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Biomolecules Feb 2021Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with... (Review)
Review
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 , 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 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.
Topics: Anemia, Dyserythropoietic, Congenital; Genetic Predisposition to Disease; Homeostasis; Humans; Immunologic Deficiency Syndromes; Inflammasomes; Models, Biological; Mutation; Osteomyelitis
PubMed: 33670882
DOI: 10.3390/biom11030367 -
Rheumatic Diseases Clinics of North... Nov 2013Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous... (Review)
Review
Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous inflammatory process. The inflammatory bone lesions in these disorders are characterized by chronic inflammation that is typically culture negative with no demonstrable organism on histopathology. The most common autoinflammatory bone diseases in childhood include chronic nonbacterial osteomyelitis (CNO), synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist, and cherubism. In this article, the authors focus on CNO and summarize the distinct genetic autoinflammatory bone syndromes.
Topics: Acne Vulgaris; Acquired Hyperostosis Syndrome; Anemia, Dyserythropoietic, Congenital; Bone Diseases; Cherubism; Chronic Disease; Hereditary Autoinflammatory Diseases; Humans; Hyperostosis; Immunologic Deficiency Syndromes; Inflammation; Interleukin 1 Receptor Antagonist Protein; Osteitis; Osteomyelitis; Syndrome; Synovitis
PubMed: 24182852
DOI: 10.1016/j.rdc.2013.05.002 -
Archives of Rheumatology Dec 2022
PubMed: 36879569
DOI: 10.46497/ArchRheumatol.2022.9437 -
Arthritis & Rheumatology (Hoboken, N.J.) Jun 2021To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile...
OBJECTIVE
To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis.
METHODS
Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA).
RESULTS
A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1β secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade.
CONCLUSION
We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.
Topics: Anemia, Dyserythropoietic, Congenital; Antibodies, Monoclonal, Humanized; Case-Control Studies; Child, Preschool; Cryopyrin-Associated Periodic Syndromes; Female; Hereditary Autoinflammatory Diseases; Heterozygote; Humans; Immunologic Deficiency Syndromes; Inflammation; Interleukin 1 Receptor Antagonist Protein; MAP Kinase Kinase 4; Macrophages; Mitogen-Activated Protein Kinases; NFATC Transcription Factors; Nuclear Proteins; Osteogenesis; Osteomyelitis; src-Family Kinases
PubMed: 33314777
DOI: 10.1002/art.41624 -
Children (Basel, Switzerland) Jun 2021Chronic nonbacterial osteomyelitis (CNO) is an auto-inflammatory bone disorder with a wide spectrum of clinical manifestations, from unifocal to multifocal lesions. When... (Review)
Review
Chronic nonbacterial osteomyelitis (CNO) is an auto-inflammatory bone disorder with a wide spectrum of clinical manifestations, from unifocal to multifocal lesions. When it manifests with multifocal lesions, it is also referred to as chronic recurrent multifocal osteomyelitis (CRMO). CNO/CRMO can affect all age groups, with the pediatric population being the most common. Patients may present with systemic inflammation, but there is no pathognomonic laboratory finding. Magnetic resonance imaging (MRI) is the gold standard radiological tool for diagnosis. In the absence of validated diagnostic criteria, CNO/CRMO remains an exclusion diagnosis. Bone biopsy does not show a specific disease pattern, but it may be necessary in unifocal or atypical cases to differentiate it from malignancy or infection. First-line treatments are non-steroidal anti-inflammatory drugs (NSAIDs), while bisphosphonates or TNF-α blockers can be used in refractory cases. The disease course is unpredictable, and uncontrolled lesions can complicate with bone fractures and deformations, underlying the importance of long-term follow-up in these patients.
PubMed: 34202154
DOI: 10.3390/children8070551 -
Clinical Immunology (Orlando, Fla.) Jun 2013The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described... (Review)
Review
The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.
Topics: Cryopyrin-Associated Periodic Syndromes; Exanthema; Granuloma; Hereditary Autoinflammatory Diseases; Humans; Skin Diseases
PubMed: 23711932
DOI: 10.1016/j.clim.2013.03.016 -
Dermatologic Clinics Jan 2017Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever, rash, and disease-specific patterns of organ inflammation.... (Review)
Review
Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever, rash, and disease-specific patterns of organ inflammation. Gain-of-function mutations in innate danger-sensing pathways, including the inflammasomes and the nucleic acid sensing pathways, play critical roles in the pathogenesis of IL-1 and Type-I IFN-mediated disorders and point to an important role of excessive proinflammatory cytokine signaling, including interleukin (IL)-1b , Type-I interferons, IL-18, TNF and others in causing the organ specific immune dysregulation. The article discusses the concept of targeting proinflammatory cytokines and their signaling pathways with cytokine blocking treatments that have been life changing for some patients.
Topics: Adrenal Cortex Hormones; Anemia, Dyserythropoietic, Congenital; Antirheumatic Agents; Autoimmune Diseases; Colchicine; Hereditary Autoinflammatory Diseases; Humans; Immunologic Deficiency Syndromes; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-18; Macrophage Activation Syndrome; Osteomyelitis; Skin Diseases; Tubulin Modulators; Tumor Necrosis Factor-alpha
PubMed: 27890235
DOI: 10.1016/j.det.2016.07.005 -
EMBO Reports Dec 2023Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet...
Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL-1β production in lipin-2-deficient animals in a model of viral infection. Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin-2 and open new perspectives for the future management of patients with LPIN2 mutations.
Topics: Animals; Humans; DNA, Mitochondrial; Interferons; Phosphatidate Phosphatase
PubMed: 37929625
DOI: 10.15252/embr.202357238