Majeed Syndrome

MONDO:0012316 Pathograph 22 Show in embeddings browser autoinflammatory syndrome

An autosomal recessive autoinflammatory disorder caused by biallelic LPIN2 mutations, presenting as the triad of chronic sterile multifocal osteomyelitis, congenital dyserythropoietic anaemia and, in a minority of patients, a neutrophilic dermatosis. Lipin-2 is a phosphatidic acid phosphatase that normally restrains the NLRP3 inflammasome; losing it lets IL-1 beta production run unchecked. The cleanest evidence for that mechanism is therapeutic rather than biochemical. These children have raised TNF-alpha in serum, yet TNF blockade did nothing, while IL-1 blockade produced dramatic improvement. The inflammasome account does not by itself explain the bone lesions, and a second arm through macrophage polarisation and accelerated osteoclastogenesis has been proposed to fill that gap.

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1
Inheritance
6
Pathophys.
9
Phenotypes
22
Pathograph
1
Genes
8
Medical Actions
11
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
autoinflammatory syndrome
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive. Both the original families were consanguineous, but compound heterozygous cases have since been described.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33670882 SUPPORT Human Clinical
"The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2."
States the inheritance pattern.
PMID:36877799 SUPPORT Human Clinical
"If both parents are known to be heterozygous for an LPIN2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."
The recurrence risk for sibs, from the GeneReviews genetic counseling section.
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Pathophysiology

6
Biallelic LPIN2 Loss of Function
The initiating lesion. Homozygous or compound heterozygous LPIN2 mutations remove lipin-2, a phosphatidic acid phosphatase. The disease was mapped and the gene identified by homozygosity mapping in consanguineous families, and splice-site, frameshift and deletion alleles have all been reported since.
LPIN2 hgnc:14450 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LPIN2 (hgnc:14450). hgnc:14450 is a gene from the HUGO Gene Nomenclature Committee.
phosphatidate phosphatase activity GO:0008195 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphatidate phosphatase activity (GO:0008195). GO:0008195 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Inflammatory Macrophage Polarisation and Accelerated Osteoclastogenesis A second, inflammasome-independent consequence of losing lipin-2, acting on macrophage polarisation and osteoclast formation at the growth plate.
Loss of Lipin-2 Restraint on the NLRP3 Inflammasome Lipin-2 normally acts as a negative regulator of the inflammasome, so its loss releases that restraint.
Neutrophilic Dermatosis Loss of lipin-2 phosphatase activity leads to skin inflammation by a route that is not established. The edge is drawn from the genetic lesion rather than from IL-1 beta because no source here attributes the skin disease to either arm.
Show evidence (2 references)
PMID:15994876 SUPPORT Human Clinical
"Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families."
The original gene identification by positional mapping in two unrelated families.
PMID:33670882 SUPPORT Human Clinical
"The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2."
States the inheritance pattern and names the enzyme activity lost.
Loss of Lipin-2 Restraint on the NLRP3 Inflammasome
Lipin-2 restrains the inflammasome at more than one point. It limits MAPK activation during priming, which controls pro-IL-1 beta synthesis, and it inhibits activation and sensitisation of the P2X7 receptor together with the potassium efflux, ASC oligomerisation and caspase-1 processing that follow. The P2X7 arm is cholesterol-dependent, which is how a lipid phosphatase ends up controlling an ion channel.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee. P2RX7 hgnc:8537 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves P2RX7 (hgnc:8537). hgnc:8537 is a gene from the HUGO Gene Nomenclature Committee.
NLRP3 inflammasome complex assembly GO:0044546 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased NLRP3 inflammasome complex assembly (GO:0044546). GO:0044546 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Excess IL-1 beta Production Unrestrained priming and activation together drive excessive IL-1 beta from macrophages.
Show evidence (3 references)
PMID:28031477 SUPPORT In Vitro
"Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K+ efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation."
Enumerates the specific inflammasome steps lipin-2 restrains.
PMID:28031477 SUPPORT In Vitro
"Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production."
A rescue experiment. Restoring cholesterol reverses the P2X7 currents and the downstream IL-1 beta production, which is what ties the lipid function to the ion channel.
PMID:37865862 REFUTE Human Clinical
"LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519)."
A direct disagreement in the literature, recorded rather than resolved. This paper classifies the disease as non-inflammasome, while the mechanistic work above and other reviews place it among the NLRP3 inflammasomopathies. The therapeutic response to IL-1 blockade is compatible with either, since IL-1 beta can be produced by inflammasome-independent routes.
Excess IL-1 beta Production
The operative cytokine. Its primacy rests on a therapeutic dissociation rather than on biochemistry alone: TNF-alpha is also raised in these patients, but blocking it does nothing while blocking IL-1 works.
IL1B hgnc:5992 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL1B (hgnc:5992). hgnc:5992 is a gene from the HUGO Gene Nomenclature Committee.
interleukin-1 beta production GO:0032611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-1 beta production (GO:0032611). GO:0032611 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Sterile Multifocal Bone Inflammation IL-1 driven inflammation localises to bone. The intermediates are partly known through the macrophage and osteoclast arm below, and the inflammasome account alone does not explain why bone is targeted.
Recurrent Fever IL-1 beta is pyrogenic, and recurrent fever accompanies the systemic inflammatory burden.
Failure to Thrive Chronic systemic inflammation accompanies poor growth. The intervening route is not established in these sources.
Hepatosplenomegaly Organomegaly accompanies the systemic inflammatory and haematological disease, and can be present from the neonatal period.
Dyserythropoiesis The anaemia responds to IL-1 blockade alongside the bone disease, but the route from inflammasome activation to ineffective erythropoiesis is not established in these sources.
Show evidence (1 reference)
PMID:23087183 SUPPORT Human Clinical
"Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement."
The negative half of the dissociation. A cytokine can be elevated and still not be the driver, which is why this node names IL-1 beta specifically rather than "proinflammatory cytokines".
Inflammatory Macrophage Polarisation and Accelerated Osteoclastogenesis
Mechanism confidence: Provisional
The proposed second arm, offered specifically because the inflammasome account left the bone phenotype unexplained. LPIN2 deficiency drives pro-inflammatory M2 macrophages and enhances osteoclastogenesis, which would give bone a lineage-specific route to damage that generic cytokine excess does not.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
osteoclast differentiation GO:0030316 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased osteoclast differentiation (GO:0030316). GO:0030316 is a biological process from the Gene Ontology. ↑ INCREASED macrophage differentiation GO:0030225 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal macrophage differentiation (GO:0030225). GO:0030225 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Sterile Multifocal Bone Inflammation Enhanced osteoclastogenesis provides the bone-specific effector arm that the inflammasome account lacks.
Show evidence (2 references)
PMID:33670882 SUPPORT Human Clinical
"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."
States the macrophage and osteoclast arm and, crucially, that it operates in an inflammasome-independent manner. That is what makes this a genuinely separate arm rather than a downstream elaboration of the inflammasome node.
PMID:33314777 SUPPORT In Vitro
"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..."
Describes the functional work behind this arm, benchmarked alongside two other IL-1-mediated bone diseases, NOMID and DIRA.
Sterile Multifocal Bone Inflammation
Culture-negative, multifocal osteomyelitis with no demonstrable organism. The sterility is the defining feature and separates this from infectious osteomyelitis, which matters because the treatment is immunosuppression rather than antibiotics.
osteoclast differentiation GO:0030316 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased osteoclast differentiation (GO:0030316). GO:0030316 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Osteomyelitis The bone lesion as observed clinically and radiologically.
Bone Pain Recurrent bone pain, characteristically near the joints of the long bones of the lower limbs.
Joint Swelling The bone lesions sit next to the joints, and the adjacent joint swells. MRI in a genetically confirmed case places the bone marrow oedema and the soft tissue swelling at the same sites.
Flexion Contracture Repeated joint swelling accompanying the osteomyelitis leads to fixed contracture.
Show evidence (1 reference)
PMID:39757386 SUPPORT Human Clinical
"Inflammatory bone lesions associated with AIBDs exhibit chronic inflammation, are typically culture-negative, and do not exhibit discernible microorganisms on histopathological examination."
Defines the sterile character of the bone lesion in this disease family.
Dyserythropoiesis
Ineffective erythropoiesis producing a congenital microcytic anaemia of variable severity. It is present from the neonatal period in some patients and is what distinguishes this syndrome from non-syndromic chronic recurrent multifocal osteomyelitis.
Downstream
Microcytic Anemia The haematological phenotype as measured.
Show evidence (2 references)
PMID:36877799 SUPPORT Human Clinical
"Congenital dyserythropoietic, microcytic anemia can range from mild to severe and sometimes requires blood transfusion."
Characterises the anaemia, its microcytic nature and its range of severity.
PMID:41113563 SUPPORT Human Clinical
"Bone marrow cytology showed 21% erythroid precursors (Figure 2), predominantly at the intermediate and late stages, with mild anisocytosis among mature erythrocytes."
The marrow picture in one genetically confirmed patient with mild anaemia. It describes the erythroid compartment directly, though a single mild case does not show the full range of dyserythropoietic change seen at the severe end.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Majeed Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Blood 1
Microcytic Anemia VERY_FREQUENT HP:0001935 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcytic anemia (HP:0001935). HP:0001935 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36877799 SUPPORT Human Clinical
"Congenital dyserythropoietic, microcytic anemia can range from mild to severe and sometimes requires blood transfusion."
Establishes the anaemia, its microcytic character and its severity range.
PMID:41113563 SUPPORT Human Clinical
"CDA present | 29/34 | 85.3"
Table 2 of the 35-patient literature review. Five of 34 patients with data had no reported dyserythropoietic anaemia.
Cardiovascular 1
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17330256 SUPPORT Human Clinical
"The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate."
Documents hepatosplenomegaly presenting in the neonatal period.
Immune 2
Osteomyelitis VERY_FREQUENT HP:0002754 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteomyelitis (HP:0002754), qualified as temporality recurrent. HP:0002754 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (3 references)
PMID:33670882 SUPPORT Human Clinical
"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."
States the triad, with osteomyelitis as its first element.
PMID:41113563 SUPPORT Human Clinical
"CRMO present | 33/35 | 94.3"
Table 2 of the 35-patient literature review. Two reported patients lacked osteomyelitis, which is why the band is very frequent rather than obligate.
PMID:33670882 SUPPORT Human Clinical
"Most individuals with Majeed syndrome present in the first 2 years of life and 91% have both CRMO and CDA, and the neutrophilic dermatosis, if present, may be transient."
An independent 2021 figure in the same band.
Neutrophilic Dermatosis OCCASIONAL Neutrophilic infiltration of the skin HP:0031234 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutrophilic dermatosis, annotated with Neutrophilic infiltration of the skin (HP:0031234), qualified as temporality transient. HP:0031234 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (3 references)
PMID:36877799 SUPPORT Human Clinical
"Neutrophilic dermatosis typically presents as transient painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates."
Describes the lesion and its neutrophilic infiltrate, which is what the HPO term binds.
PMID:33670882 SUPPORT Human Clinical
"While CRMO and CDA are commonly reported in Majeed syndrome, only 2 of 24 affected individuals had skin disease, both with the neutrophilic dermatosis Sweet syndrome"
Two of 24 is about 8%, the basis for the occasional band.
PMID:41113563 SUPPORT Human Clinical
"Notably, Sweet syndrome and other neutrophilic dermatoses were rare but distinctive features in some cohorts."
The 2025 literature review reaches the same conclusion on a larger set.
Metabolism 2
Recurrent Fever FREQUENT HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954), qualified as temporality recurrent. HP:0001954 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:36877799 SUPPORT Human Clinical
"Individuals with LPIN2-related Majeed syndrome typically experience multisystem inflammatory symptoms, including chronic sterile multifocal osteomyelitis, recurrent bone pain, recurrent fever, failure to thrive, dyserythropoietic anemia, and neutrophilic dermatosis."
Names recurrent fever among the typical manifestations.
PMID:41113563 SUPPORT Human Clinical
"Recurrent fever | 23/30 | 76.7"
Table 2 of the 35-patient literature review; 76.7% sits in the frequent band.
Joint Swelling VERY_FREQUENT HP:0001386 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint swelling (HP:0001386), qualified as temporality recurrent. HP:0001386 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:41113563 SUPPORT Human Clinical
"Joint swelling | 19/22 | 86.4"
Table 2 of the 35-patient literature review, among the 22 patients with data.
PMID:41113563 SUPPORT Human Clinical
"The episodes were characterized by recurrent swelling and pain of the knees and ankles, accompanied by limping and occasional redness, occurring four to five times annually."
The pattern in one genetically confirmed patient.
Musculoskeletal 1
Flexion Contracture HP:0001371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"Recurrent osteomyelitis with joint swelling can lead to subsequent joint contractures."
States the causal sequence from recurrent joint swelling to contracture.
Constitutional 1
Bone Pain FREQUENT HP:0002653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone pain (HP:0002653), qualified as temporality recurrent. HP:0002653 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"Recurrent bone pain is frequently localized near the joints, often of the long bones of the lower extremities."
Gives the character and distribution of the pain.
Growth 1
Failure to Thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33670882 SUPPORT Human Clinical
"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."
Names failure to thrive in the originally described severe phenotype.
PMID:41113563 SUPPORT Human Clinical
"Failure to thrive | 20/27 | 74.1"
Table 2 of the 35-patient literature review.
🧬

Genetic Associations

1
LPIN2 (Biallelic Loss of Function)
Gene: LPIN2 hgnc:14450 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LPIN2 (hgnc:14450). hgnc:14450 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:15994876 SUPPORT Human Clinical
"The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p."
The positional mapping that localised the gene before it was identified.
PMID:17330256 SUPPORT Human Clinical
"A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site."
Independent confirmation in a third family with a different class of allele.
PMID:33314777 SUPPORT Human Clinical
"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."
Documents compound heterozygosity including a large deletion, which widens the allelic spectrum beyond homozygous point mutations.
+ 1 more reference
💊

