-
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 -
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 -
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 -
Frontiers in Pediatrics 2023Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms,... (Review)
Review
Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.
PubMed: 37342528
DOI: 10.3389/fped.2023.1169659 -
Pediatric Rheumatology Online Journal Oct 2022Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease... (Review)
Review
BACKGROUND
Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease with early-onset, severe condition and difficult diagnosis, which seriously affects the growth and development of children. Most children need a genetic diagnosis. However, with the limitation of access to genetic testing and the detection of somatic mutations, the diagnosis of SAIDs remains challenging. IL-1 is one of the important cytokines involved in the pathogenesis of SAIDs. Here we briefly review monogenic SAIDs mediated by aberrant IL-1 production, with the aim to further understand the pathogenesis, clinical manifestations and treatments of IL-1 mediated SAIDs.
METHODS
Literature reviews were performed using "PubMed" and "Web of Science" by searching for the terms "autoinflammatory diseases" and "IL-1".
RESULTS
Monogenic SAIDs mediated by IL-1 include MKD, FMF, TRAPS, PAAND, PAPA, CAPS, DIRA, Majeed syndrome, NAIAD, NLRC4-MAS, PFIT, APLAID. Monogenic SAIDs have early onset, various clinical manifestations and difficult diagnosis, so early recognition and early treatment can reduce the complications and enhance the quality of life.
CONCLUSIONS
There are many kinds of IL-1 mediated SAIDs. Pediatricians should be alert to SAIDs in the face of the patients with repeated fever, repeated rash and poor effect of routine treatment. The patients should be carried out with gene testing and treatment in time.
Topics: Animals; Child; Cytokines; Genetic Testing; Hereditary Autoinflammatory Diseases; Humans; Quality of Life; Simian Acquired Immunodeficiency Syndrome
PubMed: 36253853
DOI: 10.1186/s12969-022-00728-0 -
Allergy, Asthma, and Clinical... Aug 2023Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms...
BACKGROUND
Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms that were seen at St. Joesph's Healthcare in Hamilton for severe asthma management diagnosed with rare autoinflammatory conditions using genetic molecular analysis.
CASE PRESENTATION
Five patients are included in this case series. Gene mutations associated with familial Mediterranean fever, Yao syndrome, Cryopyrin-associated periodic syndrome, and Majeed syndrome were considered to explain partly the patient's clinical manifestation after comprehensive clinical, biochemical, hematological investigations ruled out other disorders such as parasitosis, Allergic Bronchopulmonary Fungosis, Eosinophilic Granulomatosis with Poly Angitis, IgG4 disease, and Hypereosinophilia syndrome.
CONCLUSIONS
Complex patients initially presenting with respiratory conditions in addition to unexplained autoinflammatory conditions are a diagnostic challenge. Genetic molecular testing provides healthcare practitioners with useful information that may diagnose underlying auto-inflammatory diseases in undifferentiated patients. Role of inflammasome-activation in asthma and eosinophilia needs further investigation.
PubMed: 37644591
DOI: 10.1186/s13223-023-00837-9 -
Rheumatology (Oxford, England) Feb 2020
Topics: Anemia, Dyserythropoietic, Congenital; DNA Mutational Analysis; Diphosphonates; Humans; Immunologic Deficiency Syndromes; Infant; Interleukin 1 Receptor Antagonist Protein; Mutation; Nuclear Proteins; Osteomyelitis
PubMed: 31377798
DOI: 10.1093/rheumatology/kez317