Phenotypic Variability in Majeed Syndrome

Chronic Recurrent Multifocal Osteomyelitis and Related Diseases—Update on Pathogenesis

“…It is an autosomal recessive disease due to mutations in LPIN2 , which encodes LIPIN2, a phosphatidic acid phosphatase (PAP) that is important in lipid metabolism (34). Thirteen mutation-positive patients have been confirmed in the literature (24, 30, 33, 35, 36). With each reported case, it has become increasingly apparent that there is phenotypic variability.…”

“…Majeed syndrome (OMIM #609628) is an exceedingly rare autoinflammatory disorder that presents with CRMO and dyserythropoietic anemia with or without a neutrophilic dermatosis [Sweet syndrome or pustulosis] (24, 30–33). It is an autosomal recessive disease due to mutations in LPIN2 , which encodes LIPIN2, a phosphatidic acid phosphatase (PAP) that is important in lipid metabolism (34).…”

“…The CRMO in Majeed syndrome typically has early onset (prior to the age of 2 years), with frequent flares that can be accompanied by fever (31–33, 35, 37). However, two recent reports describe 2 cases with onset of the disease at 4 years of age and 8 years of age (30, 36). All 13 had anemia and of the 11 biopsied, all had dyserythropoiesis on the bone marrow examination.…”

“…All but one had microcytic red cells and six required blood transfusions at some point in their disease course (31, 32). Two recent reports describe mutation-positive Majeed syndrome with very mild phenotypes with an older age of onset (as old as 8 years) and a milder bone disease that mimic non-syndromic CRMO (30, 36). The outcomes in Majeed syndrome are more variable than the children initially reported by Dr. Majeed and colleagues.…”

“…Yet the same mutation was found in the children reported by Moussa et al , one of whom had only very mild normocytic anemia and mild CRMO with onset of disease at 8 years of age (36). Treatment of Majeed syndrome remains empiric with reports of partial improvement with NSAIDs, steroids, methotrexate or pamidronate (30–33, 36). However, Herlin et al report sustained clinical, laboratory and radiographic improvement in 2 Majeed syndrome patients when treated with either the recombinant IL-1 receptor antagonist anakinra or the IL-1β blocker canakinumab (after TNF inhibition with etanercept had previously failed to produce clinical improvement) suggesting that Majeed syndrome is an IL-1β driven disease (35, 39).…”