Abstract
Colony stimulating factor-1 receptor (CSF1R) plays important roles in the differentiation and proliferation of macrophage and microglia in systemic organs and the brain. A genetic defect in CSF1R causes hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS mainly affects the cerebral white matter and shows pre-senile cognitive decline, motor disturbance, and epilepsy. However, systemic manifestations outside the brain have not yet been described in patients with HDLS. Here, we report the case of a 41-year-old man with HDLS carrying the p. K793T mutation in CSF1R, who unexpectedly died of sepsis and hemophagocytic syndrome shortly after the onset of HDLS. The fetal sequence of sepsis and hemophagocytic syndrome was triggered by enterocolitis. An autopsy revealed that focal inflammation in the intestine had almost resolved. Most strikingly, massive infiltration of cluster of differentiation (CD) 68- and CD163-immunopositive macrophages with hemophagocytosis was observed in the bone marrow, spleen, and liver. Less abundant infiltration of CD68- and CD204-immunopositive macrophages without hemophagocytosis was also seen in the lung and intestine. At present, the pathogenetic link between CSF1R mutation and hemophagocytic syndrome in this patient is unclear. Our case, however, clearly shows that even in patients with HDLS, aberrant activation of functional macrophages can be induced under certain conditions in visceral organs.
Highlights
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant cerebral white matter disease showing pre-senile cognitive, behavioral, and motor impairment
colony stimulating factor-1 receptor gene (CSF1R) is mainly expressed in innate immune cells such as monocytes, macrophages, dendritic cells, and microglia in the brain, and CSF-1 signal is considered to play a role in differentiation, proliferation, and functioning of these cells [2] [3]
We report an autopsy case of HDLS in which the patient died of systemic hemophagocytic syndrome triggered by acute enterocolitis approximately 1 year after onset of HDLS
Summary
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant cerebral white matter disease showing pre-senile cognitive, behavioral, and motor impairment. Mutation in the colony stimulating factor-1 receptor gene (CSF1R) is the only causative factor for HDLS identified to date [1]. CSF1R is mainly expressed in innate immune cells such as monocytes, macrophages, dendritic cells, and microglia in the brain, and CSF-1 signal is considered to play a role in differentiation, proliferation, and functioning of these cells [2] [3]. It is very likely that the CSF-1 signal is critically important in the maintenance and functioning of the immune system, but to our best knowledge, no patients with HDLS have been reported to develop immunocompromised status. We report an autopsy case of HDLS in which the patient died of systemic hemophagocytic syndrome triggered by acute enterocolitis approximately 1 year after onset of HDLS
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