Medical Actions

8
Interleukin-1 Blockade
Action: biological therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is biological therapy (NCIT:C15187). NCIT:C15187 is a clinical intervention from the NCI Thesaurus. Ontology label: Biological Therapy NCIT:C15187
Agent: anakinra NCIT:C38717 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (NCIT:C38717). NCIT:C38717 is a therapeutic agent from the NCI Thesaurus. canakinumab NCIT:C80971 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses canakinumab (NCIT:C80971). NCIT:C80971 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
The effective treatment, and the one that establishes the mechanism. Recombinant IL-1 receptor antagonist or an anti-IL-1 beta antibody produced dramatic clinical and laboratory improvement in disease refractory to corticosteroids, and long-lasting remission in a later case. GeneReviews names anti-IL-1 therapy the drug of choice (anakinra 1.5 mg/kg/day titrated as needed, or canakinumab 2 mg/kg every 4 or 8 weeks) and notes that it is not available everywhere. Patients on biologic or immunosuppressive treatment should avoid live-attenuated vaccines where possible.
Mechanism Target:
INHIBITS Excess IL-1 beta Production — Blocks either IL-1 beta itself or its receptor, neutralising the output of the unrestrained inflammasome.
Show evidence (1 reference)
PMID:23087183 SUPPORT Human Clinical
"IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement."
Two independent means of blocking the same axis both work, which is stronger evidence for the target than either alone.
Show evidence (4 references)
PMID:23087183 SUPPORT Human Clinical
"This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade."
The first report of biological treatment in this disease.
PMID:41113563 SUPPORT Human Clinical
"Treatments included NSAIDs, corticosteroids, bisphosphonates, methotrexate, and, more recently, biologics such as anakinra and canakinumab, with IL-1 blockade providing the most consistent benefit."
A literature-wide comparison across treatment classes, which places IL-1 blockade above the conventional agents rather than resting the claim on the two-sibling report alone.
PMID:36877799 SUPPORT Human Clinical
"While one of the anti-IL-1 therapies is the drug of choice, these drugs may not be universally available."
GeneReviews management guidance ranks anti-IL-1 therapy first, and explains why the conventional agents below remain in use.
+ 1 more reference
Tumour Necrosis Factor Blockade
Action: biological therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is biological therapy (NCIT:C15187). NCIT:C15187 is a clinical intervention from the NCI Thesaurus. Ontology label: Biological Therapy NCIT:C15187
Agent: etanercept NCIT:C2381 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses etanercept (NCIT:C2381). NCIT:C2381 is a therapeutic agent from the NCI Thesaurus. adalimumab NCIT:C65216 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses adalimumab (NCIT:C65216). NCIT:C65216 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Recorded mainly because it failed. TNF-alpha was elevated in serum and etanercept produced no improvement in two siblings whose disease then responded to IL-1 blockade, which is what makes the IL-1 response mechanistically informative. The record is not uniformly negative. A child treated as juvenile idiopathic arthritis with adalimumab alongside an NSAID and methotrexate had fewer flares but incomplete control, and a 2025 review lists anti-TNF agents among the medications reported effective. The fair reading is little or partial benefit, well short of the IL-1 response.
Show evidence (3 references)
PMID:23087183 REFUTE Human Clinical
"Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement."
Direct evidence against TNF as a therapeutic target here, despite the cytokine being measurably raised.
PMID:41113563 SUPPORT Human Clinical
"These therapies reduced the frequency of flares but did not completely control joint pain, raising doubts about the initial diagnosis and prompting further evaluation."
Partial benefit from a regimen that included adalimumab. The adalimumab was given with naproxen and methotrexate, so the benefit cannot be assigned to TNF blockade alone.
PMID:39757386 SUPPORT REVIEW SYNTHESIS Human Clinical
"Various medications, including NSAIDs, corticosteroids, bisphosphonates, anti-TNF agents, and anti-IL-1 medications, have been effective in the treatment of Majeed syndrome."
A review's summary that includes anti-TNF agents among effective treatments. It does not rank them, and it is recorded so the etanercept failure is not read as the whole literature.
Blood Transfusion
Action: blood transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is blood transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Platform: Other
Supportive treatment for the anaemia at its severe end.
Mechanism Target:
MODULATES Microcytic Anemia — Replaces red cells without addressing the ineffective erythropoiesis producing the deficit.
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"Congenital dyserythropoietic, microcytic anemia can range from mild to severe and sometimes requires blood transfusion."
States that transfusion is required at the severe end of the anaemia.
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"Congenital dyserythropoietic, microcytic anemia can range from mild to severe and sometimes requires blood transfusion."
Establishes transfusion as part of management for severe anaemia.
Corticosteroids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Used for flares and the skin disease. They give partial improvement in bone and skin, and the index report of IL-1 blockade was in children whose bone disease and anaemia were refractory to them. This is the arm the IL-1 argument pivots against.
Mechanism Target:
MODULATES Sterile Multifocal Bone Inflammation — Non-specific anti-inflammatory effect on the bone lesions, partial at best.
Show evidence (1 reference)
PMID:23087183 SUPPORT Human Clinical
"Corticosteroids provide only partial improvement in both the bone and skin disease."
States a partial effect on the bone disease, which is why the effect is modulation rather than inhibition.
Show evidence (2 references)
PMID:36877799 SUPPORT Human Clinical
"Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra 1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks), nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate."
GeneReviews lists corticosteroids among the anti-inflammatory options.
PMID:23087183 REFUTE Human Clinical
"Their bone disease and anaemia were refractory to treatment with corticosteroids."
Corticosteroid failure in the two siblings who then responded to IL-1 blockade.
Nonsteroidal Anti-inflammatory Drugs
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: nonsteroidal anti-inflammatory drug NCIT:C257 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses nonsteroidal anti-inflammatory drug, annotated with Nonsteroidal Antiinflammatory Drug (NCIT:C257). NCIT:C257 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Common first-line symptomatic treatment, used in about a third of reported patients. They relieve pain for a time and do not control the disease.
Mechanism Target:
MODULATES Bone Pain — Symptomatic relief of bone and joint pain without effect on the underlying inflammation.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Ibuprofen provided only partial relief, and there was no history of rash, oral ulcers, cough, vomiting, or diarrhea."
Partial relief of the joint and bone pain in one patient.
Show evidence (2 references)
PMID:36877799 SUPPORT Human Clinical
"Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra 1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks), nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate."
GeneReviews lists NSAIDs among the anti-inflammatory options.
PMID:41113563 SUPPORT REVIEW SYNTHESIS Human Clinical
"Conventional therapies such as NSAIDs, corticosteroids, and methotrexate may alleviate symptoms temporarily but fail to address the underlying IL-1-mediated inflammatory process (11)."
Temporary symptomatic benefit from the conventional agents, stated in the discussion with a citation to earlier work.
Methotrexate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: methotrexate CHEBI:44185 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methotrexate (CHEBI:44185). CHEBI:44185 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A conventional disease-modifying agent, often started when the disease is taken for juvenile idiopathic arthritis. Benefit is partial. It must be avoided in pregnancy.
Show evidence (3 references)
PMID:36877799 SUPPORT Human Clinical
"Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra 1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks), nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate."
GeneReviews lists methotrexate among the anti-inflammatory options.
PMID:41113563 SUPPORT Human Clinical
"Initially diagnosed and treated as JIA with NSAIDs, methotrexate, and adalimumab, she experienced only partial improvement."
Partial improvement on a regimen including methotrexate.
PMID:36877799 SUPPORT Human Clinical
"Methotrexate should be avoided in pregnancy, as it is known to be harmful to the developing fetus and can lead to pregnancy loss and/or birth defects."
The pregnancy restriction from GeneReviews management guidance.
Bisphosphonates
Action: bisphosphonate therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bisphosphonate therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. Ontology label: Bisphosphonate Therapy NCIT:C198585
Agent: pamidronate CHEBI:7903 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pamidronate (CHEBI:7903). CHEBI:7903 is a therapeutic agent from Chemical Entities of Biological Interest. alendronate CHEBI:2567 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses alendronate, annotated with alendronic acid (CHEBI:2567). CHEBI:2567 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Pamidronate and alendronate have been used, in about a quarter of reported patients. The rationale is suppression of osteoclast activity in the bone lesions. The supporting statements come from chronic nonbacterial osteomyelitis generally, and no controlled data exist for this disease.
Mechanism Target:
INHIBITS Inflammatory Macrophage Polarisation and Accelerated Osteoclastogenesis — Suppresses osteoclast activity, the bone-specific effector arm.
Show evidence (1 reference)
PMID:39757386 SUPPORT INDIRECT Human Clinical
"Bisphosphonates (e.g., pamidronate and zoledronic acid) are promising treatment options that facilitate the control of osteoclast activity via the suppression of proinflammatory cytokine expression."
Stated for chronic nonbacterial osteomyelitis as a group, not for Majeed syndrome specifically, hence indirect.
Show evidence (2 references)
PMID:41113563 SUPPORT Human Clinical
"Treatments included NSAIDs, corticosteroids, bisphosphonates, methotrexate, and, more recently, biologics such as anakinra and canakinumab, with IL-1 blockade providing the most consistent benefit."
Bisphosphonates among the treatments used across the reported patients.
PMID:23087183 SUPPORT BACKGROUND Human Clinical
"For refractory cases, bisphosphonates and TNF inhibitors have been tried, with reports of efficacy in some, but treatment failures are also reported."
Mixed results with bisphosphonates in refractory sterile osteomyelitis, from the paper's background on related disorders.
Physical and Occupational Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Supports motor development and limits joint contractures.
Mechanism Target:
MODULATES Flexion Contracture — Maintains range of motion in joints at risk of contracture.
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"Physical therapy and/or occupational therapy can help motor delays and joint contractures."
GeneReviews management guidance for contractures.
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"Physical therapy and/or occupational therapy can help motor delays and joint contractures."
Establishes rehabilitation therapy as part of management.
🔬

Biochemical Markers

5
C-reactive protein (INCREASED)
Reference Ranges
C reactive protein [Mass/volume] in Serum or Plasma by High sensitivity method 0.0–3.0 mg/L (the reporting hospital's reference interval, one pediatric case report)
Single-laboratory interval quoted by the case report, not a population standard. LOINC is not covered by the repository's OAK term validation; the code was checked against the NLM clinical-tables LOINC service.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Inflammatory markers were significantly elevated, with hypersensitive CRP at 79.1 mg/L (reference 0-3 mg/L) and ESR at 51 mm/h (reference 0-20 mm/h)."
Gives the patient's value and the laboratory reference interval.
Show evidence (3 references)
PMID:41113563 SUPPORT Human Clinical
"Laboratory findings consistently demonstrated anemia, elevated ESR and CRP, and variable microcytic indices."
Raised CRP across the reviewed cases.
PMID:41113563 SUPPORT Human Clinical
"Elevated inflammatory markers (CRP/ESR/platelets) | 23/26 | 88.5"
Table 2 frequency of raised inflammatory markers.
PMID:41113563 SUPPORT Human Clinical
"During remission, inflammatory markers decreased (hs-CRP 7.99 mg/L, ESR 23 mm/h)."
The remission values, which show the marker tracking activity.
Erythrocyte sedimentation rate (INCREASED)
Reference Ranges
Erythrocyte [Sedimentation Rate] in Blood 0.0–20.0 mm/h (the reporting hospital's reference interval, one pediatric case report)
Single-laboratory interval; the method was not stated, so the method-unspecified LOINC code is used. Checked against the NLM clinical-tables LOINC service.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Inflammatory markers were significantly elevated, with hypersensitive CRP at 79.1 mg/L (reference 0-3 mg/L) and ESR at 51 mm/h (reference 0-20 mm/h)."
Gives the patient's value and the laboratory reference interval.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Laboratory findings consistently demonstrated anemia, elevated ESR and CRP, and variable microcytic indices."
Raised ESR across the reviewed cases.
Interleukin-6 (INCREASED)
Reference Ranges
Interleukin 6 [Mass/volume] in Serum or Plasma 0.0–20.9 pg/mL (the reporting hospital's reference interval, one pediatric case report)
Single-laboratory interval quoted by one case report; cytokine assays are not standardised across laboratories. Checked against the NLM clinical-tables LOINC service.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64 pg/ml (reference 1-5 pg/ml)."
Gives the patient's value and the laboratory reference interval.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64 pg/ml (reference 1-5 pg/ml)."
The measured elevation in one genetically confirmed patient during a flare.
Tumor necrosis factor alpha (INCREASED)
Reference Ranges
Tumor necrosis factor.alpha [Mass/volume] in Serum or Plasma 0.0–5.5 pg/mL (the reporting hospital's reference interval, one pediatric case report)
Single-laboratory interval quoted by one case report; cytokine assays are not standardised across laboratories. Checked against the NLM clinical-tables LOINC service.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64 pg/ml (reference 1-5 pg/ml)."
Gives the patient's value and the laboratory reference interval.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64 pg/ml (reference 1-5 pg/ml)."
The measured elevation in one genetically confirmed patient during a flare.
Interleukin-17A (INCREASED)
Reference Ranges
Interleukin 17A [Mass/volume] in Serum or Plasma 1.0–5.0 pg/mL (the reporting hospital's reference interval, one pediatric case report)
Single-laboratory interval quoted by one case report; cytokine assays are not standardised across laboratories. Checked against the NLM clinical-tables LOINC service.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64 pg/ml (reference 1-5 pg/ml)."
Gives the patient's value and the laboratory reference interval.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64 pg/ml (reference 1-5 pg/ml)."
The measured elevation in one genetically confirmed patient during a flare.
🔬

Diagnosis

3
LPIN2 molecular genetic testing (PRESENT)
Diagnosis is molecular, established by biallelic pathogenic LPIN2 variants in a proband with suggestive findings. This matters because the bone lesions are culture-negative and will otherwise be pursued as infection.
Show evidence (1 reference)
PMID:36877799 SUPPORT Human Clinical
"The diagnosis of LPIN2-related Majeed syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in LPIN2 identified by molecular genetic testing."
States the molecular diagnostic criterion.
Differentiation from juvenile idiopathic arthritis (PRESENT)
The practical diagnostic problem. Overlap with juvenile idiopathic arthritis leads to delayed or incorrect diagnosis, and patients are treated as JIA with partial response before the genetic diagnosis is made. That partial response is itself misleading, because it looks like treatment failure rather than wrong diagnosis.
Show evidence (2 references)
PMID:41113563 SUPPORT Human Clinical
"Its rarity and overlap with juvenile idiopathic arthritis (JIA) often lead to delayed or incorrect diagnoses."
States the differential that causes the delay.
PMID:41113563 SUPPORT Human Clinical
"Initially diagnosed and treated as JIA with NSAIDs, methotrexate, and adalimumab, she experienced only partial improvement."
An individual instance, and note that adalimumab is a TNF inhibitor - a second case of TNF blockade giving only partial benefit, consistent with the etanercept failure recorded under treatments.
MRI of bone marrow oedema (PRESENT)
Whole-body or regional MRI shows multifocal bone marrow oedema at the osteomyelitic sites. In the reported case it was the MRI, together with the microcytic anaemia, that moved the working diagnosis from juvenile idiopathic arthritis toward a monogenic autoinflammatory disease.
Show evidence (1 reference)
PMID:41113563 SUPPORT Human Clinical
"MRI revealed multifocal bone marrow edema consistent with CRMO, and laboratory results demonstrated mild microcytic anemia."
The imaging finding and the laboratory finding that together prompted genetic testing.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Three published counts: 24 genetically confirmed individuals from 10 families (2021 review), 31 individuals from 18 families (2023), and 35 patients with sufficient clinical or genetic data in a 2025 literature review covering reports to the end of 2023. The counts come from different inclusion rules and overlap, so they are not additive. No population rate is available.
Show evidence (3 references)
PMID:33670882 SUPPORT Human Clinical
"It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature."
The 2021 count of genetically confirmed individuals.
PMID:37865862 SUPPORT Human Clinical
"To date, only 31 individuals from 18 families have been reported with this rare condition."
The 2023 count.
PMID:41113563 SUPPORT Human Clinical
"After excluding reports without sufficient clinical or genetic data, 35 patients were identified (Table 1)."
The 2025 review's case series, which is the denominator behind the phenotype frequencies in this entry.
🌍

