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Review
. 2021 Feb 28;11(3):367.
doi: 10.3390/biom11030367.

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features

Polly J Ferguson  1 , Hatem El-Shanti  1
Affiliations
Review

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features

Polly J Ferguson et al. Biomolecules. .

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.

Keywords: LIPIN2; LPIN2; autoinflammatory; chronic non-bacterial osteomyelitis; chronic recurrent multifocal osteomyelitis; inflammasome; macrophage; majeed syndrome; osteoclast.

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Conflict of interest statement

P.J.F. has served as a consultant for Novartis.

Figures

Figure 1
Figure 1
Majeed syndrome associated mutations. LPIN2 is composed of 20 exons. Pathogenic mutations are located throughout the gene. Most disease-causing mutations reported to date are predicted to results in early truncation or in exon deletion. Two missense mutation. The in vitro functional work by Donkor et al. showed that the mutant protein is expressed but lacked PAP activity.
Figure 2
Figure 2
Impaired bone homeostasis as a disease model for the osteomyelitis phenotype in Majeed syndrome. In Majeed syndrome proinflammatory M2-like macrophages produce increased amounts of IL-8 and osteoclastogenic chemokines and lower IL-10 levels thus shifting towards a pro-inflammatory “environment”. The increased production of chemokines such as CXCL1 with IL-8 lead to recruitment of neutrophils while MCP-1 and MIP-1α/β recruit monocytes and affect macrophage differentiation. The chemokines released by the inflammatory M2-like macrophages further propagate osteoclastogenesis leading to the bone destruction seen in Majeed syndrome and DIRA. In contrast, the M1-like macrophages in NOMID (an NLRP3 inflammasomopathy) also produce increased IL-1β, yet the M2-like macrophages are not inflammatory and osteoclastogenesis is not increased thus osteomyelitis is not part of their phenotype. (Reprinted from Bhuyan et al. Arthritis and Rheumatology, 2021—Reference [81]).
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