Case Report of Pediatric Onset CSF1R-Related Disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
We present a pediatric case of CSF1R-related disorder, a neurodegenerative disorder with both autosomal dominant and autosomal recessive presentations and for which there is limited literature and notable variable expressivity in the pediatric course. The genetic testing results have an element of uncertainty, which has made genetic counseling more challenging.
Case Presentation
The proband is a 4 year old boy with infantile history of benign enlargement of extraaxial spaces, who was incidentally found to have bilateral periventricular supratentorial white matter calcifications after an injury, leading to referral to Genetics. Other than toe walking and early asymmetric crawl, he had normal early developmental milestones. He has recently been diagnosed with attention deficit hyperactivity disorder, cognitive and language deficits, fine motor delay, and developmental coordination disorder. Physical exam was remarkable for pectus carinatum and knee hypermobility.
Diagnostic Workup
Extensive testing was performed for possible TORCH infections, which was negative. Genetic evaluation was pursued, including chromosomal microarray, metabolic testing, and exome sequencing. The exome sequencing trio revealed two heterozygous variants in the CSF1R gene. One variant, c.2533C>T, was classified as likely pathogenic and de novo. The other variant, c.1885G>T, was classified as of uncertain clinical significance (VUS) and was inherited from his mother; this variant notably has been reported in an individual with CSF1R-related features. The lab was not able to confirm the phasing of the variants.
Treatment and Management
Given the finding of at least one likely pathogenic variant and a phenotype consistent with CSF1R-related disorder, supportive care recommendations were made for appropriate multi-specialty surveillance.
Outcome and Follow-Up
The proband will require long term follow-up and supportive care.
Discussion
These results complicate counseling, as it is uncertain whether our proband has heterozygosity versus compound heterozygosity, for which the presentation of CSF1R-related disorder can vary significantly. Pathogenic heterozygous CSF1R variants (dominant) are typically associated with adult-onset neurodegenerative disease with leukoencephalopathy and leukodystrophy, often progressive to vegetative state and death within years of onset. Compound heterozygosity or homozygosity (autosomal recessive) is typically associated with an early-onset pediatric presentation with hypotonia, developmental delays, brain calcifications and other MRI findings, facial osteosclerosis, other skeletal findings, and optic nerve atrophy, but also with expected neurodegenerative involvement, referred to as BANDDOS (brain abnormalities, neurodegeneration, & dysosteosclerosis). However, there is limited literature on pediatric cases and progression, and we do note prior reports of adult-onset neurodegenerative disease with compound heterozygosity, even into older ages (resembling the dominant form of inheritance). We suspect that the proband has the pediatric form with compound heterozygosity, based on his phenotype and the finding of two gene variants. We recognize that further functional studies and larger cohorts of recessive presentations are necessary to clarify the natural course and variable expressivity of the disorder.
Conclusion
In summary, the variant classification, limited information on variant phasing, and limitations in current knowledge created challenges in genetic counseling of anticipatory guidance and prognosis for the proband, during which we additionally had to counsel his mother about her own risks if her VUS is indeed pathogenic. We share this CSF1R-related disorder case report to expand the phenotype, as well as to make our medical community aware of this rare disorder and to encourage greater collaboration to enhance knowledge.
We present a pediatric case of CSF1R-related disorder, a neurodegenerative disorder with both autosomal dominant and autosomal recessive presentations and for which there is limited literature and notable variable expressivity in the pediatric course. The genetic testing results have an element of uncertainty, which has made genetic counseling more challenging.
Case Presentation
The proband is a 4 year old boy with infantile history of benign enlargement of extraaxial spaces, who was incidentally found to have bilateral periventricular supratentorial white matter calcifications after an injury, leading to referral to Genetics. Other than toe walking and early asymmetric crawl, he had normal early developmental milestones. He has recently been diagnosed with attention deficit hyperactivity disorder, cognitive and language deficits, fine motor delay, and developmental coordination disorder. Physical exam was remarkable for pectus carinatum and knee hypermobility.
Diagnostic Workup
Extensive testing was performed for possible TORCH infections, which was negative. Genetic evaluation was pursued, including chromosomal microarray, metabolic testing, and exome sequencing. The exome sequencing trio revealed two heterozygous variants in the CSF1R gene. One variant, c.2533C>T, was classified as likely pathogenic and de novo. The other variant, c.1885G>T, was classified as of uncertain clinical significance (VUS) and was inherited from his mother; this variant notably has been reported in an individual with CSF1R-related features. The lab was not able to confirm the phasing of the variants.
Treatment and Management
Given the finding of at least one likely pathogenic variant and a phenotype consistent with CSF1R-related disorder, supportive care recommendations were made for appropriate multi-specialty surveillance.
Outcome and Follow-Up
The proband will require long term follow-up and supportive care.
Discussion
These results complicate counseling, as it is uncertain whether our proband has heterozygosity versus compound heterozygosity, for which the presentation of CSF1R-related disorder can vary significantly. Pathogenic heterozygous CSF1R variants (dominant) are typically associated with adult-onset neurodegenerative disease with leukoencephalopathy and leukodystrophy, often progressive to vegetative state and death within years of onset. Compound heterozygosity or homozygosity (autosomal recessive) is typically associated with an early-onset pediatric presentation with hypotonia, developmental delays, brain calcifications and other MRI findings, facial osteosclerosis, other skeletal findings, and optic nerve atrophy, but also with expected neurodegenerative involvement, referred to as BANDDOS (brain abnormalities, neurodegeneration, & dysosteosclerosis). However, there is limited literature on pediatric cases and progression, and we do note prior reports of adult-onset neurodegenerative disease with compound heterozygosity, even into older ages (resembling the dominant form of inheritance). We suspect that the proband has the pediatric form with compound heterozygosity, based on his phenotype and the finding of two gene variants. We recognize that further functional studies and larger cohorts of recessive presentations are necessary to clarify the natural course and variable expressivity of the disorder.
Conclusion
In summary, the variant classification, limited information on variant phasing, and limitations in current knowledge created challenges in genetic counseling of anticipatory guidance and prognosis for the proband, during which we additionally had to counsel his mother about her own risks if her VUS is indeed pathogenic. We share this CSF1R-related disorder case report to expand the phenotype, as well as to make our medical community aware of this rare disorder and to encourage greater collaboration to enhance knowledge.