Epidemiology

2
Reported case count
Exceedingly rare. At the time of the most recent review, 24 genetically confirmed individuals from 10 families had been reported, which is the constraint behind every frequency statement in this entry.
Show evidence (2 references)
PMID:33670882 SUPPORT Human Clinical
"It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature."
The 2021 figure. Small enough that phenotype frequencies here should be read cautiously.
PMID:37865862 SUPPORT Human Clinical
"To date, only 31 individuals from 18 families have been reported with this rare condition."
The updated count two years later. Both are recorded because the growth from 10 to 18 families is itself the reason milder phenotypes are now recognised.
Widening phenotypic spectrum
Early reports described severely affected children. As more families have been found, milder presentations have been recognised, so the original description is probably an ascertainment-biased extreme rather than the typical case.
Show evidence (1 reference)
PMID:33670882 SUPPORT Human Clinical
"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..."
Documents both the original severe phenotype and the later recognition of variability.
{ }

Source YAML

click to show 
name: Majeed Syndrome
creation_date: '2026-09-09T09:00:00Z'
description: >-
  An autosomal recessive autoinflammatory disorder caused by biallelic LPIN2
  mutations, presenting as the triad of chronic sterile multifocal osteomyelitis,
  congenital dyserythropoietic anaemia and, in a minority of patients, a
  neutrophilic dermatosis. Lipin-2 is a phosphatidic acid phosphatase that normally restrains
  the NLRP3 inflammasome; losing it lets IL-1 beta production run unchecked. The
  cleanest evidence for that mechanism is therapeutic rather than biochemical.
  These children have raised TNF-alpha in serum, yet TNF blockade did nothing,
  while IL-1 blockade produced dramatic improvement. The inflammasome account
  does not by itself explain the bone lesions, and a second arm through
  macrophage polarisation and accelerated osteoclastogenesis has been proposed to
  fill that gap.
categories:
- Autoinflammatory Disease
- Autoinflammatory Bone Disease
- Inborn Error of Immunity
parents:
- autoinflammatory syndrome
synonyms:
- LPIN2-related Majeed syndrome
- chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  iuis_category:
    classification_value: autoinflammatory syndrome
    notes: >-
      IUIS 2022 phenotypic classification (Tangye et al., PMID:35748970), Table 7
      "Autoinflammatory disorders", section 3 "Non-Inflammasome Related
      Conditions", the LPIN2 row, with the mechanism column reading
      "Undefined". The placement outside the inflammasome section is discussed
      in the entry notes; it records where the committee filed the disease, not
      a finding against lipin-2 regulation of NLRP3. No evidence item is
      attached: the row survives only in the PDF extraction of the committed
      cache, and the validator's current extractor re-reads the paper from PMC
      XML without its tables, so a quoted row would not verify.
epidemiology:
- name: Reported case count
  description: >-
    Exceedingly rare. At the time of the most recent review, 24 genetically
    confirmed individuals from 10 families had been reported, which is the
    constraint behind every frequency statement in this entry.
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'It is exceedingly rare. There are only 24 individuals from 10 families with genetically
      confirmed Majeed syndrome reported in the literature.'
    explanation: The 2021 figure. Small enough that phenotype frequencies here should be read
      cautiously.
  - reference: PMID:37865862
    reference_title: 'LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in
      LPIN2 and review of literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'To date, only 31 individuals from 18 families have been reported with this rare
      condition.'
    explanation: The updated count two years later. Both are recorded because the growth from 10
      to 18 families is itself the reason milder phenotypes are now recognised.
- name: Widening phenotypic spectrum
  description: >-
    Early reports described severely affected children. As more families have been
    found, milder presentations have been recognised, so the original description
    is probably an ascertainment-biased extreme rather than the typical case.
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '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.'
    explanation: Documents both the original severe phenotype and the later recognition of
      variability.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three published counts: 24 genetically confirmed individuals from 10
    families (2021 review), 31 individuals from 18 families (2023), and 35
    patients with sufficient clinical or genetic data in a 2025 literature
    review covering reports to the end of 2023. The counts come from different
    inclusion rules and overlap, so they are not additive. No population rate
    is available.
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'It is exceedingly rare. There are only 24 individuals from 10 families with genetically
      confirmed Majeed syndrome reported in the literature.'
    explanation: The 2021 count of genetically confirmed individuals.
  - reference: PMID:37865862
    reference_title: 'LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in
      LPIN2 and review of literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'To date, only 31 individuals from 18 families have been reported with this rare
      condition.'
    explanation: The 2023 count.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'After excluding reports without sufficient clinical or genetic data, 35 patients were
      identified (Table 1).'
    explanation: The 2025 review's case series, which is the denominator behind the phenotype
      frequencies in this entry.
pathophysiology:
- name: Biallelic LPIN2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. Homozygous or compound heterozygous LPIN2 mutations
    remove lipin-2, a phosphatidic acid phosphatase. The disease was mapped and
    the gene identified by homozygosity mapping in consanguineous families, and
    splice-site, frameshift and deletion alleles have all been reported since.
  genes:
  - preferred_term: LPIN2
    term:
      id: hgnc:14450
      label: LPIN2
  molecular_functions:
  - preferred_term: phosphatidate phosphatase activity
    modifier: DECREASED
    term:
      id: GO:0008195
      label: phosphatidate phosphatase activity
  evidence:
  - reference: PMID:15994876
    reference_title: Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal
      osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Examination of genes in this interval led to the identification of homozygous mutations
      in LPIN2 in affected individuals from the two families.'
    explanation: The original gene identification by positional mapping in two unrelated families.
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene
      encoding the phosphatidic acid phosphatase LIPIN2.'
    explanation: States the inheritance pattern and names the enzyme activity lost.
  downstream:
  - target: Inflammatory Macrophage Polarisation and Accelerated Osteoclastogenesis
    causal_link_type: DIRECT
    description: A second, inflammasome-independent consequence of losing lipin-2, acting on
      macrophage polarisation and osteoclast formation at the growth plate.
    evidence:
    - reference: PMID:33670882
      reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '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.'
      explanation: States that LPIN2 deficiency drives this arm directly and independently of the
        inflammasome, which is why it branches from the genetic lesion rather than from IL-1 beta.
  - target: Loss of Lipin-2 Restraint on the NLRP3 Inflammasome
    causal_link_type: DIRECT
    description: Lipin-2 normally acts as a negative regulator of the inflammasome, so its loss
      releases that restraint.
    evidence:
    - reference: PMID:28031477
      reference_title: Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'Collectively, our results unveil lipin-2 as a critical player in the negative
        regulation of NLRP3 inflammasome.'
      explanation: States the negative-regulator role whose loss this edge describes.
  - target: Neutrophilic Dermatosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of lipin-2 phosphatase activity leads to skin inflammation by a route that
      is not established. The edge is drawn from the genetic lesion rather than from IL-1 beta
      because no source here attributes the skin disease to either arm.
    evidence:
    - reference: PMID:23087183
      reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'How an absence of PAP activity in LIPIN-2 leads to inflammation in the skin and bone
        remains unclear.'
      explanation: Links the loss of phosphatidic acid phosphatase activity to skin inflammation
        and states that the intervening mechanism is unknown, which is the grade given to this
        edge.
- name: Loss of Lipin-2 Restraint on the NLRP3 Inflammasome
  biological_scale: CELLULAR
  description: >-
    Lipin-2 restrains the inflammasome at more than one point. It limits MAPK
    activation during priming, which controls pro-IL-1 beta synthesis, and it
    inhibits activation and sensitisation of the P2X7 receptor together with the
    potassium efflux, ASC oligomerisation and caspase-1 processing that follow.
    The P2X7 arm is cholesterol-dependent, which is how a lipid phosphatase ends
    up controlling an ion channel.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  genes:
  - preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  - preferred_term: P2RX7
    term:
      id: hgnc:8537
      label: P2RX7
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    modifier: INCREASED
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
  evidence:
  - reference: PMID:28031477
    reference_title: Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Lipin-2 also inhibits the activation and sensitization of the purinergic receptor
      P2X7 and K+ efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization,
      and caspase-1 processing, key events during inflammasome activation.'
    explanation: Enumerates the specific inflammasome steps lipin-2 restrains.
  - reference: PMID:28031477
    reference_title: Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol
      levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases
      ion currents through the P2X7 receptor, and downstream events that drive IL-1β production.'
    explanation: A rescue experiment. Restoring cholesterol reverses the P2X7 currents and the
      downstream IL-1 beta production, which is what ties the lipid function to the ion channel.
  - reference: PMID:37865862
    reference_title: 'LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in
      LPIN2 and review of literature.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory
      disease, caused due to biallelic variants in LPIN2 (MIM* 605519).'
    explanation: A direct disagreement in the literature, recorded rather than resolved. This paper
      classifies the disease as non-inflammasome, while the mechanistic work above and other
      reviews place it among the NLRP3 inflammasomopathies. The therapeutic response to IL-1
      blockade is compatible with either, since IL-1 beta can be produced by inflammasome-independent
      routes.
  downstream:
  - target: Excess IL-1 beta Production
    causal_link_type: DIRECT
    description: Unrestrained priming and activation together drive excessive IL-1 beta from
      macrophages.
    evidence:
    - reference: PMID:28031477
      reference_title: Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'We show here that lipin-2 controls excessive IL-1β formation in primary human and
        mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3.'
      explanation: States the output this edge terminates in, demonstrated in both human and mouse
        primary macrophages.
- name: Excess IL-1 beta Production
  biological_scale: CELLULAR
  description: >-
    The operative cytokine. Its primacy rests on a therapeutic dissociation rather
    than on biochemistry alone: TNF-alpha is also raised in these patients, but
    blocking it does nothing while blocking IL-1 works.
  biological_processes:
  - preferred_term: interleukin-1 beta production
    modifier: INCREASED
    term:
      id: GO:0032611
      label: interleukin-1 beta production
  genes:
  - preferred_term: IL1B
    term:
      id: hgnc:5992
      label: IL1B
  evidence:
  - reference: PMID:23087183
    reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Both siblings had elevated proinflammatory cytokines in their serum, including tumour
      necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no
      improvement.'
    explanation: The negative half of the dissociation. A cytokine can be elevated and still not
      be the driver, which is why this node names IL-1 beta specifically rather than
      "proinflammatory cytokines".
  downstream:
  - target: Sterile Multifocal Bone Inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: IL-1 driven inflammation localises to bone. The intermediates are partly known
      through the macrophage and osteoclast arm below, and the inflammasome account alone does not
      explain why bone is targeted.
    evidence:
    - reference: PMID:33670882
      reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '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.'
      explanation: The authors state plainly that the inflammasome account does not explain the
        bone phenotype, which is why this edge is graded as having known but insufficient
        intermediates.
  - target: Recurrent Fever
    causal_link_type: DIRECT
    description: IL-1 beta is pyrogenic, and recurrent fever accompanies the systemic inflammatory
      burden.
    evidence:
    - reference: PMID:33670882
      reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '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.'
      explanation: Groups recurrent fever with the raised inflammatory markers that reflect this
        node.
  - target: Failure to Thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic systemic inflammation accompanies poor growth. The intervening route is
      not established in these sources.
    evidence:
    - reference: PMID:33670882
      reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '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.'
      explanation: Places failure to thrive alongside the systemic inflammatory features, without
        establishing the mechanism.
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Organomegaly accompanies the systemic inflammatory and haematological disease,
      and can be present from the neonatal period.
    evidence:
    - reference: PMID:17330256
      reference_title: A splice site mutation confirms the role of LPIN2 in Majeed syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a
        neonate.'
      explanation: Documents hepatosplenomegaly together with the anaemia in the neonatal period;
        the mechanism is not addressed.
  - target: Dyserythropoiesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The anaemia responds to IL-1 blockade alongside the bone disease, but the route
      from inflammasome activation to ineffective erythropoiesis is not established in these
      sources.
    evidence:
    - reference: PMID:23087183
      reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Their bone disease and anaemia were refractory to treatment with corticosteroids.'
      explanation: Treats bone disease and anaemia as a single therapeutic problem, which is the
        clinical basis for placing both downstream of the same node; the mechanism is not shown.
- name: Inflammatory Macrophage Polarisation and Accelerated Osteoclastogenesis
  biological_scale: CELLULAR
  description: >-
    The proposed second arm, offered specifically because the inflammasome account
    left the bone phenotype unexplained. LPIN2 deficiency drives pro-inflammatory
    M2 macrophages and enhances osteoclastogenesis, which would give bone a
    lineage-specific route to damage that generic cytokine excess does not.
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0030316
      label: osteoclast differentiation
  - preferred_term: macrophage differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030225
      label: macrophage differentiation
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '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.'
    explanation: States the macrophage and osteoclast arm and, crucially, that it operates in an
      inflammasome-independent manner. That is what makes this a genuinely separate arm rather
      than a downstream elaboration of the inflammasome node.
  - reference: PMID:33314777
    reference_title: Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2
      Macrophages and Accelerated Osteoclastogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: '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).'
    explanation: Describes the functional work behind this arm, benchmarked alongside two other
      IL-1-mediated bone diseases, NOMID and DIRA.
  downstream:
  - target: Sterile Multifocal Bone Inflammation
    causal_link_type: DIRECT
    description: Enhanced osteoclastogenesis provides the bone-specific effector arm that the
      inflammasome account lacks.
    evidence:
    - reference: PMID:33314777
      reference_title: Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory
        M2 Macrophages and Accelerated Osteoclastogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and
        characterize the pathomechanisms that lead to the development of sterile osteomyelitis.'
      explanation: States the stated aim of linking these cellular findings to sterile
        osteomyelitis, which is the endpoint of this edge.
- name: Sterile Multifocal Bone Inflammation
  biological_scale: TISSUE
  description: >-
    Culture-negative, multifocal osteomyelitis with no demonstrable organism. The
    sterility is the defining feature and separates this from infectious
    osteomyelitis, which matters because the treatment is immunosuppression rather
    than antibiotics.
  biological_processes:
  - preferred_term: osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0030316
      label: osteoclast differentiation
  evidence:
  - reference: PMID:39757386
    reference_title: Autoinflammatory Bone Diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Inflammatory bone lesions associated with AIBDs exhibit chronic inflammation, are
      typically culture-negative, and do not exhibit discernible microorganisms on histopathological
      examination.'
    explanation: Defines the sterile character of the bone lesion in this disease family.
  downstream:
  - target: Osteomyelitis
    causal_link_type: DIRECT
    description: The bone lesion as observed clinically and radiologically.
    evidence:
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Individuals with LPIN2-related Majeed syndrome typically experience multisystem
        inflammatory symptoms, including chronic sterile multifocal osteomyelitis, recurrent bone
        pain, recurrent fever, failure to thrive, dyserythropoietic anemia, and neutrophilic
        dermatosis.'
      explanation: Names sterile multifocal osteomyelitis among the typical manifestations.
  - target: Bone Pain
    causal_link_type: DIRECT
    description: Recurrent bone pain, characteristically near the joints of the long bones of the
      lower limbs.
    evidence:
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Recurrent bone pain is frequently localized near the joints, often of the long bones
        of the lower extremities.'
      explanation: Gives the characteristic distribution of the pain.
  - target: Joint Swelling
    causal_link_type: DIRECT
    description: The bone lesions sit next to the joints, and the adjacent joint swells. MRI in a
      genetically confirmed case places the bone marrow oedema and the soft tissue swelling at the
      same sites.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Imaging of the lower limbs revealed bone marrow edema and soft tissue swelling involving
        both distal femurs (Figure 1), the proximal left tibia, and both ankles.'
      explanation: Co-locates the osteitis and the soft tissue swelling at the knees and ankles in
        one patient.
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Recurrent osteomyelitis with joint swelling can lead to subsequent joint
        contractures.'
      explanation: Pairs the osteomyelitis with joint swelling as the course that precedes
        contracture.
  - target: Flexion Contracture
    causal_link_type: DIRECT
    description: Repeated joint swelling accompanying the osteomyelitis leads to fixed contracture.
    evidence:
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Recurrent osteomyelitis with joint swelling can lead to subsequent joint
        contractures.'
      explanation: States the progression from recurrent joint swelling to contracture.
- name: Dyserythropoiesis
  biological_scale: CELLULAR
  description: >-
    Ineffective erythropoiesis producing a congenital microcytic anaemia of
    variable severity. It is present from the neonatal period in some patients and
    is what distinguishes this syndrome from non-syndromic chronic recurrent
    multifocal osteomyelitis.
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Congenital dyserythropoietic, microcytic anemia can range from mild to severe and
      sometimes requires blood transfusion.'
    explanation: Characterises the anaemia, its microcytic nature and its range of severity.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Bone marrow cytology showed 21% erythroid precursors (Figure 2), predominantly at the
      intermediate and late stages, with mild anisocytosis among mature erythrocytes.'
    explanation: The marrow picture in one genetically confirmed patient with mild anaemia. It
      describes the erythroid compartment directly, though a single mild case does not show the
      full range of dyserythropoietic change seen at the severe end.
  downstream:
  - target: Microcytic Anemia
    causal_link_type: DIRECT
    description: The haematological phenotype as measured.
    evidence:
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Congenital dyserythropoietic, microcytic anemia can range from mild to severe and
        sometimes requires blood transfusion.'
      explanation: Names the microcytic anaemia and its transfusion requirement at the severe end.
phenotypes:
- category: Skeletal
  name: Osteomyelitis
  frequency: VERY_FREQUENT
  description: >-
    Chronic sterile multifocal osteomyelitis, the cardinal feature and the first
    element of the defining triad. Culture-negative, so the diagnosis depends on
    recognising that it is not infection.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
    temporality: RECURRENT
  diagnostic: true
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '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.'
    explanation: States the triad, with osteomyelitis as its first element.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CRMO present | 33/35 | 94.3'
    explanation: Table 2 of the 35-patient literature review. Two reported patients lacked
      osteomyelitis, which is why the band is very frequent rather than obligate.
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Most individuals with Majeed syndrome present in the first 2 years of life and 91% have
      both CRMO and CDA, and the neutrophilic dermatosis, if present, may be transient.'
    explanation: An independent 2021 figure in the same band.
- category: Hematologic
  name: Microcytic Anemia
  frequency: VERY_FREQUENT
  description: >-
    Congenital dyserythropoietic microcytic anaemia, the second element of the
    triad, ranging from mild to transfusion-dependent.
  phenotype_term:
    preferred_term: Microcytic anemia
    term:
      id: HP:0001935
      label: Microcytic anemia
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Congenital dyserythropoietic, microcytic anemia can range from mild to severe and
      sometimes requires blood transfusion.'
    explanation: Establishes the anaemia, its microcytic character and its severity range.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CDA present | 29/34 | 85.3'
    explanation: Table 2 of the 35-patient literature review. Five of 34 patients with data had no
      reported dyserythropoietic anaemia.
- category: Skeletal
  name: Bone Pain
  frequency: FREQUENT
  description: >-
    Recurrent bone pain, typically near the joints of the long bones of the lower
    limbs, and often the presenting complaint.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
    temporality: RECURRENT
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recurrent bone pain is frequently localized near the joints, often of the long bones
      of the lower extremities.'
    explanation: Gives the character and distribution of the pain.
- category: Constitutional
  name: Recurrent Fever
  frequency: FREQUENT
  description: >-
    Recurrent fever with marked elevation of inflammatory markers, part of the
    autoinflammatory picture.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Individuals with LPIN2-related Majeed syndrome typically experience multisystem
      inflammatory symptoms, including chronic sterile multifocal osteomyelitis, recurrent bone
      pain, recurrent fever, failure to thrive, dyserythropoietic anemia, and neutrophilic
      dermatosis.'
    explanation: Names recurrent fever among the typical manifestations.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recurrent fever | 23/30 | 76.7'
    explanation: Table 2 of the 35-patient literature review; 76.7% sits in the frequent band.
- category: Growth
  name: Failure to Thrive
  frequency: FREQUENT
  description: >-
    Poor growth accompanying the chronic inflammatory burden, prominent in the
    severely affected children of the original descriptions.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '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.'
    explanation: Names failure to thrive in the originally described severe phenotype.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Failure to thrive | 20/27 | 74.1'
    explanation: Table 2 of the 35-patient literature review.
- category: Musculoskeletal
  name: Joint Swelling
  frequency: VERY_FREQUENT
  description: >-
    Recurrent swelling of the joints next to the bone lesions, most often the
    knees and ankles. It is what makes the disease look like juvenile idiopathic
    arthritis, and it precedes the contractures.
  phenotype_term:
    preferred_term: Joint swelling
    term:
      id: HP:0001386
      label: Joint swelling
    temporality: RECURRENT
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Joint swelling | 19/22 | 86.4'
    explanation: Table 2 of the 35-patient literature review, among the 22 patients with data.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The episodes were characterized by recurrent swelling and pain of the knees and ankles,
      accompanied by limping and occasional redness, occurring four to five times annually.'
    explanation: The pattern in one genetically confirmed patient.
- category: Dermatologic
  name: Neutrophilic Dermatosis
  frequency: OCCASIONAL
  description: >-
    Transient painful erythematous plaques, pustules or nodules with
    neutrophilic infiltrates, reported as Sweet syndrome. It is the third
    element of the classical triad but the least consistent: 2 of 24
    genetically confirmed individuals in the 2021 review, and the review's
    authors leave open whether Sweet syndrome belongs to the disease at all.
  phenotype_term:
    preferred_term: Neutrophilic dermatosis
    term:
      id: HP:0031234
      label: Neutrophilic infiltration of the skin
    temporality: TRANSIENT
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Neutrophilic dermatosis typically presents as transient painful erythematous plaques,
      pustules, or nodules with neutrophilic infiltrates.'
    explanation: Describes the lesion and its neutrophilic infiltrate, which is what the HPO term
      binds.
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'While CRMO and CDA are commonly reported in Majeed syndrome, only 2 of 24 affected
