Abstract
Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.
Highlights
While a direct connection to IL-1 signaling is evident in deficiency of the interleukin-1 receptor antagonist (DIRA), that connection had been less clear in the Majeed syndrome which is caused by pathogenic variants in LPIN2, in which the encoded protein plays a central role in lipid metabolism
Low intra cellular cholesterol leads to altered function of the P2X7R and subsequent K+ efflux and NLRP3 inflammasome activation leading to enhance production of proinflammatory cytokines including IL-1
IL-1β has been utilized in 10 patients with Majeed syndrome and all have reported significant benefit with resolution of the inflammatory bone disease and normalization of inflammatory markers
Summary
Autoinflammatory diseases present with recurrent or persistent inflammation that occurs in the absence of self-reactive T or B cells which distinguishes them from autoimmune disorders [1,2]. Mediterranean fever (FMF) due to pathogenic variants in MEFV and cryopyrin associated periodic syndrome (CAPS) due to pathogenic variants in NLRP3, affecting the pyrin and NLRP3 inflammasome function, respectively, and leading to dysregulation of IL-1 production [3,4,5] Since that time, there has been a flurry of discovery in the autoinflammatory disorder field [6] These disorders can affect many organ systems including a subgroup of autoinflammatory disorders that target the bone [7,8,9]. The molecular mechanisms of non-syndromic CRMO remains unclear but the existing data suggests that it is a genetically complex disorder leading to an imbalance between proand anti-inflammatory cytokines produced by innate immune cells, leading to osteoclast activation with osteolytic destruction of the bone [9]. CRMO has been classified as an autoinflammatory disorder [2,22]
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