CSF1R-Related Disorder

Clinical characteristics: The spectrum of CSF1R-related disorder ranges from early-onset disease (age <18 years) to late-onset disease (age ≥18 years). Early-onset disease is associated with hypotonia, delayed acquisition of developmental milestones, and non-neurologic manifestations (such as skeletal abnormalities); both early- and late-onset disease have similar neurodegenerative involvement. Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk. They lose speech and voluntary movement and appear to be generally unaware of their surroundings. The last stage of disease progresses to a vegetative state with presence of primitive reflexes, such as visual and tactile grasp, mouth-opening reflex, and sucking reflex. Death most commonly results from pneumonia or other infections. About 500 individuals with CSF1R-related disorder have been reported to date.

Diagnosis/testing: The diagnosis of CSF1R-related disorder is established in a proband with suggestive findings and a heterozygous CSF1R pathogenic variant or biallelic CSF1R pathogenic variants identified by molecular genetic testing.

Management: Treatment of manifestations: Multidisciplinary care by specialists in neurology, psychotherapy, neuropsychological rehabilitation, physical therapy, occupational therapy, speech-language therapy, social services for family support, and genetic counseling.

Surveillance: Monitoring of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations as specified by the multidisciplinary care providers.

Agents/circumstances to avoid: For individuals with gait problems and cognitive decline, sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously.

Genetic counseling: Early-onset CSF1R-related disorder is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner; rarely, early-onset CSF1R-related disorder may be caused by a heterozygous pathogenic variant. Late-onset CSF1R-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner; rarely, late-onset CSF1R-related disorder may be caused by biallelic CSF1R pathogenic variants. While biallelic pathogenic variants are usually associated with early-onset disease and heterozygous pathogenic variants are usually associated with late-onset disease, definitive prediction of phenotype based on CSF1R genotype is not possible at this time.

Autosomal recessive inheritance: The parents of an individual with CSF1R-related disorder caused by biallelic pathogenic variants are presumed to be heterozygous for a CSF1R pathogenic variant. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial CSF1R pathogenic variants. Sibs who inherit the same biallelic CSF1R pathogenic variants do not necessarily have the same clinical manifestations early in the disease course; however, in the end stage, all individuals with CSF1R-related disorder typically have devastating neurologic involvement. The heterozygous sibs of an individual with CSF1R-related disorder caused by biallelic pathogenic variants are typically asymptomatic.

Autosomal dominant inheritance: Many individuals with CSF1R-related disorder caused by a heterozygous pathogenic variant have an affected parent. Some individuals with CSF1R-related disorder caused by a heterozygous pathogenic variant represent a simplex case; such individuals may have the disorder as the result of a pathogenic variant that occurred de novo in the proband; a pathogenic variant inherited from a mosaic parent; or a pathogenic variant inherited from an asymptomatic heterozygous parent. Each child of an individual with a heterozygous CSF1R pathogenic variant has a 50% chance of inheriting the pathogenic variant. Family members who are heterozygous for the same CSF1R pathogenic variant do not necessarily have the same clinical manifestations early in the disease course; however, in the end stage, all individuals with CSF1R-related disorder typically have devastating neurologic involvement.

Once the CSF1R pathogenic variant(s) have been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for CSF1R-related disorder are possible.