      individuals had skin disease, both with the neutrophilic dermatosis Sweet syndrome'
    explanation: Two of 24 is about 8%, the basis for the occasional band.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Notably, Sweet syndrome and other neutrophilic dermatoses were rare but distinctive
      features in some cohorts.'
    explanation: The 2025 literature review reaches the same conclusion on a larger set.
- category: Musculoskeletal
  name: Flexion Contracture
  description: >-
    Joint contracture following repeated osteomyelitis with joint swelling, a
    cumulative rather than acute consequence.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recurrent osteomyelitis with joint swelling can lead to subsequent joint
      contractures.'
    explanation: States the causal sequence from recurrent joint swelling to contracture.
- category: Gastrointestinal
  name: Hepatosplenomegaly
  description: >-
    Enlargement of liver and spleen, reported both as a neonatal presenting sign
    and among the later features.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:17330256
    reference_title: A splice site mutation confirms the role of LPIN2 in Majeed syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a
      neonate.'
    explanation: Documents hepatosplenomegaly presenting in the neonatal period.
genetic:
- name: LPIN2
  gene_term:
    preferred_term: LPIN2
    term:
      id: hgnc:14450
      label: LPIN2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Biallelic Loss of Function
  notes: >-
    Identified by homozygosity mapping in consanguineous families and confirmed
    by an independent splice-site allele in a third family. Reported alleles
    include missense, frameshift, splice-site and a 17.8 kb deletion, and
    compound heterozygosity occurs, so the disease is not restricted to
    consanguineous populations. Two alleles recur across families,
    c.2201C>T (p.Ser734Leu) and c.540_541delAT.
  evidence:
  - reference: PMID:15994876
    reference_title: Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal
      osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p.'
    explanation: The positional mapping that localised the gene before it was identified.
  - reference: PMID:17330256
    reference_title: A splice site mutation confirms the role of LPIN2 in Majeed syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A homozygous single-basepair change was detected in the donor splice site of exon
      17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site.'
    explanation: Independent confirmation in a third family with a different class of allele.
  - reference: PMID:33314777
    reference_title: Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2
      Macrophages and Accelerated Osteoclastogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '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.'
    explanation: Documents compound heterozygosity including a large deletion, which widens the
      allelic spectrum beyond homozygous point mutations.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Several recurrent hotspots, such as c.2201C>T (p.Ser734Leu) and c.540_541delAT, were
      noted, but novel variants continue to expand the mutational spectrum.'
    explanation: Names the two recurrent alleles across the 35 reported patients.
inheritance:
- name: Autosomal recessive
  description: >-
    Autosomal recessive. Both the original families were consanguineous, but
    compound heterozygous cases have since been described.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33670882
    reference_title: 'Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene
      encoding the phosphatidic acid phosphatase LIPIN2.'
    explanation: States the inheritance pattern.
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'If both parents are known to be heterozygous for an LPIN2 pathogenic variant, each sib
      of an affected individual has at conception a 25% chance of being affected, a 50% chance of
      being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial
      pathogenic variants.'
    explanation: The recurrence risk for sibs, from the GeneReviews genetic counseling section.
diagnosis:
- name: LPIN2 molecular genetic testing
  presence: PRESENT
  description: >-
    Diagnosis is molecular, established by biallelic pathogenic LPIN2 variants in
    a proband with suggestive findings. This matters because the bone lesions are
    culture-negative and will otherwise be pursued as infection.
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The diagnosis of LPIN2-related Majeed syndrome is established in a proband with
      suggestive findings and biallelic pathogenic variants in LPIN2 identified by molecular genetic
      testing.'
    explanation: States the molecular diagnostic criterion.
- name: Differentiation from juvenile idiopathic arthritis
  presence: PRESENT
  description: >-
    The practical diagnostic problem. Overlap with juvenile idiopathic arthritis
    leads to delayed or incorrect diagnosis, and patients are treated as JIA with
    partial response before the genetic diagnosis is made. That partial response
    is itself misleading, because it looks like treatment failure rather than
    wrong diagnosis.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Its rarity and overlap with juvenile idiopathic arthritis (JIA) often lead to delayed
      or incorrect diagnoses.'
    explanation: States the differential that causes the delay.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Initially diagnosed and treated as JIA with NSAIDs, methotrexate, and adalimumab,
      she experienced only partial improvement.'
    explanation: An individual instance, and note that adalimumab is a TNF inhibitor - a second
      case of TNF blockade giving only partial benefit, consistent with the etanercept failure
      recorded under treatments.
- name: MRI of bone marrow oedema
  presence: PRESENT
  description: >-
    Whole-body or regional MRI shows multifocal bone marrow oedema at the
    osteomyelitic sites. In the reported case it was the MRI, together with the
    microcytic anaemia, that moved the working diagnosis from juvenile
    idiopathic arthritis toward a monogenic autoinflammatory disease.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'MRI revealed multifocal bone marrow edema consistent with CRMO, and laboratory results
      demonstrated mild microcytic anemia.'
    explanation: The imaging finding and the laboratory finding that together prompted genetic
      testing.
treatments:
- name: Interleukin-1 Blockade
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    The effective treatment, and the one that establishes the mechanism.
    Recombinant IL-1 receptor antagonist or an anti-IL-1 beta antibody produced
    dramatic clinical and laboratory improvement in disease refractory to
    corticosteroids, and long-lasting remission in a later case. GeneReviews
    names anti-IL-1 therapy the drug of choice (anakinra 1.5 mg/kg/day titrated
    as needed, or canakinumab 2 mg/kg every 4 or 8 weeks) and notes that it is
    not available everywhere. Patients on biologic or immunosuppressive
    treatment should avoid live-attenuated vaccines where possible.
  treatment_term:
    preferred_term: biological therapy
    term:
      id: NCIT:C15187
      label: Biological Therapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  target_mechanisms:
  - target: Excess IL-1 beta Production
    treatment_effect: INHIBITS
    description: Blocks either IL-1 beta itself or its receptor, neutralising the output of the
      unrestrained inflammasome.
    evidence:
    - reference: PMID:23087183
      reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or
        an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory
        improvement.'
      explanation: Two independent means of blocking the same axis both work, which is stronger
        evidence for the target than either alone.
  evidence:
  - reference: PMID:23087183
    reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'This is the first report detailing the treatment of Majeed syndrome with biological
      agents and demonstrates clinical improvement with IL-1blockade.'
    explanation: The first report of biological treatment in this disease.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Treatments included NSAIDs, corticosteroids, bisphosphonates, methotrexate, and, more
      recently, biologics such as anakinra and canakinumab, with IL-1 blockade providing the most
      consistent benefit.'
    explanation: A literature-wide comparison across treatment classes, which places IL-1 blockade
      above the conventional agents rather than resting the claim on the two-sibling report alone.
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'While one of the anti-IL-1 therapies is the drug of choice, these drugs may not be
      universally available.'
    explanation: GeneReviews management guidance ranks anti-IL-1 therapy first, and explains why
      the conventional agents below remain in use.
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'For affected individuals managed with biologic or immunosuppressive medications,
      live-attenuated vaccines should be avoided, when possible.'
    explanation: The precaution that accompanies this treatment. The schema has no slot for agents
      to avoid, so it is attached to the therapy that creates the need for it.
- name: Tumour Necrosis Factor Blockade
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Recorded mainly because it failed. TNF-alpha was elevated in serum and
    etanercept produced no improvement in two siblings whose disease then
    responded to IL-1 blockade, which is what makes the IL-1 response
    mechanistically informative. The record is not uniformly negative. A child
    treated as juvenile idiopathic arthritis with adalimumab alongside an NSAID
    and methotrexate had fewer flares but incomplete control, and a 2025
    review lists anti-TNF agents among the medications reported effective. The
    fair reading is little or partial benefit, well short of the IL-1 response.
  treatment_term:
    preferred_term: biological therapy
    term:
      id: NCIT:C15187
      label: Biological Therapy
    therapeutic_agent:
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  evidence:
  - reference: PMID:23087183
    reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'Both siblings had elevated proinflammatory cytokines in their serum, including tumour
      necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no
      improvement.'
    explanation: Direct evidence against TNF as a therapeutic target here, despite the cytokine
      being measurably raised.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'These therapies reduced the frequency of flares but did not completely control joint
      pain, raising doubts about the initial diagnosis and prompting further evaluation.'
    explanation: Partial benefit from a regimen that included adalimumab. The adalimumab was given
      with naproxen and methotrexate, so the benefit cannot be assigned to TNF blockade alone.
  - reference: PMID:39757386
    reference_title: Autoinflammatory Bone Diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Various medications, including NSAIDs, corticosteroids, bisphosphonates, anti-TNF agents,
      and anti-IL-1 medications, have been effective in the treatment of Majeed syndrome.'
    explanation: A review's summary that includes anti-TNF agents among effective treatments. It
      does not rank them, and it is recorded so the etanercept failure is not read as the whole
      literature.
- name: Blood Transfusion
  therapeutic_modality: OTHER
  description: >-
    Supportive treatment for the anaemia at its severe end.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Microcytic Anemia
    treatment_effect: MODULATES
    description: Replaces red cells without addressing the ineffective erythropoiesis producing the
      deficit.
    evidence:
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Congenital dyserythropoietic, microcytic anemia can range from mild to severe and
        sometimes requires blood transfusion.'
      explanation: States that transfusion is required at the severe end of the anaemia.
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Congenital dyserythropoietic, microcytic anemia can range from mild to severe and
      sometimes requires blood transfusion.'
    explanation: Establishes transfusion as part of management for severe anaemia.
- name: Corticosteroids
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Used for flares and the skin disease. They give partial improvement in
    bone and skin, and the index report of IL-1 blockade was in children whose
    bone disease and anaemia were refractory to them. This is the arm the
    IL-1 argument pivots against.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Sterile Multifocal Bone Inflammation
    treatment_effect: MODULATES
    description: Non-specific anti-inflammatory effect on the bone lesions, partial at best.
    evidence:
    - reference: PMID:23087183
      reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Corticosteroids provide only partial improvement in both the bone and skin
        disease.'
      explanation: States a partial effect on the bone disease, which is why the effect is
        modulation rather than inhibition.
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra
      1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks),
      nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate.'
    explanation: GeneReviews lists corticosteroids among the anti-inflammatory options.
  - reference: PMID:23087183
    reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'Their bone disease and anaemia were refractory to treatment with corticosteroids.'
    explanation: Corticosteroid failure in the two siblings who then responded to IL-1 blockade.
- name: Nonsteroidal Anti-inflammatory Drugs
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Common first-line symptomatic treatment, used in about a third of reported
    patients. They relieve pain for a time and do not control the disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nonsteroidal anti-inflammatory drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
  target_mechanisms:
  - target: Bone Pain
    treatment_effect: MODULATES
    description: Symptomatic relief of bone and joint pain without effect on the underlying
      inflammation.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Ibuprofen provided only partial relief, and there was no history of rash, oral ulcers,
        cough, vomiting, or diarrhea.'
      explanation: Partial relief of the joint and bone pain in one patient.
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra
      1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks),
      nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate.'
    explanation: GeneReviews lists NSAIDs among the anti-inflammatory options.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Conventional therapies such as NSAIDs, corticosteroids, and methotrexate may alleviate
      symptoms temporarily but fail to address the underlying IL-1-mediated inflammatory process
      (11).'
    explanation: Temporary symptomatic benefit from the conventional agents, stated in the
      discussion with a citation to earlier work.
- name: Methotrexate
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A conventional disease-modifying agent, often started when the disease is
    taken for juvenile idiopathic arthritis. Benefit is partial. It must be
    avoided in pregnancy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra
      1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks),
      nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate.'
    explanation: GeneReviews lists methotrexate among the anti-inflammatory options.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Initially diagnosed and treated as JIA with NSAIDs, methotrexate, and adalimumab, she
      experienced only partial improvement.'
    explanation: Partial improvement on a regimen including methotrexate.
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Methotrexate should be avoided in pregnancy, as it is known to be harmful to the
      developing fetus and can lead to pregnancy loss and/or birth defects.'
    explanation: The pregnancy restriction from GeneReviews management guidance.
- name: Bisphosphonates
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Pamidronate and alendronate have been used, in about a quarter of reported
    patients. The rationale is suppression of osteoclast activity in the bone
    lesions. The supporting statements come from chronic nonbacterial
    osteomyelitis generally, and no controlled data exist for this disease.
  treatment_term:
    preferred_term: bisphosphonate therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
    therapeutic_agent:
    - preferred_term: pamidronate
      term:
        id: CHEBI:7903
        label: pamidronate
    - preferred_term: alendronate
      term:
        id: CHEBI:2567
        label: alendronic acid
  target_mechanisms:
  - target: Inflammatory Macrophage Polarisation and Accelerated Osteoclastogenesis
    treatment_effect: INHIBITS
    description: Suppresses osteoclast activity, the bone-specific effector arm.
    evidence:
    - reference: PMID:39757386
      reference_title: Autoinflammatory Bone Diseases.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Bisphosphonates (e.g., pamidronate and zoledronic acid) are promising treatment options
        that facilitate the control of osteoclast activity via the suppression of proinflammatory
        cytokine expression.'
      explanation: Stated for chronic nonbacterial osteomyelitis as a group, not for Majeed syndrome
        specifically, hence indirect.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Treatments included NSAIDs, corticosteroids, bisphosphonates, methotrexate, and, more
      recently, biologics such as anakinra and canakinumab, with IL-1 blockade providing the most
      consistent benefit.'
    explanation: Bisphosphonates among the treatments used across the reported patients.
  - reference: PMID:23087183
    reference_title: Efficacy of anti-IL-1 treatment in Majeed syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: 'For refractory cases, bisphosphonates and TNF inhibitors have been tried, with reports of
      efficacy in some, but treatment failures are also reported.'
    explanation: Mixed results with bisphosphonates in refractory sterile osteomyelitis, from the
      paper's background on related disorders.
- name: Physical and Occupational Therapy
  therapeutic_modality: BEHAVIORAL
  description: >-
    Supports motor development and limits joint contractures.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Flexion Contracture
    treatment_effect: MODULATES
    description: Maintains range of motion in joints at risk of contracture.
    evidence:
    - reference: PMID:36877799
      reference_title: LPIN2-Related Majeed Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Physical therapy and/or occupational therapy can help motor delays and joint
        contractures.'
      explanation: GeneReviews management guidance for contractures.
  evidence:
  - reference: PMID:36877799
    reference_title: LPIN2-Related Majeed Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Physical therapy and/or occupational therapy can help motor delays and joint
      contractures.'
    explanation: Establishes rehabilitation therapy as part of management.
biochemical:
- name: C-reactive protein
  presence: INCREASED
  biomarker_term:
    preferred_term: C-reactive protein
    term:
      id: NCIT:C60651
      label: C-Reactive Protein
  notes: >-
    Raised in flares. In one genetically confirmed patient hs-CRP was 79.1 mg/L
    during an attack and 7.99 mg/L in remission, so it tracks activity but did
    not normalise. Across the 35-patient review, 23 of 26 with data had raised
    inflammatory markers.
  reference_ranges:
  - loinc_term:
      id: LOINC:30522-7
      label: C reactive protein [Mass/volume] in Serum or Plasma by High sensitivity method
    lower_bound: 0.0
    upper_bound: 3.0
    unit: mg/L
    population: the reporting hospital's reference interval, one pediatric case report
    notes: >-
      Single-laboratory interval quoted by the case report, not a population
      standard. LOINC is not covered by the repository's OAK term validation;
      the code was checked against the NLM clinical-tables LOINC service.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Inflammatory markers were significantly elevated, with hypersensitive CRP at 79.1 mg/L
        (reference 0-3 mg/L) and ESR at 51 mm/h (reference 0-20 mm/h).'
      explanation: Gives the patient's value and the laboratory reference interval.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Laboratory findings consistently demonstrated anemia, elevated ESR and CRP, and variable
      microcytic indices.'
    explanation: Raised CRP across the reviewed cases.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Elevated inflammatory markers (CRP/ESR/platelets) | 23/26 | 88.5'
    explanation: Table 2 frequency of raised inflammatory markers.
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'During remission, inflammatory markers decreased (hs-CRP 7.99 mg/L, ESR 23 mm/h).'
    explanation: The remission values, which show the marker tracking activity.
- name: Erythrocyte sedimentation rate
  presence: INCREASED
  biomarker_term:
    preferred_term: erythrocyte sedimentation rate
    term:
      id: NCIT:C74611
      label: Erythrocyte Sedimentation Rate Measurement
  notes: >-
    Raised in flares. 51 mm/h during an attack and 23 mm/h in remission in one
    patient.
  reference_ranges:
  - loinc_term:
      id: LOINC:30341-2
      label: Erythrocyte [Sedimentation Rate] in Blood
    lower_bound: 0.0
    upper_bound: 20.0
    unit: mm/h
    population: the reporting hospital's reference interval, one pediatric case report
    notes: >-
      Single-laboratory interval; the method was not stated, so the
      method-unspecified LOINC code is used. Checked against the NLM
      clinical-tables LOINC service.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Inflammatory markers were significantly elevated, with hypersensitive CRP at 79.1 mg/L
        (reference 0-3 mg/L) and ESR at 51 mm/h (reference 0-20 mm/h).'
      explanation: Gives the patient's value and the laboratory reference interval.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Laboratory findings consistently demonstrated anemia, elevated ESR and CRP, and variable
      microcytic indices.'
    explanation: Raised ESR across the reviewed cases.
- name: Interleukin-6
  presence: INCREASED
  biomarker_term:
    preferred_term: Interleukin-6
    term:
      id: NCIT:C20451
      label: Interleukin-6
  notes: >-
    IL-6 38.18 pg/mL during an attack.
  reference_ranges:
  - loinc_term:
      id: LOINC:26881-3
      label: Interleukin 6 [Mass/volume] in Serum or Plasma
    lower_bound: 0.0
    upper_bound: 20.9
    unit: pg/mL
    population: the reporting hospital's reference interval, one pediatric case report
    notes: >-
      Single-laboratory interval quoted by one case report; cytokine assays are
      not standardised across laboratories. Checked against the NLM
      clinical-tables LOINC service.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml
        (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64
        pg/ml (reference 1-5 pg/ml).'
      explanation: Gives the patient's value and the laboratory reference interval.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml
      (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64
      pg/ml (reference 1-5 pg/ml).'
    explanation: The measured elevation in one genetically confirmed patient during a flare.
- name: Tumor necrosis factor alpha
  presence: INCREASED
  biomarker_term:
    preferred_term: Tumor necrosis factor alpha
    term:
      id: NCIT:C20535
      label: Tumor Necrosis Factor
  notes: >-
    TNF-alpha 6.44 pg/mL during an attack. This is the measurement behind the therapeutic dissociation: TNF-alpha is raised, and TNF blockade still gives little benefit. Raised is not the same as driving.
  reference_ranges:
  - loinc_term:
      id: LOINC:3074-2
      label: Tumor necrosis factor.alpha [Mass/volume] in Serum or Plasma
    lower_bound: 0.0
    upper_bound: 5.5
    unit: pg/mL
    population: the reporting hospital's reference interval, one pediatric case report
    notes: >-
      Single-laboratory interval quoted by one case report; cytokine assays are
      not standardised across laboratories. Checked against the NLM
      clinical-tables LOINC service.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml
        (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64
        pg/ml (reference 1-5 pg/ml).'
      explanation: Gives the patient's value and the laboratory reference interval.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml
      (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64
      pg/ml (reference 1-5 pg/ml).'
    explanation: The measured elevation in one genetically confirmed patient during a flare.
- name: Interleukin-17A
  presence: INCREASED
  biomarker_term:
    preferred_term: Interleukin-17A
    term:
      id: NCIT:C20519
      label: Interleukin-17A
  notes: >-
    IL-17A 40.64 pg/mL during an attack. One patient; no source here tests whether IL-17 contributes.
  reference_ranges:
  - loinc_term:
      id: LOINC:82334-4
      label: Interleukin 17A [Mass/volume] in Serum or Plasma
    lower_bound: 1.0
    upper_bound: 5.0
    unit: pg/mL
    population: the reporting hospital's reference interval, one pediatric case report
    notes: >-
      Single-laboratory interval quoted by one case report; cytokine assays are
      not standardised across laboratories. Checked against the NLM
      clinical-tables LOINC service.
    evidence:
    - reference: PMID:41113563
      reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
        mutation and literature review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml
        (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64
        pg/ml (reference 1-5 pg/ml).'
      explanation: Gives the patient's value and the laboratory reference interval.
  evidence:
  - reference: PMID:41113563
    reference_title: Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous
      mutation and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Pro-inflammatory cytokines were markedly increased, including IL-6 at 38.18 pg/ml
      (reference 0-20.9 pg/ml), TNF-α at 6.44 pg/ml (reference 0-5.5 pg/ml), and IL-17A at 40.64
      pg/ml (reference 1-5 pg/ml).'
    explanation: The measured elevation in one genetically confirmed patient during a flare.
references:
- reference: PMID:15994876
  title: "Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)."
- reference: PMID:17330256
  title: "A splice site mutation confirms the role of LPIN2 in Majeed syndrome."
- reference: PMID:23087183
  title: "Efficacy of anti-IL-1 treatment in Majeed syndrome."
- reference: PMID:28031477
  title: "Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation."
- reference: PMID:33314777
  title: "Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis."
- reference: PMID:33670882
  title: "Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features."
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
- reference: PMID:36877799
  title: "LPIN2-Related Majeed Syndrome."
  tags:
  - GeneReviews
- reference: PMID:37865862
  title: "LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in LPIN2 and review of literature."
- reference: PMID:39757386
  title: "Autoinflammatory Bone Diseases."
- reference: PMID:41113563
  title: "Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous mutation and literature review."
disease_term:
  preferred_term: Majeed syndrome
  term:
    id: MONDO:0012316
    label: Majeed syndrome
notes: >-
  The therapeutic dissociation is the load-bearing evidence. These patients have
  measurably elevated TNF-alpha, and TNF blockade did nothing; IL-1 blockade by
  two independent means produced dramatic improvement in corticosteroid-refractory
  disease. That pattern is stronger evidence for IL-1 as the operative cytokine
  than any cytokine measurement, and it is why the failed TNF treatment is
  recorded as its own entry with REFUTE evidence rather than omitted. An elevated
  biomarker is not a demonstrated driver.

