSF1R sequencing in appropriate clinical presentations.

References

• BioImpacts • 2023 • Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). PMID:37431483
• American Journal of Medical Genetics Part A • 2024 • Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings. PMID:38934054
• American Journal of Medical Genetics Part A • 2021 • Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features. PMID:33749994

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