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International Journal of Rheumatic... Nov 2022Chronic recurrent multifocal osteomyelitis (CRMO) is a bone inflammatory disorder characterized by osteolytic, usually multiple, symmetric lesions. Diagnosis is one of...
BACKGROUND
Chronic recurrent multifocal osteomyelitis (CRMO) is a bone inflammatory disorder characterized by osteolytic, usually multiple, symmetric lesions. Diagnosis is one of exclusion, and no standardized therapies are available. Presumed deregulation of the interleukin (IL)-1β axis, as observed in 2 monogenic autoinflammatory conditions such as Majeed syndrome (LPIN2 mutations) and deficiency of IL-1 receptor antagonist (IL1RN mutations) with CRMO-like bone involvement, suggests the blockade of IL-1 as potentially useful also in this condition, even if scarce data are available.
CASE PRESENTATION
We report the case of a 13-year-old girl affected by a multidrug-resistant and pyoderma gangrenosum-complicated CRMO treated with canakinumab, a human monoclonal antibody targeting IL-1β.
CONCLUSION
In this young patient pyoderma gangrenosum and CRMO showed a rapid and satisfactory response to canakinumab, although over time a decreased efficacy in controlling bone disease was observed.
Topics: Female; Humans; Adolescent; Pyoderma Gangrenosum; Osteomyelitis; Anemia, Dyserythropoietic, Congenital
PubMed: 36004431
DOI: 10.1111/1756-185X.14425 -
American Journal of Medical Genetics.... Jul 2022Hereditary sensory and autonomic neuropathy type 2B (HSAN2B) is a rare autosomal recessive peripheral neuropathy caused by biallelic variants in RETREG1...
Hereditary sensory and autonomic neuropathy type 2B (HSAN2B) is a rare autosomal recessive peripheral neuropathy caused by biallelic variants in RETREG1 (formerly FAM134B). HSAN2B is characterized by sensory impairment resulting in skin ulcerations, amputations, and osteomyelitis as well as variable weakness, spasticity, and autonomic dysfunction. Here, we report four affected individuals with recurrent osteomyelitis, ulceration, and amputation of hands and feet, sensory neuropathy, hyperhidrosis, urinary incontinence, and renal failure from a family without any known shared parental ancestry. Due to the history of chronic recurrent multifocal osteomyelitis and microcytic anemia, a diagnosis of Majeed syndrome was considered; however, sequencing of LPIN2 was negative. Family-based exome sequencing (ES) revealed a novel homozygous ultrarare RETREG1 variant NM_001034850.2:c.321G>A;p.Trp107Ter. Electrophysiological studies of the proband demonstrated axonal sensorimotor neuropathy predominantly in the lower extremities. Consistent with the lack of shared ancestry, the coefficient of inbreeding calculated from ES data was low (F = 0.002), but absence of heterozygosity (AOH) analysis demonstrated a 7.2 Mb AOH block surrounding the variant consistent with a founder allele. Two of the four affected individuals had unexplained renal failure which has not been reported in HSAN2B cases to date. Therefore, this report describes a novel RETREG1 founder allele and suggests renal failure may be an unrecognized feature of the RETREG1-disease spectrum.
Topics: Alleles; Hereditary Sensory and Autonomic Neuropathies; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Osteomyelitis; Pedigree; Renal Insufficiency
PubMed: 35332675
DOI: 10.1002/ajmg.a.62727 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Aug 2021To explore the clinical feature, diagnosis and phenotype of Majeed syndrome.
OBJECTIVE
To explore the clinical feature, diagnosis and phenotype of Majeed syndrome.
METHODS
Clinical manifestation, diagnostic process, imaging feature and genetic testing of an ethnic Han Chinese patient with Majeed syndrome were reviewed.
RESULTS
The patient, a 3-year-9-month-old boy, had featured psychomotor retardation and developed bone pain from 8 month on. The child had tenderness of the lower limbs and presented with repeatedly joint swelling and pain accompanied by fever. Physical signs included limb muscle weakening, slightly decreased muscle tone, reduced muscle volume and positive Gower sign. High-throughput sequencing revealed that the child has carried compound heterozygous variants of the LPIN2 gene, including c.1966A>G and c.2534delG. MRI showed multiple lesions in bilateral knee joints and distal middle tibia presenting as patchy SPAIR high signals with unclear edge, in addition with edema of soft tissue surrounding the right distal femur.
CONCLUSION
Majeed syndrome is characterized by chronic and recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and growth retardation. Surrounding muscle tissue of osteomyelitis may also be involved. The syndrome may also affect the central nervous system, resulting in delayed language and motor development. Discovery of multiple pathological variants of the LPIN2 gene suggested that the clinical phenotype of this syndrome may vary between patients to some extent.
