Majeed syndrome

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, Australia, 2011.


What is Majeed syndrome?

Majeed syndrome (MIM609628) is a very rare inherited autoinflammatory condition that presents in early childhood with chronic recurrent multifocal osteomyelitis (CRMO, or inflamed bones) and congenital dyserythropoietic anaemia (CDA, or anaemia due to inadequate manufacture of red cells by the bone marrow). Transient neutrophilic skin inflammation can occur, often resembling Sweet disease, in which biopsy reveals many polymorphonuclear neutrophil white blood cells.

What is the cause of Majeed syndrome and who gets it?

Majeed syndrome is an autosomal recessive genetic condition, meaning two copies of the mutated gene are required, one from each carrier parent.

The gene altered in Majeed syndrome is called LPIN2, located on chromosome 18p11.31, encoding the Lipin 2 protein. Homozygotes (two copies of the same mutation) and compound heterozygotes (two different mutations affecting the same gene) have been identified. Nonsense and missense mutations have been found. The incidence of such gene mutations has been estimated to be 1 in 35,000 in an ethnically-matched population, but have not been detected in other populations. Other missense mutations in this gene have been reported in psoriasis. Lipin 2 is an enzyme involved in lipid (fat) metabolism. The mechanism of disease is so far unknown, but probably involves the innate immune system.

Only a small number of families have so far been identified with Majeed syndrome, and all have come from the Middle East. The rate of carriage of the mutations in Arab populations would predict this syndrome should be seen more commonly. It has therefore been postulated that it is under-diagnosed.

Clinical features develop in early childhood, no later than 2 years of age. The youngest reported onset has been at 3 weeks of age.

Clinical features of Majeed syndrome

Majeed syndrome presents clinically as acute episodes of fever, pain and joint swelling that last several days, with 1-3 attacks per month.

The cardinal features of Majeed syndrome are:

  • Chronic recurrent multifocal osteomyelitis
  • Congenital dyserythropoietic anaemia
  • Skin inflammation

Chronic recurrent multifocal osteomyelitis (CRMO)

  • Early onset
  • Severe pain
  • Tender swelling around joints
  • Usually affects large joints, but can involve small joints
  • Distinguished from sporadic CRMO:
    • More frequent episodes (at least monthly)
    • Lifelong
    • Remission is rare and brief
    • Results in growth delay
    • Contractures are common

Congenital dyserythropoietic anaemia

  • Microcytic hypochromic anaemia (lowered blood count with small pale red cells)
  • Onset in first year of life
  • Ranges from mild to transfusion-dependent

Skin inflammation

Other features

Other inconsistent features reported include:

  • Liver enlargement (hepatomegaly)
  • Neonatal cholestatic jaundice (yellow skin in newborn baby due to blocked biliary tract)

Involvement of the bones results in:

  • Delayed bone age
  • Short adult height
  • Permanent flexion contractures

Quality of life can be poor due to:

  • Recurrent pain
  • Chronic anaemia
  • Contractures
  • Muscle atrophy (wasting) due to under-use

It is possible carriers may develop the skin features alone, such as psoriasis and pustulosis, although the numbers are too small to be sure yet.

How is Majeed syndrome diagnosed?

Diagnosis of CRMO is based on:

  • at least 2 typical bony lesions on x-ray
  • duration at least 6 months
  • typical histologic features on bone biopsy
  • age less than 18 years at diagnosis

LPIN2 gene mutations can be identified on molecular genetic testing. This is the only gene so far found to be affected in Majeed syndrome.

X-Rays: typical lesions are found in the metaphyses of long bones as irregular radiolucent areas (osteolysis) surrounded by increased radiodensity (sclerosis).

Skeletal scans: increased uptake of Tc-99 or Ga-67 in inflammatory lesions and can detect asymptomatic lesions.

MRI: is the most sensitive investigation for active bone lesions especially in the vertebrae.

Bone biopsy: histology shows nonspecific inflammation with granulocytes.

Bone marrow biopsy: increased erythropoiesis including dyserythropoiesis with binucleated and trinucleated normoblasts.

Skin biopsy: intraepidermal neutrophil abscesses

Cultures: from bone, bone marrow, blood and skin are always negative

Blood tests:

  • Microcytic hypochromic anaemia
  • Elevated erythrocyte sedimentation rate (ESR) – consistent
  • White cell count may be normal or increased

Majeed syndrome must be distinguished from the distinct clinical entity Chronic Recurrent Multifocal Osteomyelitis (CRMO, MIM 259680), which is usually a sporadic condition but has also been reported in families. It typically begins later in childhood (onset 4-14 years) and usually resolves. Episodes usually occur less frequently with longer periods of remission between attacks than have been reported in Majeed syndrome. It is not associated with anaemia although the skin can be involved (psoriasis, palmoplantar pustulosis, Sweet syndrome), as can joints and bowel.

Treatment of Majeed syndrome

For the osteomyelitis:

  • Non-steroidal anti-inflammatory drugs (NSAID)
  • Short course systemic corticosteroids
  • Physiotherapy to maintain muscles and joints
  • Avoid prolonged bed rest
  • Colchicine has been reported as unhelpful in 3 patients

For the anaemia:

  • Regular blood counts
  • Blood transfusions
  • Splenectomy

For the skin:

  • Short course oral corticosteroids

Prenatal testing can be considered in subsequent pregnancies as siblings of an affected child have a 25% chance of also developing the syndrome and a 50% chance of being a carrier for the mutated gene. Testing can only be done if the actual mutation has been identified in the affected child. All children of an affected individual must be carriers for the syndrome.

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References:

  • Al-Mosawi ZS, Khulood K. Al-Saad KK, Roya Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 2007; 56: 960–964.
  • De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, Breda L, Chiarelli F. Autoinflammatory syndromes: diagnosis and management. Italian Journal of Pediatrics 2010; 36: 57. http://www.ijponline.net/content/36/1/57
  • Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 2005; 42: 551–557.
  • Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. Journal of Dermatology 2007; 34: 601– 618.
  • Majeed HA, El-Shanti H. Majeed Syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2008 Sep 23.
  • Reue K. The lipin family: Mutations and metabolism. Curr Opin Lipidol 2009; 20: 165-170.

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