Majeed syndrome

Overview

Majeed syndrome is a rare, inherited autoinflammatory disorder primarily affecting children. It is characterized by the triad of chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and in some cases, neutrophilic dermatosis. First described in 1989 in a consanguineous Arab family, the syndrome represents a severe, early-onset form of chronic inflammation involving both the skeletal and hematologic systems. Unlike infectious osteomyelitis, CRMO in Majeed syndrome is sterile, meaning it occurs without detectable infection.

This condition is considered part of the spectrum of monogenic autoinflammatory diseases and typically presents in infancy or early childhood. Affected individuals may suffer from bone pain, fevers, anemia-related symptoms, and recurrent skin rashes. The disorder follows an autosomal recessive inheritance pattern and requires lifelong management.

Causes

Majeed syndrome is caused by mutations in the LPIN2 gene, which encodes the enzyme lipin-2. This protein plays a role in lipid metabolism and the regulation of inflammatory responses within the innate immune system. The mutations lead to a dysregulated inflammatory cascade, particularly involving the interleukin-1 (IL-1) signaling pathway.

The condition is inherited in an autosomal recessive manner, meaning an affected child must inherit two copies of the mutated gene—one from each parent. Carriers of a single mutation (heterozygotes) are typically asymptomatic.

Symptoms

Symptoms of Majeed syndrome typically manifest in infancy or early childhood and may vary in severity. Common features include:

• Chronic Recurrent Multifocal Osteomyelitis (CRMO):

  • Recurrent episodes of bone pain and swelling

  • Multiple sites affected, especially the long bones and pelvis

  • Episodes can mimic bacterial osteomyelitis but lack infection

• Congenital Dyserythropoietic Anemia (CDA):

  • Mild to moderate anemia present from birth or infancy

  • Fatigue, pallor, and poor growth in affected children

  • Abnormal erythrocyte morphology on blood smear

• Neutrophilic Dermatosis (in some cases):

  • Recurrent, sterile skin lesions such as pustules or plaques

  • Histologically shows infiltration of neutrophils in the skin

• Fever and systemic inflammation: Occasional low-grade fevers and elevated inflammatory markers

Symptoms can fluctuate, and some patients may have incomplete forms of the syndrome, exhibiting only one or two of the classic triad.

Diagnosis

Diagnosis of Majeed syndrome requires a combination of clinical evaluation, imaging studies, blood tests, and genetic analysis. Key diagnostic approaches include:

• Clinical history and physical exam: Recurrent bone pain, anemia, and family history of consanguinity may raise suspicion.

• Radiologic imaging (X-rays, MRI): Shows lytic bone lesions without signs of infection, consistent with CRMO.

• Blood tests:

  • Low hemoglobin levels with signs of dyserythropoiesis on blood smear

  • Elevated ESR, CRP, and other markers of systemic inflammation

• Bone biopsy: May be performed to rule out bacterial osteomyelitis; shows sterile inflammation.

• Genetic testing: Identification of biallelic pathogenic variants in the LPIN2 gene confirms the diagnosis.

It is essential to distinguish Majeed syndrome from infectious osteomyelitis, malignancies, and other causes of anemia and bone pain in children.

Treatment

There is currently no cure for Majeed syndrome, and treatment focuses on controlling inflammation and managing anemia. Therapeutic strategies include:

• Non-steroidal anti-inflammatory drugs (NSAIDs): May help relieve bone pain and reduce inflammation during mild flares.

• Corticosteroids: Used for moderate to severe episodes, especially in controlling bone and skin inflammation.

• IL-1 inhibitors: Targeted biologic agents such as anakinra (IL-1 receptor antagonist) or canakinumab have shown significant benefit in controlling systemic inflammation and reducing flare frequency.

• Management of anemia:

  • Folic acid supplementation and blood transfusions in cases of severe anemia

  • Monitoring of iron stores and growth parameters in children

• Multidisciplinary care: Involving pediatric rheumatologists, hematologists, and geneticists for long-term management.

In some cases, bone lesions may resolve over time with proper anti-inflammatory treatment, though relapses can occur.

Prognosis

The prognosis of Majeed syndrome varies depending on the severity of symptoms and response to treatment. With the advent of targeted biologic therapies such as IL-1 inhibitors, many patients experience improved quality of life, reduced disease flares, and better growth outcomes.

However, untreated or poorly managed cases can lead to chronic pain, skeletal deformities, and growth delays. The anemia associated with Majeed syndrome is typically non-life-threatening but may cause fatigue and reduced exercise tolerance.

Lifelong monitoring is essential to assess for disease progression, treatment side effects, and overall development. Genetic counseling is recommended for affected families, especially in populations with a high rate of consanguinity, to discuss recurrence risks in future pregnancies.