  Where the mechanism is incomplete, stated by its own authors. The review that
  establishes the inflammasome account says in the same sentence that these
  findings did not explain the bone phenotype. That admission is quoted directly
  on the edge from IL-1 beta to bone inflammation, and it is why the macrophage
  and osteoclast arm is modelled as a separate branch from the genetic lesion,
  graded PROVISIONAL. A reader should be able to see that the bone-specific step
  is the weak link, not infer it. The bone arm still reaches bone inflammation,
  so the two arms converge there even though they diverge at the top.

  Relationship to chronic recurrent multifocal osteomyelitis. Majeed syndrome is
  a monogenic, syndromic form of CRMO, which is curated separately here. The
  distinguishing features are the congenital dyserythropoietic anaemia and the
  neutrophilic dermatosis, neither of which belongs to non-syndromic CRMO, plus a
  defined recessive gene. The two entries should be read together; this one does
  not restate the CRMO mechanism.

  A phenotype mapping compromise. HPO has no term for congenital dyserythropoietic
  anaemia of the microcytic type. The only dyserythropoietic term available,
  HP:0005532, is macrocytic and therefore wrong here. The haematological phenotype
  is bound to HP:0001935 Microcytic anemia, with the dyserythropoietic character
  carried in the description and in the pathophysiology node rather than forced
  into an inaccurate term.

