LPIN2 – Majeed syndrome

Majeed syndrome is an autosomal recessive autoinflammatory disorder characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis caused by biallelic LPIN2 variants (PMID:15994876).

Genetic studies have identified 24 individuals from 10 unrelated families harboring LPIN2 loss-of-function alleles, chiefly frameshift, nonsense, and splice-site mutations, establishing a consistent AR inheritance pattern (PMID:33670882).

Segregation analyses demonstrate homozygous mutations in six affected members across two consanguineous pedigrees (PMID:15994876), a third family with a homozygous splice-site change c.2327+1G>C (PMID:17330256), and two brothers with c.1316_1317del (p.Ser439TrpfsTer15) confirming full concordance (PMID:23087183).

The variant spectrum includes frameshift (e.g., c.1316_1317del (p.Ser439TrpfsTer15)), nonsense (c.1684C>T (p.Arg562Ter)), and canonical splice-site changes, with no evidence of common founder alleles outside specific consanguineous populations.

Functional assays in Lpin2–knockout murine macrophages reveal enhanced NF-κB signaling and NLRP3 inflammasome activation with increased osteoclastogenesis (PMID:33809261). Patient monocyte studies show elevated IL-1β secretion that normalizes upon anakinra therapy in a central-European case (PMID:39255247).

No significant conflicting evidence has been reported; LPIN2 polymorphisms in other disorders (e.g., high-grade myopia) lack functional or clinical impact on Majeed syndrome status (PMID:15862761).

Together, these data support a loss-of-function mechanism in LPIN2 leading to aberrant inflammasome activation and sterile bone inflammation. Early genetic diagnosis and IL-1 blockade are effective, improving both osteomyelitis and dyserythropoiesis.

Key Take-home: LPIN2 genetic testing with subsequent IL-1 inhibitor therapy is critical for accurate diagnosis and management of Majeed syndrome.

References

• Annals of the rheumatic diseases • 2013 • Efficacy of anti-IL-1 treatment in Majeed syndrome. PMID:23087183
• Journal of medical genetics • 2005 • Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). PMID:15994876
• Biomolecules • 2021 • Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features. PMID:33670882
• International journal of molecular sciences • 2021 • Deficiency of Lipin2 Results in Enhanced NF-κB Signaling and Osteoclast Formation in RAW-D Murine Macrophages. PMID:33809261
• Rheumatology (Oxford, England) • 2025 • Majeed syndrome: first description in a patient of central-European ancestry. PMID:39255247
• Arthritis and rheumatism • 2007 • A splice site mutation confirms the role of LPIN2 in Majeed syndrome. PMID:17330256
• Gene • 2005 • Evaluation of Lipin 2 as a candidate gene for autosomal dominant 1 high-grade myopia. PMID:15862761

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