Majeed syndrome

Majeed syndrome is a rare genetic condition caused by pathogenic variants in the LPIN2 gene, which codes for an enzyme critical in lipid signalling. Affected patients typically present in early childhood with variable features of chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anaemia and neutrophilic dermatoses.

Majeed syndrome is a multi-system disease of the innate immune system, causing skeletal, haematological, dermatological and systemic inflammatory clinical features that may include the following.

• CRMO:
  • sterile multifocal bone inflammation, occurring in episodic flares and typically affecting femur, tibia and vertebrae;
  • radiographs reveal lytic and sclerotic lesions, typically in the metaphyses of long bones; and
  • complications include bone deformities, asymmetric or disrupted growth or vertebral compression.
• Congenital dyserythropoietic anaemia:
  • hypochromic microcytic anaemia (small, pale red blood cells) that typically presents in early infancy;
  • bone marrow findings include dyserythropoiesis (atypical red cell development) and bi-nucleated erythroblasts with megaloblastic changes; and
  • complications include fatigue, failure to thrive and iron overload caused by repeated blood transfusions.
• Neutrophilic dermatoses:
  • acute, painful erythematous plaques or nodules;
  • recurrent episodic flares with coinciding fever; and
  • skin biopsy shows neutrophilic infiltrate.
• Systemic inflammation:
  • recurrent fever;
  • fatigue;
  • elevated CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate); and
  • hepatosplenomegaly.

Symptoms commonly present during infancy, with anaemia unresponsive to iron supplementation, raised inflammatory markers without infection, and poor feeding with failure to thrive. However, some patients have been described as having mild, incomplete features of Majeed syndrome and present later in childhood.

Majeed syndrome is caused by biallelic pathogenic variants in the LPIN2 gene, which codes for lipin 2, a key lipid metabolism enzyme that catalyses phosphatidic acid to diacylglycerol.

Reduction or complete absence of lipin-2 leads to the accumulation of phosphatidic acid, which is thought to trigger inflammation via dysregulation of NF-kB (nuclear factor kappa B). Lipin 2 deficiency also triggers inflammasome activity. This leads to increased IL-1β activity, which promotes production of other pro-inflammatory cytokines. Cytokines recruit inflammatory cells that cause damage in tissues, particularly those with high cell turnover, such as skin and blood cells.

Most of the pathogenic variants described are biallelic loss-of-function variants that result in early truncation or absence of lipin 2. Missense, nonsense, frameshift and splice-site variants have all been reported, as have small intragenic deletions and duplications that disrupt gene function. There is no clear genotype:phenotype correlation. Heterozygous carriers do not appear to be affected.

A diagnosis of Majeed syndrome may be made in patients presenting with suggestive clinical features, as listed above, alongside molecular confirmation of biallelic pathogenic variants in LPIN2.

Laboratory and imaging tests can help support the diagnosis if they show:

• elevated inflammatory markers (CRP, ESR, ferritin) during episodic flares;
• raised white cell count (leukocytosis); and/or
• soft tissue inflammation and bone destruction in the absence of infection (shown on multiple CT/MRI/bone scans).

For information about testing, see ‘Child with suspected autoinflammatory conditions‘.

Majeed syndrome may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

Majeed syndrome is caused by biallelic pathogenic variants in the LPIN2 gene. It is inherited in an autosomal recessive pattern and is a rare primary immunodeficiency, with fewer than 50 cases described in the literature.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise. Carriers do not appear to be affected by disease, though a small number have been reported to have mild inflammatory skin conditions, such as psoriasis.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Majeed syndrome is a rare, complex condition and is best managed by a multidisciplinary autoinflammatory and/or specialist rheumatology service. Treatment is aimed at controlling bone inflammation and managing life-threatening episodes of anaemia. Growth should also be monitored to support nutrition, manage possible bone deformities and minimise steroid exposure.

No consensus guidelines have been developed as yet, but case reports suggest a good response in patients using IL-1 inhibitors, such as anakinra (IL-1β receptor antagonist) and canakinumab (monoclonal antibody against IL-1β). Anti-inflammatory agents, such as corticosteroids, may also be used to manage disease flares and may be used as bridge therapy to specific disease-modifying treatment. Bisphosphonates such as pamidronate have also been used to prevent bone inflammation and chronic destruction.

Repeated blood transfusions are often required for symptomatic anaemia. Iron chelation may be required in patients who have had regular transfusions.

Majeed syndrome may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• GeneReviews: LPIN2-related Majeed syndrome
• OMIM: 609628 Majeed syndrome

References:

• Chavan PP, Aksentijevich I, Daftary A and others. ‘Majeed syndrome – Five cases with novel mutations from unrelated families in India with a review of literature‘. The Journal of Rheumatology 2021: volume 48, issue 12, pages 1,850–1,855. DOI: 10.3899/jrheum.201663
• Ferguson PJ and El-Shanti H. ‘Majeed syndrome: A review of the clinical, genetic and immunologic features‘. Biomolecules 2021: volume 11, issue 3, page 367. DOI: 10.3390/biom11030367
• Roy NBA, Zaal AI, Hall G and others. ‘Majeed syndrome: Description of a novel mutation and therapeutic response to bisphosphonates and IL-1 blockade with anakinra‘. Rheumatology 2020: volume 59, issue 2, pages 448–451. DOI: 10.1093/rheumatology/kez317

For patients

• Autoinflammatory UK