  Is this an inflammasomopathy? The apparent disagreement largely dissolves, and
  the way it dissolves is why the pathograph branches at the genetic lesion. One
  2023 report calls the disease "a rare non-inflammasome autoinflammatory
  disease", while the mechanistic work and the major review place it among the
  NLRP3 inflammasomopathies. The IUIS 2022 classification files it under
  "Non-Inflammasome Related Conditions" with the mechanism column reading
  "Undefined", which matches the 2023 wording; this entry records that
  placement under classifications without treating it as a finding against
  the lipin-2 and NLRP3 work. The reconciliation is in the review's own sentence:
  the macrophage and osteoclast arm controls growth-plate homeostasis "in an
  inflammasome-independent manner". So the systemic inflammation is inflammasome
  driven and the bone arm is not. Both arms therefore branch directly from LPIN2
  loss rather than one sitting downstream of the other, and the dissenting
  characterisation is retained as REFUTE evidence on the inflammasome node so a
  reader meeting that claim can find what it does and does not contradict.

  Scale of the evidence. Twenty-four genetically confirmed individuals from ten
  families in 2021, and 31 from 18 families by 2023. Both counts are recorded,
  because the growth is what explains the widening phenotype: as more families
  are found, milder cases appear and the original severe descriptions look
  ascertainment-biased. Frequency values in this entry should be read against
  numbers this small. Phenotype bands follow Table 2 of the 2025 literature
  review of 35 patients (osteomyelitis 94.3%, dyserythropoietic anaemia 85.3%,
  joint swelling 86.4%, recurrent fever 76.7%, failure to thrive 74.1%), each
  over the patients with data rather than all 35. No feature reaches 100%, so
  none is recorded as obligate.

  CURIEs the deep-research report got wrong. The report gave HGNC:14100 for
  LPIN2. That identifier does not resolve; the correct one is hgnc:14450, which
  is what this entry uses. Three of its eleven HPO CURIEs name a different
  concept from the one claimed: HP:0025573 is Mild myopia (offered for
  neutrophilic dermatosis), HP:0040211 is Abnormal skin morphology of the palm
  (offered for recurrent osteomyelitis), and HP:0001939 is Abnormality of
  metabolism/homeostasis (offered for dyserythropoietic anaemia). Four wrong
  identifiers in one report is the reason every identifier here was resolved
  against the local ontology database rather than copied.

  Neutrophilic dermatosis is bound to HP:0031234 Neutrophilic infiltration of
  the skin, which names the histological feature GeneReviews describes. In the
  local HPO build, search "l~Sweet" returns only HP:0030221 Sweet craving, and
  "l~dermatosis" returns HP:0032178 Flaky paint dermatosis and HP:0033167
  Neutrophilic urticarial dermatosis. The last is an urticarial eruption, which
  is not the plaque, pustule and nodule picture described here.

  Known extension points: gastrointestinal features including recurrent
  abdominal pain and diarrhoea; and long-term outcome, described as poor before
  IL-1 blockade but without quotable quantitative follow-up in these sources.
  The dietary and microbiome work on sterile osteomyelitis is in the Pstpip2
  cmo mouse, a different gene and a model of non-syndromic chronic
  osteomyelitis. It may bear on the bone arm by analogy, and it is not evidence
  about LPIN2 disease.

  Provenance. Curated from PubMed with a five-iteration OpenScientist
  deep-research job as a cross-check. Seven of the eleven cached references are
  full text rather than abstracts, and content_type was checked before writing.
📚

References & Deep Research

References

11
PMID:15994876
Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).
No top-level findings curated for this source.
PMID:17330256
A splice site mutation confirms the role of LPIN2 in Majeed syndrome.
No top-level findings curated for this source.
PMID:23087183
Efficacy of anti-IL-1 treatment in Majeed syndrome.
No top-level findings curated for this source.
PMID:28031477
Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
No top-level findings curated for this source.
PMID:33314777
Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis.
No top-level findings curated for this source.
PMID:33670882
Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.
No top-level findings curated for this source.
PMID:35748970
Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.
No top-level findings curated for this source.
PMID:36877799
LPIN2-Related Majeed Syndrome.
No top-level findings curated for this source.
PMID:37865862
LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in LPIN2 and review of literature.
No top-level findings curated for this source.
PMID:39757386
Autoinflammatory Bone Diseases.
No top-level findings curated for this source.
PMID:41113563
Clinical and genetic analysis of Majeed syndrome caused by LPIN2 complex heterozygous mutation and literature review.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

The therapeutic dissociation is the load-bearing evidence. These patients have measurably elevated TNF-alpha, and TNF blockade did nothing; IL-1 blockade by two independent means produced dramatic improvement in corticosteroid-refractory disease. That pattern is stronger evidence for IL-1 as the operative cytokine than any cytokine measurement, and it is why the failed TNF treatment is recorded as its own entry with REFUTE evidence rather than omitted. An elevated biomarker is not a demonstrated driver. Where the mechanism is incomplete, stated by its own authors. The review that establishes the inflammasome account says in the same sentence that these findings did not explain the bone phenotype. That admission is quoted directly on the edge from IL-1 beta to bone inflammation, and it is why the macrophage and osteoclast arm is modelled as a separate branch from the genetic lesion, graded PROVISIONAL. A reader should be able to see that the bone-specific step is the weak link, not infer it. The bone arm still reaches bone inflammation, so the two arms converge there even though they diverge at the top. Relationship to chronic recurrent multifocal osteomyelitis. Majeed syndrome is a monogenic, syndromic form of CRMO, which is curated separately here. The distinguishing features are the congenital dyserythropoietic anaemia and the neutrophilic dermatosis, neither of which belongs to non-syndromic CRMO, plus a defined recessive gene. The two entries should be read together; this one does not restate the CRMO mechanism. A phenotype mapping compromise. HPO has no term for congenital dyserythropoietic anaemia of the microcytic type. The only dyserythropoietic term available, HP:0005532, is macrocytic and therefore wrong here. The haematological phenotype is bound to HP:0001935 Microcytic anemia, with the dyserythropoietic character carried in the description and in the pathophysiology node rather than forced into an inaccurate term. Is this an inflammasomopathy? The apparent disagreement largely dissolves, and the way it dissolves is why the pathograph branches at the genetic lesion. One 2023 report calls the disease "a rare non-inflammasome autoinflammatory disease", while the mechanistic work and the major review place it among the NLRP3 inflammasomopathies. The IUIS 2022 classification files it under "Non-Inflammasome Related Conditions" with the mechanism column reading "Undefined", which matches the 2023 wording; this entry records that placement under classifications without treating it as a finding against the lipin-2 and NLRP3 work. The reconciliation is in the review's own sentence: the macrophage and osteoclast arm controls growth-plate homeostasis "in an inflammasome-independent manner". So the systemic inflammation is inflammasome driven and the bone arm is not. Both arms therefore branch directly from LPIN2 loss rather than one sitting downstream of the other, and the dissenting characterisation is retained as REFUTE evidence on the inflammasome node so a reader meeting that claim can find what it does and does not contradict. Scale of the evidence. Twenty-four genetically confirmed individuals from ten families in 2021, and 31 from 18 families by 2023. Both counts are recorded, because the growth is what explains the widening phenotype: as more families are found, milder cases appear and the original severe descriptions look ascertainment-biased. Frequency values in this entry should be read against numbers this small. Phenotype bands follow Table 2 of the 2025 literature review of 35 patients (osteomyelitis 94.3%, dyserythropoietic anaemia 85.3%, joint swelling 86.4%, recurrent fever 76.7%, failure to thrive 74.1%), each over the patients with data rather than all 35. No feature reaches 100%, so none is recorded as obligate. CURIEs the deep-research report got wrong. The report gave HGNC:14100 for LPIN2. That identifier does not resolve; the correct one is hgnc:14450, which is what this entry uses. Three of its eleven HPO CURIEs name a different concept from the one claimed: HP:0025573 is Mild myopia (offered for neutrophilic dermatosis), HP:0040211 is Abnormal skin morphology of the palm (offered for recurrent osteomyelitis), and HP:0001939 is Abnormality of metabolism/homeostasis (offered for dyserythropoietic anaemia). Four wrong identifiers in one report is the reason every identifier here was resolved against the local ontology database rather than copied. Neutrophilic dermatosis is bound to HP:0031234 Neutrophilic infiltration of the skin, which names the histological feature GeneReviews describes. In the local HPO build, search "l~Sweet" returns only HP:0030221 Sweet craving, and "l~dermatosis" returns HP:0032178 Flaky paint dermatosis and HP:0033167 Neutrophilic urticarial dermatosis. The last is an urticarial eruption, which is not the plaque, pustule and nodule picture described here. Known extension points: gastrointestinal features including recurrent abdominal pain and diarrhoea; and long-term outcome, described as poor before IL-1 blockade but without quotable quantitative follow-up in these sources. The dietary and microbiome work on sterile osteomyelitis is in the Pstpip2 cmo mouse, a different gene and a model of non-syndromic chronic osteomyelitis. It may bear on the bone arm by analogy, and it is not evidence about LPIN2 disease. Provenance. Curated from PubMed with a five-iteration OpenScientist deep-research job as a cross-check. Seven of the eleven cached references are full text rather than abstracts, and content_type was checked before writing.

Review round: frequencies, dermatosis, joint swelling, treatments, biochemical · 2026-09-24T19:41:10Z · View source

Response to the ai4c-reviewer CHANGES_REQUESTED review of 2026-09-09. The branch was also rebased onto main; the only conflict was cache/hgnc/terms.csv, where main's P2RX3 row and this branch's P2RX7 row were both kept. Findings addressed: 1. PMID:36877799 tagged GeneReviews in references. just check-genereviews reports TAGGED=1. 2. Osteomyelitis and Microcytic Anemia moved from OBLIGATE to VERY_FREQUENT, citing Table 2 of PMID:41113563 (CRMO 33/35, CDA 29/34) and the 91% figure in PMID:33670882. Recurrent Fever and Failure to Thrive now cite their Table 2 rows; Failure to Thrive gained FREQUENT. 3. Neutrophilic Dermatosis added, bound to HP:0031234, OCCASIONAL (2 of 24 in PMID:33670882). It is wired from the LPIN2 lesion with an INDIRECT_UNKNOWN_INTERMEDIATES edge quoting PMID:23087183. The notes sentence saying no HPO term existed was removed, and the searches actually run are recorded instead. Description changed from "in many patients" to "in a minority of patients". 4. Joint Swelling added (HP:0001386, VERY_FREQUENT, 19/22), wired from Sterile Multifocal Bone Inflammation. 5. GeneReviews genetic counseling (25/50/25 sib risk) added to inheritance; drug-of-choice, dosing and the live-attenuated vaccine precaution added to IL-1 blockade; methotrexate pregnancy restriction and physical/occupational therapy added. 6. Treatments added: Corticosteroids (with the refractory report as REFUTE), NSAIDs, Methotrexate, Bisphosphonates (pamidronate, alendronate; the osteoclast target is graded INDIRECT because the source statement is about CNO generally), Physical and Occupational Therapy. TNF blockade gained adalimumab, the partial-response case, and the 2025 review's statement that anti-TNF agents have been effective, and its description now reads as little or partial benefit. 7. biochemical block added: CRP, ESR, IL-6, TNF-alpha, IL-17A, each with the case report's laboratory reference interval. LOINC codes were checked against the NLM clinical-tables service because LOINC has no OAK validation here. Suggestions taken: hotspot alleles in genetic; MRI bone marrow oedema in diagnosis; marrow cytology on the Dyserythropoiesis node; structured prevalence as CASES_IN_LITERATURE; classifications (Harrison's chapters and IUIS autoinflammatory); the three wrong HPO CURIEs in the deep-research report named in notes; the Pstpip2 cmo mouse caveat rewritten. Suggestion not taken: the deep-research _artifacts directory and citations sidecar. They are not present on the machine that ran this round, so there is nothing to commit. The IUIS classification carries no evidence item. The LPIN2 row (section 3, Non-Inflammasome Related Conditions, Table 7) exists in the committed PDF extraction of PMID:35748970, but linkml-reference-validator 0.3.0rc1 re-extracts that cache from PMC XML without its tables during just validate, and the quoted row then fails. The placement is recorded in the classification notes and the entry notes. Validation: just validate passed (96 snippets, 0 issues); just count-verified-snippets 96/96 against the committed caches; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-coarse-phenotypes, check-reference-titles and check-delivery-system all OK; list-disconnected-phenotypes reports 9 of 9 phenotypes causally connected. just validate rewrote the eleven cited reference caches as a side effect; those rewrites were discarded and not committed.

Create: Majeed Syndrome MONDO:0012316 · 2026-09-08T19:21:19Z · View source

Created from PubMed literature with a five-iteration OpenScientist deep-research job as a cross-check, launched before writing so it ran in parallel. The load-bearing evidence in this entry is a therapeutic dissociation rather than a biochemical measurement. These patients have measurably elevated TNF-alpha, and TNF blockade with etanercept produced no improvement, while IL-1 blockade by two independent agents produced dramatic improvement in corticosteroid-refractory disease. A second, later case treated as juvenile idiopathic arthritis with adalimumab also improved only partially. The failed TNF treatment is therefore recorded as its own treatment entry with REFUTE evidence rather than omitted, because an elevated biomarker is not a demonstrated driver and the negative result is what makes the IL-1 response mechanistically informative. An apparent contradiction in the literature was resolved by reading a full sentence rather than a truncated one. A 2023 report classifies the disease as non-inflammasome, while the mechanistic work and the major review place it among the NLRP3 inflammasomopathies. The reconciliation is inside the review's own sentence, which the first draft had quoted only up to the word "critica": the macrophage and osteoclast arm controls growth-plate homeostasis in an inflammasome-independent manner. So systemic inflammation is inflammasome driven and the bone arm is not. That changed the graph: both arms now branch directly from the LPIN2 lesion and converge on bone inflammation, rather than the bone arm sitting downstream of IL-1 beta. The dissenting characterisation is kept as REFUTE evidence on the inflammasome node so a reader meeting it can find what it does and does not contradict. The final check battery, run after the report was folded in, caught four defects that reading had not: three snippets cut mid-word, a stranded second root, and three orphan phenotypes. One of those truncations was the sentence that resolved the inflammasome question, so extending it changed the entry's structure rather than merely tidying a quote. This is the second consecutive entry where running the battery last was decisive. A CURIE error in the deep-research report was caught by resolving identifiers rather than copying them. The report gave HGNC:14100 for LPIN2; that identifier does not resolve and the correct one is hgnc:14450, which the entry already used. Recorded in notes because it is the specific failure mode these reports are prone to. Other report contributions, each verified against the cited paper before use: an updated case count of 31 individuals from 18 families in 2023 against 24 from 10 families in 2021, with both retained because the growth explains the widening phenotype; and the overlap with juvenile idiopathic arthritis as a cause of diagnostic delay. A phenotype mapping compromise is recorded in notes. HPO has no term for congenital dyserythropoietic anaemia of the microcytic type; its only dyserythropoietic term is macrocytic and therefore wrong here. The phenotype binds HP:0001935 Microcytic anemia with the dyserythropoietic character carried in the description and in a dedicated pathophysiology node. Process. Content_type was checked on all ten caches before writing; six were full text. Validation: 46/46 snippets verified, term validation passes, qualifier terms pass, weighted compliance 100.0 percent, no truncations, no value/prose contradictions, one root, no orphan phenotypes, no dangling targets.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 26 citations 2026-09-08T15:09:00.138005

1. Disease Information

Majeed syndrome is a monogenic, multi-system autoinflammatory disorder of the innate immune system. As summarized in a comprehensive 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" (PMID: 33670882).

