Majeed Syndrome

Overview

Majeed syndrome is an ultra-rare autoinflammatory disorder characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and neutrophilic dermatosis. It represents a genetic form of chronic recurrent multifocal osteomyelitis with additional manifestations.

Key Points

• Inheritance: Autosomal recessive
• Gene involved: LPIN2 mutations
• Age of onset: Early childhood (usually before age 2)
• Geographic prevalence: Higher in Middle Eastern populations
• First described: By Majeed et al. in 1989

Historical Context

The syndrome was first identified in three related Arab children from Jordan and was subsequently named after Dr. Majeed who first described the condition. Since its initial description, fewer than 20 cases have been reported worldwide, making it one of the rarest autoinflammatory syndromes.

Genetics & Pathophysiology

Genetic Basis

• Gene: LPIN2 (Lipin 2)
  • Location: Chromosome 18p
  • Protein function: Phosphatidate phosphatase activity
  • Role in lipid metabolism and inflammation
• Mutations
  • Multiple pathogenic variants identified
  • Most mutations result in loss of protein function
  • Founder mutations in certain populations

Molecular Pathophysiology

• Lipin-2 Deficiency Effects:
  • Disrupted phospholipid metabolism
  • Enhanced inflammasome activation
  • Increased pro-inflammatory cytokine production
  • Dysregulated osteoclast function
• Impact on Different Systems:
  • Bone: Enhanced osteoclastogenesis
  • Bone marrow: Impaired erythropoiesis
  • Skin: Neutrophilic inflammation
  • Systemic inflammation markers elevation

Disease Mechanisms

The syndrome involves complex interactions between:

• Innate immunity dysregulation
• Altered lipid metabolism
• Bone homeostasis disruption
• Hematopoietic system abnormalities

Clinical Features

Major Clinical Components

Associated Features

• Growth retardation
• Delayed motor milestones
• Joint contractures
• Hepatosplenomegaly
• Periodic fevers

Diagnosis & Workup

Diagnostic Approach

• Clinical Assessment:
  • Detailed family history
  • Physical examination
  • Growth monitoring
  • Joint mobility assessment
• Laboratory Studies:
  • Complete blood count
  • Iron studies
  • Inflammatory markers (ESR, CRP)
  • Bone metabolism markers
  • Genetic testing for LPIN2 mutations

Imaging Studies

• Radiographic Imaging:
  • X-rays of affected bones
  • MRI with contrast
  • Whole-body MRI for disease extent
  • Bone scintigraphy
• Key Findings:
  • Lytic lesions
  • Sclerotic changes
  • Periosteal reaction
  • Multiple bone involvement

Differential Diagnosis

• Primary conditions to consider:
  • Sporadic CRMO
  • SAPHO syndrome
  • Other autoinflammatory bone disorders
  • Infectious osteomyelitis
  • Malignancies (leukemia, lymphoma)

Treatment & Management

Multidisciplinary Approach

• Core Team Members:
  • Pediatric Rheumatologist
  • Hematologist
  • Orthopedic Surgeon
  • Dermatologist
  • Physiotherapist
  • Genetic Counselor

Medical Management

• Anti-inflammatory Therapy:
  • NSAIDs as first-line treatment
  • Corticosteroids for flares
  • TNF-α inhibitors in refractory cases
  • IL-1 inhibitors (emerging therapy)
• Anemia Management:
  • Regular monitoring of hemoglobin
  • Iron supplementation
  • Blood transfusions when needed
  • Erythropoiesis-stimulating agents

Supportive Care

• Physical Therapy:
  • Joint mobility exercises
  • Strength training
  • Prevention of contractures
• Pain Management:
  • Analgesic medications
  • Physical modalities
  • Psychological support

Research & Updates

Recent Developments

• Novel Therapeutic Approaches:
  • Targeted biologics
  • JAK inhibitors investigation
  • Gene therapy potential
• Research Focus Areas:
  • Genotype-phenotype correlations
  • Biomarker identification
  • Treatment optimization
  • Natural history studies

Clinical Trials & Registries

• Active Studies:
  • International patient registries
  • Natural history studies
  • Treatment response monitoring