Topics: Anemia, Dyserythropoietic, Congenital; Child; Genetic Testing; Humans; Immunologic Deficiency Syndromes; Infant; Male; Osteomyelitis
PubMed: 34365623
DOI: 10.3760/cma.j.cn511374-20200612-00432 -
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 -
The Journal of Rheumatology Dec 2021Majeed syndrome (MJS) is an autosomal recessive, systemic autoinflammatory disease (SAID) caused by biallelic loss-of-function variants in the gene. It is characterized... (Review)
Review
OBJECTIVE
Majeed syndrome (MJS) is an autosomal recessive, systemic autoinflammatory disease (SAID) caused by biallelic loss-of-function variants in the gene. It is characterized by early-onset chronic recurrent multifocal osteomyelitis (CRMO), dyserythropoietic anemia, and neutrophilic dermatosis. We analyzed a cohort of uncharacterized Indian patients for pathogenic variants in and other genes associated with SAIDs.
METHODS
We performed whole-exome sequencing (WES) for 1 patient and next-generation sequencing (NGS) targeted gene panel for SAIDs in 3 patients. One patient was a referral from neurology after clinical exome sequencing identified a novel variant in . We reviewed the literature for all published studies of mutation-positive MJS patients and have summarized their clinical features and disease-causing variants.
RESULTS
We describe the largest series of patients with MJS outside of the Middle East. All 5 patients are homozygous for novel, possibly pathogenic variants in the gene. Two of these variants are missense substitutions, and 3 are predicted to alter transcript splicing and create a truncated protein. In addition to the classical features of CRMO and anemia, patients exhibited previously unreported features, including abdominal pain, recurrent diarrhea/ear discharge, and erythema nodosum.
CONCLUSION
Patients with MJS may present initially to different specialists, and thus it is important to create awareness in the medical community. In India, consanguinity is a common sociocultural factor in many ethnic communities and an abbreviated NGS gene panel for autoinflammatory diseases should include MJS. The unavailability of interleukin 1 inhibitors in some countries poses a treatment challenge.
Topics: Anemia, Dyserythropoietic, Congenital; Humans; Immunologic Deficiency Syndromes; Mutation; Osteomyelitis
PubMed: 33993107
DOI: 10.3899/jrheum.201663 -
International Journal of Molecular... Mar 2021Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in , which encodes lipin2, cause the autoinflammatory bone disorder...
Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in , which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.
Topics: Adipose Tissue; Anemia, Dyserythropoietic, Congenital; Animals; Bone Resorption; Cell Differentiation; Humans; Immunologic Deficiency Syndromes; Inflammation; Lipopolysaccharides; MAP Kinase Kinase Kinases; Macrophages; Mice; Mice, Knockout; NF-kappa B; NFATC Transcription Factors; Nuclear Proteins; Osteoclasts; Osteogenesis; Osteomyelitis; RANK Ligand; Signal Transduction; Transcription Factor RelA
PubMed: 33809261
DOI: 10.3390/ijms22062893 -
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 -
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 -
Rheumatology International Jan 2020To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to...
Pattern and diagnostic evaluation of systemic autoinflammatory diseases other than familial Mediterranean fever among Arab children: a multicenter study from the Pediatric Rheumatology Arab Group (PRAG).
To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1-12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1-10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries.
Topics: Acne Vulgaris; Adolescent; Anemia, Dyserythropoietic, Congenital; Antirheumatic Agents; Arabs; Arthritis; Arthritis, Infectious; Arthritis, Juvenile; Bahrain; Child; Child, Preschool; Consanguinity; Crohn Disease; Cross-Sectional Studies; Cryopyrin-Associated Periodic Syndromes; Diagnostic Errors; Female; Fever; Hereditary Autoinflammatory Diseases; Humans; Immunologic Deficiency Syndromes; Infant; Intracellular Signaling Peptides and Proteins; Jordan; Kuwait; Libya; Male; Mevalonate Kinase Deficiency; Oman; Osteomyelitis; Pyoderma Gangrenosum; Retrospective Studies; Sarcoidosis; Saudi Arabia; Synovitis; United Arab Emirates; Uveitis
PubMed: 31741047
DOI: 10.1007/s00296-019-04478-3 -
BMC Medical Genetics Nov 2019Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of...
BACKGROUND
Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome.
CASE PRESENTATION
We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327 + 1G > C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2.
CONCLUSIONS
Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.
Topics: Anemia, Dyserythropoietic, Congenital; Female; Fever; Humans; Immunologic Deficiency Syndromes; Infant; Male; Mutation; Neutropenia; Nuclear Proteins; Osteomyelitis; Pedigree; Recurrence; Severity of Illness Index
PubMed: 31727123
DOI: 10.1186/s12881-019-0919-3