Key identifiers | Resource | Identifier | |---|---| | MONDO | MONDO:0012316 | | OMIM (disease) | #609628 | | OMIM (gene) | *605519 (LPIN2) | | Orphanet | ORPHA:77297 | | MeSH | Majeed syndrome / autoinflammatory syndromes | | HGNC (gene) | HGNC:14100 (LPIN2) |

Synonyms / alternative names: Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (CRMO with CDA); CRMO–CDA syndrome; LPIN2-related autoinflammatory syndrome.

Data source type: The disease-level knowledge in this report is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO) supplemented by individual patient case reports and small case series in the primary literature. There is no large EHR-derived cohort; because only ~31–35 patients have ever been reported, all epidemiologic and phenotypic estimates rest on aggregated case reports.

2. Etiology

Disease causal factors — genetic. Majeed syndrome is a monogenic disease caused by biallelic (homozygous or compound-heterozygous) loss-of-function mutations in LPIN2. Homozygosity mapping in six affected individuals from two unrelated consanguineous Arab families mapped the locus to a 5.5 cM (1.8 Mb) interval on chromosome 18p; "Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families" (PMID: 15994876). The gene "was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p." Inheritance is autosomal recessive.

Genetic risk factors. The single causal locus is LPIN2. Consanguinity is the dominant risk factor because the disease is recessive: in a multicenter Arab pediatric autoinflammatory cohort, parental consanguinity was 74.6% (PMID: 31741047). No independent susceptibility loci or modifier genes have been established.

Environmental / lifestyle risk factors. No environmental exposure is required to cause the disease. However, a well-defined gene–environment interaction exists: in murine and human macrophages, "Depletion of lipin-2 promotes the increased expression of the proinflammatory genes Il6, Ccl2, and Tnfα, which depends on the overstimulation of the JNK1/c-Jun pathway by saturated fatty acids" (PMID: 22334674). Thus dietary saturated fatty acids amplify inflammation specifically in a lipin-2-deficient background. In the related cmo mouse model of CRMO, "dietary manipulation can alter the microbiome and protect these mice from the development of sterile osteomyelitis in vivo" (PMID: 28361334), suggesting diet/microbiome as environmental modifiers of disease expression.

Protective factors. No human genetic protective variants are documented. The murine data above indicate that a low-saturated-fat diet or microbiome modulation could be environmentally protective, but this has not been validated in patients.

3. Phenotypes

Onset is typically in infancy, usually before age three: a review of 35 reported patients found "most presented before age three with CRMO and recurrent fever, but the severity of CDA varied widely" (PMID: 41113563) — documenting both the neonatal/early-childhood onset and the marked variable expressivity of the anemia.

Phenotype Type HPO term Onset Severity / course Frequency
Chronic recurrent multifocal osteomyelitis (sterile) Clinical sign / imaging HP:0040211 (Recurrent multifocal osteomyelitis) Infancy (<3 y) Recurrent, relapsing; episodic flares Near-universal (defining)
Bone pain Symptom HP:0002653 Infancy/childhood Episodic, painful Very frequent
Congenital dyserythropoietic anemia (microcytic) Laboratory abnormality HP:0001939 / HP:0001935 Congenital/neonatal Variable — mild to transfusion-dependent Frequent; severity variable
Neutrophilic dermatosis (Sweet-like) Physical manifestation HP:0025573 (Neutrophilic dermatosis) Infancy/childhood Variable; "with or without" Subset of patients
Recurrent fever Symptom HP:0001954 Infancy Episodic Frequent
Growth failure / failure to thrive Clinical sign HP:0001508 Infancy/childhood Progressive if untreated Frequent
Joint swelling/contractures, arthralgia Clinical sign HP:0001386 / HP:0002829 Childhood Episodic Variable
Neutropenia (in some) Laboratory abnormality HP:0001875 Infancy Variable Occasional (PMID 31727123)
Psychomotor/developmental delay (CNS involvement) Behavioral/neurological HP:0001263 Childhood Variable Occasional (PMID 34365623)

Additional features reported in individual cases include muscle involvement adjacent to osteomyelitis, delayed language/motor development, and (rarely) severe neutropenia (PMID: 34365623, PMID: 31727123).

Quality of life impact. No formal EQ-5D/SF-36/PROMIS studies exist for this ultra-rare disease. Qualitatively, untreated disease causes chronic bone pain, recurrent fevers, transfusion dependence in severe anemia, growth failure, and functional impairment from bone lesions and joint contractures — with substantial improvement reported after IL-1 blockade.

4. Genetic / Molecular Information

Causal gene. LPIN2 (HGNC:14100; OMIM *605519; chromosome 18p11.31), encoding lipin-2, a member of the lipin/Pah family of Mg²⁺-dependent phosphatidic acid phosphatases (PAP1) that also act as transcriptional co-regulators of lipid metabolism.

Pathogenic variants. Both homozygous (in consanguineous families) and compound-heterozygous variants are reported, spanning missense, frameshift, nonsense, and splice-site classes: - Original homozygous mutations in Arab families (PMID: 15994876). - Compound heterozygous c.1966A>G and c.2534delG in a Han Chinese boy (PMID: 34365623). - Splice-donor c.2327+1G>C (paternal) with frameshift c.1691_1694delGAGA (p.Arg564Lysfs*3, maternal), associated with a mild phenotype plus severe neutropenia (PMID: 31727123). - Homozygous p.S734L reported in siblings from Qatar (PMID: 27860302). - Novel variants from Indian families (PMID: 37865862, PMID: 33993107).

Variant classification & functional consequence. Reported disease variants are classified pathogenic/likely pathogenic (ACMG/AMP) and are loss-of-function. Structurally, disease mutations cluster within the conserved N-Lip and C-Lip regions: "Disease-mutations cluster within the conserved N-Lip and C-Lip regions that are separated by 500-residues in humans" and act by two routes — "Disease-mutations disrupt catalysis or destabilize the protein fold" (PMID: 32161260).

Allele frequency / origin. Pathogenic LPIN2 alleles are extremely rare in population databases (gnomAD); several are private founder-like alleles in consanguineous families. Origin is germline; no somatic/mosaic contribution is described.

Modifier genes / epigenetics / chromosomal abnormalities. No validated modifier genes, disease-specific epigenetic marks, or chromosomal abnormalities are reported. Lipin-2 is itself IFN/STAT-1-regulated (PMID: 37929625), an expression-level regulatory context rather than a heritable modifier.

5. Environmental Information

  • Environmental factors / toxins: None required for disease causation. Dietary saturated fatty acids act as a proinflammatory amplifier in lipin-2 deficiency via JNK1/c-Jun (PMID: 22334674).
  • Lifestyle factors: Diet (saturated fat load) is the only mechanistically supported lifestyle modifier; microbiome composition modulates sterile osteomyelitis in the murine model (PMID: 28361334).
  • Infectious agents: None. The osteomyelitis is sterile/culture-negative — a defining feature distinguishing it from bacterial osteomyelitis. Lipin-2 also modulates antiviral/TLR3 responses (PMID: 37929625), but no pathogen triggers the disease.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic LOF mutation in LPIN2 results in loss of functional lipin-2 protein (via disrupted HAD-like catalysis or destabilized protein fold) (PMID: 15994876, PMID: 32161260).
  2. Loss of lipin-2 de-represses the purinergic P2X7 receptor, enhancing its activation/sensitization and K⁺ efflux, and removes a brake on MAPK-driven pro-IL-1β synthesis during priming: "Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7" (PMID: 28031477).
  3. This over-activates the NLRP3 inflammasome in macrophages/monocytes — "lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3" (PMID: 28031477). An additional branch: lipin-2 loss increases ROS generation and mtDNA release (partly via TLR3 signaling) that further activate NLRP3 — "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" (PMID: 37929625).
  4. NLRP3 activation → caspase-1 activation → excess mature IL-1β secretion (elevated caspase-1 activity and IL-1β in patient monocytes) (PMID: 28031477, PMID: 33314777).
  5. Branch A — Bone: Excess IL-1β plus a lipin-2-deficient, pro-osteoclastogenic macrophage program and enhanced NF-κB signaling accelerate osteoclastogenesis, leading to sterile CRMO. Patient M2-like macrophages "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" (PMID: 33314777); independently, "Deficiency of Lipin2 Results in Enhanced NF-κB Signaling and Osteoclast Formation in RAW-D Murine Macrophages" (PMID: 33809261).
  6. Branch B — Skin: IL-1-driven neutrophil recruitment produces neutrophilic dermatosis (Sweet-like) (inferred from IL-1 biology; clinically responsive to IL-1 blockade).
  7. Branch C — Systemic: IL-1β drives recurrent fever, acute-phase response, and growth failure.
  8. Branch D — Marrow/erythroid (partly inferred): Inflammation contributes to congenital dyserythropoietic anemia; the precise molecular link from lipin-2 loss to dyserythropoiesis is unresolved, but anemia and marrow dyserythropoiesis reverse with IL-1 blockade, implicating inflammation (PMID: 39255247).
  9. Environmental amplifier: Dietary saturated fatty acids augment steps 3–7 via JNK1/c-Jun overstimulation (PMID: 22334674).
 LPIN2 LOF  ──►  loss of lipin-2  ──►  P2X7 sensitization + ↓MAPK restraint
                      + ROS/mtDNA release (TLR3 branch)
                            │
                            ▼
                   NLRP3 inflammasome ↑
                            │
                     caspase-1 → IL-1β ↑↑
 ┌──────────────┬───────────┼──────────────┬───────────────┐
 ▼              ▼            ▼              ▼               ▼
pro-osteoclast    neutrophil     fever /       dyserythropoietic  (SFA diet
macrophages +     recruitment    acute-phase    anemia            amplifies
NF-κB → osteoclast   → skin       + growth       (inflammation-    via JNK1/
↑ → STERILE CRMO   NEUTROPHILIC   failure        driven, partly    c-Jun)
            DERMATOSIS                    inferred)

Molecular pathways: P2X7–K⁺ efflux–NLRP3 inflammasome; MAPK/JNK1–c-Jun; NF-κB; IL-1β signaling; type-I IFN/STAT-1 (regulates lipin-2). Cellular processes: innate immune activation, sterile inflammation, osteoclast differentiation, dyserythropoiesis. Protein dysfunction: loss of PAP1 (phosphatidic-acid-phosphatase) catalysis / protein destabilization. Metabolic: lipin-2 converts phosphatidic acid → diacylglycerol; its loss alters glycerolipid/TAG homeostasis and reduces TAG buffering of saturated-fatty-acid overload — "the absence of lipin-2 reduces the cellular content of triacylglycerol in saturated fatty acid-overloaded macrophages" (PMID: 22334674). Immune involvement: chronic IL-1β-driven autoinflammation (not autoimmunity/immunodeficiency).

Suggested ontology terms: GO:0006954 (inflammatory response); GO:0032611 (IL-1β production); GO:0072559 (NLRP3 inflammasome complex assembly); GO:0002548 (monocyte chemotaxis); GO:0045453 (bone resorption); GO:0016311 (dephosphorylation). Cell types (CL): CL:0000235 (macrophage), CL:0000576 (monocyte), CL:0000092 (osteoclast), CL:0000775 (neutrophil), CL:0000764 (erythroid lineage cell). Chemical entities (CHEBI): CHEBI:16337 (phosphatidic acid), CHEBI:18035 (diacylglycerol), CHEBI:26607 (saturated fatty acid), CHEBI:29108 (Mg²⁺).

7. Anatomical Structures Affected

  • Primary organ / system — Skeleton (musculoskeletal system): metaphyses of long bones (tibia, femur, fibula), and other multifocal sites; sacroiliac joints; adjacent soft tissue/muscle (PMID: 34365623, PMID: 27860302). UBERON:0002481 (bone tissue), UBERON:0001474 (bone element), UBERON:0002217 (long bone), UBERON:0000979 (tibia).
  • Bone marrow / hematopoietic system: dyserythropoiesis; UBERON:0002371 (bone marrow).
  • Skin (integumentary system): neutrophilic dermatosis; UBERON:0002097 (skin of body).
  • Secondary/occasional — CNS: developmental/psychomotor delay in some patients (PMID: 34365623); UBERON:0001017 (central nervous system).
  • Tissue types affected: bone/connective tissue, hematopoietic tissue, skin epithelium/dermis, skeletal muscle (peri-osteomyelitic).
  • Cell populations (CL): macrophages, monocytes, osteoclasts, neutrophils, erythroid precursors (see §6).
  • Subcellular compartments (GO CC): GO:0072559 (NLRP3 inflammasome complex); GO:0005741 (mitochondrial outer membrane — ROS/mtDNA source); GO:0005886 (plasma membrane — P2X7); lipin-2 localizes to ER membrane/cytosol and nucleus.
  • Lateralization: Bone lesions are typically multifocal and often bilateral/symmetric (characteristic of CRMO), though individual lesions may be asymmetric.

8. Temporal Development

  • Onset: Congenital anemia present at/near birth; osteomyelitis and fevers usually manifest in infancy, before age three (PMID: 41113563). Onset pattern is chronic with recurrent acute flares.
  • Progression / course: Relapsing–remitting/episodic bone disease with painful flares; chronic lifelong without effective therapy. If untreated, cumulative complications include growth failure, bone deformity/contractures, and transfusion dependence.
  • Disease duration: Chronic, lifelong.
  • Remission patterns: Predominantly treatment-induced remission on IL-1 blockade, which can be dramatic and sustained (PMID: 31598604, PMID: 39255247). Spontaneous durable remission is not characteristic.
  • Critical periods / window of opportunity: Early molecular diagnosis and initiation of IL-1 blockade in infancy/early childhood is the key intervention window to prevent cumulative bone damage and growth failure.

9. Inheritance and Population

  • Inheritance: Autosomal recessive (biallelic LPIN2). Requires two pathogenic alleles.
  • Prevalence / incidence: No reliable population prevalence; the disease is ultra-rare. "only 31 individuals from 18 families have been reported with this rare condition" as of 2023 (PMID: 37865862); a 2025 review tallied ~35 patients (PMID: 41113563).
  • Penetrance / expressivity: Penetrance of the biallelic genotype appears complete for the autoinflammatory phenotype, but expressivity is variable, especially for CDA severity (mild to transfusion-dependent) and presence/absence of the neutrophilic dermatosis (PMID: 41113563).
  • Genetic anticipation: Not applicable (not a repeat-expansion disorder).
  • Founder effects / consanguinity: Strong association with consanguinity; several private/founder-like alleles in Middle Eastern and Indian families. In an Arab pediatric SAID cohort, "Consanguinity rate among parents was 74.6%" (PMID: 31741047).
  • Carrier frequency: Not established; expected very low, elevated within consanguineous kindreds.
  • Population demographics: Reported predominantly in populations with high consanguinity (Arab/Middle Eastern, South Asian/Indian), with additional cases across ancestries including East Asian (PMID: 34365623) and the first patient of central-European ancestry (PMID: 39255247). No strong sex bias is established given small numbers.

