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Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome
M R Del Bigio1, C R Greenberg, L B Rorke
1Department of Pathology, University of Manitoba, Winnipeg, Canada.
Insights
Cerebro-oculo-facial-skeletal (COFS) syndrome involves severe brain abnormalities, including microcephaly and developmental delays, leading to early childhood death. Neuropathological findings reveal a progressive degenerative process affecting various brain cells starting in utero.
Area of Science:
- Neuropathology
- Neurodevelopmental Disorders
- Genetics
Background:
- Cerebro-oculo-facial-skeletal (COFS) syndrome is a rare autosomal recessive disorder.
- Characterized by microcephaly, severe mental retardation, and early childhood mortality.
- The underlying pathogenesis of COFS syndrome remains largely unknown.
Purpose of the Study:
- To present detailed neuropathological findings in eight children diagnosed with COFS syndrome.
- To elucidate the progressive nature and cellular targets of the disease process.
- To compare neuropathological features with similar genetic disorders like Cockayne syndrome.
Main Methods:
- Post-mortem neuropathological examination of brain tissue from eight pediatric patients with COFS syndrome.
- Histopathological analysis including assessment of myelination, neuronal loss, gliosis, and mineralization.
- Age range of subjects from 36 weeks gestation to 5 years 8 months.
Main Results:
- Consistent severe microencephaly and mild ventriculomegaly observed in all cases.
- Early postnatal appearance of swollen ubiquitinated granular cells in white matter.
- Progressive changes in older children include cortical neuron loss, absent myelin, gliosis, and mineralization in basal ganglia and cortex; severe cerebellar degeneration.
Conclusions:
- Neuropathological evidence suggests COFS syndrome is a progressive degenerative disorder originating in utero.
- The disease affects multiple brain cell types, leading to severe structural abnormalities.
- Findings provide a foundation for understanding COFS syndrome's complex pathophysiology and potential links to other syndromes.
Abstract:
Cerebro-oculo-facial-skeletal (COFS) syndrome is a rare autosomal recessive disorder with microcephaly, severe mental retardation, and death in childhood. The pathogenesis is unknown. Neuropathological features of 8 children with COFS syndrome are presented. Seven of the children, ranging in age from 36 weeks gestation to 5 years 8 months, are of North American aboriginal background from Manitoba, Canada. The eight child is a 3-year-old Caucasian male. In all children there was severe microencephaly and mild ventriculomegaly. Cerebral myelination appeared to be delayed in one infantile case. Swollen ubiquitinated granular cells appeared in the white matter shortly after birth. Older children displayed cortical neuron loss, patchy or diffuse absence of myelin and gliosis in the white matter, and pericapillary and parenchymal mineralization in the globus pallidus and to a lesser extent the putamen and cerebral cortex. The cerebellum of older children exhibited severe degenerative changes involving the internal granular layer and Purkinje cell layer. The neuropathological changes, previously not well documented, suggest that COFS syndrome is associated with a degenerative process that begins in utero and affects many brain cell types. Similarities to Cockayne syndrome are discussed.