10. Diagnostics

Laboratory tests / biomarkers. Elevated acute-phase reactants (ESR, CRP); microcytic anemia with bone marrow showing dyserythropoiesis; occasional neutropenia (PMID: 31727123). Elevated caspase-1 activity and IL-1β in patient monocytes are research biomarkers (PMID: 33314777). Bone cultures are negative (sterile osteomyelitis).

Imaging. MRI is the favored modality: multifocal osteomyelitic lesions appear as high-signal (STIR/SPAIR) marrow lesions with surrounding soft-tissue/muscle edema; common sites include tibia, femur, fibula, talar bones and sacroiliac joints (PMID: 34365623, PMID: 27860302).

Biopsy/pathology. Bone lesions show sterile chronic inflammation without organisms; marrow aspirate shows dyserythropoietic changes.

Genetic testing (definitive). Molecular confirmation is by identifying biallelic pathogenic LPIN2 variants, most efficiently via an autoinflammatory NGS gene panel that includes LPIN2, or WES/WGS. Because patients present across specialties, "Patients with MJS may present initially to different specialists, and thus it is important to create awareness in the medical community" (PMID: 33993107). Single-gene LPIN2 sequencing is appropriate when the phenotype is classic.

Clinical criteria / differential diagnosis. No formal consensus diagnostic criteria; diagnosis rests on the clinical triad plus biallelic LPIN2 variants. Key differentials: - Non-syndromic CRMO/CNO — no CDA, no biallelic LPIN2. - DIRA (IL1RN deficiency) — CRMO-like with pustulosis; different gene. - Juvenile idiopathic arthritis (JIA) — frequent misdiagnosis (see below). - RETREG1/FAM134B-related disease (HSAN2B) — can mimic Majeed with recurrent osteomyelitis and microcytic anemia, but LPIN2 sequencing is negative (PMID: 35332675).

Diagnostic delay. Majeed syndrome is frequently misdiagnosed: "Its rarity and overlap with juvenile idiopathic arthritis (JIA) often lead to delayed or incorrect diagnoses" (PMID: 41113563). In an Arab SAID cohort the initial diagnosis was inaccurate in 49.3% with a median time-to-diagnosis of 2.5 years (PMID: 31741047).

Screening. Cascade genetic testing and carrier testing within affected families; prenatal/preimplantation diagnosis is feasible once the family's biallelic variants are known.

11. Outcome / Prognosis

  • Survival / mortality: No formal survival statistics; the disease is generally not directly life-limiting when the inflammation is controlled, but untreated disease causes substantial morbidity. Severe transfusion-dependent anemia and complications contribute to burden.
  • Morbidity / disability: Chronic bone pain, recurrent fevers, growth failure, bone deformity/contractures, and, in severe CDA, transfusion dependence and iron overload. CNS involvement in some cases can cause developmental delay (PMID: 34365623).
  • Disease course / recovery: Chronic lifelong disease with excellent response to IL-1 blockade; anakinra produced "resolution of MRI findings, microcytic anaemia and dyserythropoiesis at bone marrow aspirate" (PMID: 39255247), indicating substantial recovery potential with targeted therapy. Response to TNF inhibitors and corticosteroids is only partial.
  • Prognostic factors: Time to correct molecular diagnosis and initiation of IL-1 blockade; CDA severity; extent of skeletal involvement. IL-1-pathway responsiveness is the key favorable prognostic determinant.

12. Treatment

First-line / most effective — IL-1 blockade. Across the reported experience, "IL-1 blockade remains the most effective treatment" (PMID: 41113563). - Anakinra (recombinant IL-1 receptor antagonist; NCIT:C1839): "Treatment with anakinra was started with a prompt resolution of the clinical picture" (PMID: 39255247); "We observed a significant clinical response to biologic anti-interleukin-1 (IL-1) therapy in our patients" (PMID: 31598604). - Canakinumab (anti-IL-1β monoclonal antibody; NCIT:C71355): long-lasting remission reported (PMID: 33314777, PMID: 27860302).

Partially effective / adjunctive. | Therapy | Class (NCIT) | Efficacy in Majeed | |---|---|---| | Anakinra / canakinumab | IL-1 blockers | Most effective; dramatic/sustained remission | | Corticosteroids | Glucocorticoid (NCIT:C381) | Partial | | NSAIDs | Anti-inflammatory | Partial/symptomatic | | Methotrexate | Antimetabolite (NCIT:C642) | Partial/ineffective | | TNF inhibitors (adalimumab, etanercept, infliximab) | TNF blockers | Partial, variable | | Bisphosphonates | Bone resorption inhibitor | Adjunctive for bone disease (PMID: 31377798) | | RBC transfusion / supportive | Supportive care | For severe CDA |

Pharmacogenomics / advanced therapeutics: None specific. No approved gene, cell, or RNA therapy exists; the strong mechanistic rationale (single-gene recessive LOF) makes LPIN2 an in-principle candidate for future gene-replacement, but no clinical program is reported. Personalized approach: genotype-driven — confirming biallelic LPIN2 LOF directs treatment toward IL-1 blockade.

13. Prevention

  • Primary prevention: Not preventable in a genetically affected individual. Genetic counseling for consanguineous couples and families with an affected child is the principal preventive tool; recurrence risk is 25% per pregnancy for carrier couples.
  • Secondary prevention: Early molecular diagnosis (autoinflammatory panels including LPIN2) to shorten the ~2.5-year diagnostic delay and enable prompt IL-1 blockade (PMID: 31741047, PMID: 33993107).
  • Tertiary prevention: Sustained IL-1 blockade to prevent cumulative bone damage, growth failure, and transfusion-related complications; bisphosphonates as bone-protective adjuncts.
  • Genetic screening: Cascade carrier testing, prenatal diagnosis, and preimplantation genetic testing once familial variants are identified.
  • Behavioral/environmental: Mechanistically, limiting dietary saturated-fat load could reduce inflammatory amplification (PMID: 22334674), but this is not clinically validated.
  • Immunization / public health / prophylaxis: No vaccine or infectious-prophylaxis relevance (disease is sterile/genetic).

14. Other Species / Natural Disease

  • Taxonomy: Human disease (NCBI:txid9606). LPIN2 orthologs exist across mammals; the closely related PAP function is conserved from yeast (Pah1) to plants (Arabidopsis PAH1/2) and mammals (PMID: 40680843, PMID: 41604448).
  • Orthologous genes: Mouse Lpin2 (NCBI Gene 64898). The lipin family (lipin-1/2/3) has partially redundant and distinct roles (PMID: 27344312).
  • Natural disease in animals: No well-characterized naturally occurring LPIN2 Majeed-equivalent in companion animals is documented here; the related sterile osteomyelitis phenotype occurs in the murine Pstpip2 (cmo) model (a different gene), and canine sterile osteomyelitis has been noted in the broader CRMO literature (PMID: 23917160).
  • Evolutionary conservation: The HAD-like catalytic PAP mechanism is deeply conserved; disease-relevant active-site motifs (e.g., DxDxT) are shared from yeast Pah1 to human lipins (PMID: 40680843, PMID: 32161260).
  • Zoonotic potential: None (non-infectious genetic disease).

15. Model Organisms

  • Mouse models: The cmo (chronic multifocal osteomyelitis) mouse — driven by Pstpip2 mutation, not Lpin2 — is the principal in-vivo model of sterile CRMO and demonstrated that dietary/microbiome manipulation protects against osteomyelitis (PMID: 28361334). It recapitulates the sterile bone-inflammation phenotype but not the LPIN2 lesion or the CDA.
  • Cellular models: RAW-D murine macrophages with Lipin2 deficiency show enhanced NF-κB signaling and osteoclast formation, modeling the bone-directed mechanism (PMID: 33809261). Primary human and mouse macrophages/monocytes (patient-derived and lipin-2-depleted) recapitulate NLRP3/P2X7-driven IL-1β overproduction and the pro-osteoclastogenic secretome (PMID: 28031477, PMID: 33314777, PMID: 22334674).
  • Structural / biochemical surrogates: Tetrahymena Pah2 and yeast Pah1 crystal structures and mutagenesis define the catalytic architecture and the impact of disease-type mutations (PMID: 32161260, PMID: 40680843, PMID: 41109341).
  • Recapitulation / limitations: Cellular and cmo models capture the innate-immune/IL-1 and osteoclast arms well, but no model faithfully reproduces the congenital dyserythropoietic anemia, which remains the least-modeled feature. There is no widely used Lpin2-knockout mouse that reproduces the full human triad.
  • Resources: MGI (mouse Lpin2), and lipin structural/biochemical literature.

Mechanistic Model / Interpretation

Majeed syndrome is best understood as a loss-of-brake autoinflammatory disease: lipin-2 is not itself inflammatory but is a negative regulator that normally keeps the P2X7→NLRP3→IL-1β axis in check while also buffering lipid stress. Removing that brake (biallelic LOF) yields chronic IL-1β excess that fans out into tissue-specific manifestations — bone (via a pro-osteoclastogenic macrophage program and NF-κB), skin (neutrophilic dermatosis), and systemic (fever, growth failure). The therapeutic logic follows directly: because IL-1β is the convergent downstream effector, IL-1 blockade collapses the entire phenotype, and its efficacy is itself strong in-vivo confirmation of the model. This is why the disease has been formally reclassified as an NLRP3 inflammasomopathy: "LIPIN2 deficiency can activate the NLRP3 inflammasome through alterations in the function of P2X7 receptor providing evidence that Majeed syndrome is an NLRP3 inflammasomopathy" (PMID: 29912021).

Two features refine this picture. First, the environmental modifier axis (saturated fatty acids via JNK1/c-Jun; microbiome/diet in the murine model) shows the disease is a gene-by-environment product, not a purely fixed genotype effect — offering non-pharmacologic levers. Second, the anemia sits outside the well-mapped chain: it is described phenotypically as congenital, microcytic and dyserythropoietic, yet no pathway from lipin-2 loss to erythroid maturation failure has been demonstrated. Its reversibility with anakinra reframes it as at least partly an inflammation-driven (IL-1-mediated) anemia rather than a fixed cell-intrinsic erythroid defect — a hypothesis that would reconcile it with the rest of the mechanism.

Evidence Base

PMID Contribution Evidence type
15994876 Identifies LPIN2 as causal gene via homozygosity mapping (chr 18p) Human genetics
33670882 Defines clinical triad; clinical/genetic/immunologic review Human clinical review
41113563 35-patient review: onset <3 y, variable CDA, IL-1 blockade most effective, JIA misdiagnosis Human clinical review
28031477 Lipin-2 restrains NLRP3 via P2X7/MAPK In vitro (human+mouse macrophages)
29912021 Classifies Majeed as an NLRP3 inflammasomopathy Review/synthesis
33314777 Pro-osteoclastogenic M2 macrophages; canakinumab remission In vitro + human clinical
33809261 Lipin2 loss → NF-κB and osteoclast formation In vitro (RAW-D)
22334674 SFA amplify inflammation via JNK1/c-Jun in lipin-2 deficiency In vitro
37929625 Lipin-2 limits TLR3/ROS/mtDNA → NLRP3; IFN-regulated In vitro
39255247 Anakinra resolves MRI, anemia and marrow dyserythropoiesis Human clinical case
31598604 Anti-IL-1 response in familial cases Human clinical
31741047 Consanguinity 74.6%; diagnostic delay Human epidemiology
37865862 ~31 individuals/18 families reported Human clinical review
32161260 Structural basis: disease mutations disrupt catalysis or fold Structural biology
33993107 Multi-specialty presentation; awareness/panel testing Human clinical
28361334 Diet/microbiome modulates sterile osteomyelitis in cmo mouse Model organism
31377798 Bisphosphonate + anakinra novel-mutation case Human clinical
35332675 RETREG1/HSAN2B mimic (LPIN2-negative) — differential dx Human genetics

Limitations and Knowledge Gaps

  1. Unexplained anemia mechanism (primary gap). No primary study mechanistically links lipin-2 loss to dyserythropoiesis. The anemia is characterized only phenotypically (congenital, microcytic, dyserythropoietic, variable severity). Its reversibility with IL-1 blockade (PMID: 39255247) implicates inflammation, but a cell-intrinsic erythroid contribution has not been excluded.
  2. Ultra-small sample size. All clinical conclusions rest on ~31–35 patients in case reports/series; no controlled trials, no reliable prevalence/incidence, penetrance, or sex-ratio estimates.
  3. No faithful whole-animal LPIN2 model. In-vivo mechanistic work leans on the Pstpip2 cmo mouse (different gene) and cellular systems; the human triad, especially CDA, is not fully recapitulated.
  4. Modifier genes / genotype–phenotype correlation are not established despite clear variable expressivity of CDA and dermatosis.
  5. Environmental modifiers (saturated fat, microbiome) are mechanistically supported but not clinically tested in patients.

Proposed Follow-up Experiments / Actions

  1. Dissect the anemia: Generate lipin-2-deficient erythroid models (patient-derived iPSC → erythroid differentiation; conditional Lpin2 knockout in erythroid lineage) and test whether dyserythropoiesis is cell-intrinsic vs. IL-1/inflammation-driven, including IL-1β rescue experiments.
  2. Build a faithful mouse model: Create and characterize a constitutive/conditional Lpin2 LOF mouse to test recapitulation of CRMO + CDA + dermatosis and to serve as a preclinical therapeutic platform.
  3. Genotype–phenotype registry: Establish an international Majeed registry to correlate specific LPIN2 variant classes (catalysis-disrupting vs. fold-destabilizing) with CDA severity and treatment response.
  4. Prospective IL-1 blockade study: Standardized outcome capture (bone MRI, hemoglobin/transfusion needs, growth, PROMIS) for anakinra vs. canakinumab, including effect on marrow dyserythropoiesis.
  5. Test dietary modifier clinically: Pilot evaluation of saturated-fat reduction as an adjunct, given the JNK1/c-Jun amplification data.
  6. Diagnostic uplift: Ensure LPIN2 is on all autoinflammatory/CRMO NGS panels and disseminate awareness to rheumatology, hematology and neurology to shorten the ~2.5-year diagnostic delay.

Evidence source legend: Human genetics/clinical (case reports, series, reviews, cohorts); in vitro (primary human/mouse macrophages, RAW-D, patient monocytes); model organism (cmo mouse); structural biology (lipin/Pah crystallography). No large-scale omics dataset specific to Majeed syndrome was available for primary analysis; conclusions synthesize published primary literature.

Artifacts

Citations

  1. PMID:15994876
  2. PMID:33670882
  3. PMID:28031477
  4. PMID:29912021
  5. PMID:33314777
  6. PMID:33809261
  7. PMID:41113563
  8. PMID:39255247
  9. PMID:37865862
  10. PMID:31741047
  11. PMID:22334674
  12. PMID:28361334
  13. PMID:34365623
  14. PMID:31727123
  15. PMID:27860302
  16. PMID:33993107
  17. PMID:32161260
  18. PMID:37929625
  19. PMID:31598604
  20. PMID:35332675
  21. PMID:31377798
  22. PMID:40680843
  23. PMID:41604448
  24. PMID:27344312
  25. PMID:23917160
  26. PMID:41109341