Showing papers on "Majeed syndrome published in 2013"

Efficacy of anti-IL-1 treatment in Majeed syndrome

Abstract: Background and objective Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2 . Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade. Methods We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome. Results Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement. Conclusions The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.

Autoinflammatory Bone Diseases

Abstract: Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous inflammatory process. The inflammatory bone lesions in these disorders are characterized by chronic inflammation that is typically culture negative with no demonstrable organism on histopathology. The most common autoinflammatory bone diseases in childhood include chronic nonbacterial osteomyelitis (CNO), synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist, and cherubism. In this article, the authors focus on CNO and summarize the distinct genetic autoinflammatory bone syndromes.

Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues.

Abstract: Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.

SP0076 Emerging genetics and molecular aspects of autoinflammatory bone disease

Abstract: Autoinflammatory disorders of the bone are innate immune system disorders that result in chronic sterile inflammation in the bone. Chronic recurrent multifocal osteomyelitis (CRMO) is the most common autoinflammatory bone disorder in children and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is the most common autoinflammatory bone disease in adults. These disorders are often seen in conjunction with chronic inflammatory disorders of the skin (palmar plantar pustulosis and psoriasis vulgaris) and intestine (Crohn disease) suggesting shared pathophysiology. The genetic basis of several autoinflammatory bone diseases have been discovered by studying single gene disorders that have CRMO as a subphenotype. Mutations in LPIN2 cause Majeed syndrome, an autosomal recessive disorder which presents with CRMO, congenital dyserythropoietic anemia and neutrophilic dermatosis. Mutations in pstpip2 cause chronic multifocal osteomyelitis in an autosomal recessive murine model of the disease that is results in a phenotype and histology that is very similar to human CRMO, however, to date no PSTPIP2 mutations have been identified in humans with CRMO. Mutations in IL1RN which encodes the interleukin 1 receptor antagonist have been identified in infants with neonatal onset chronic sterile osteitis, sterile generalized pustulosis associated with systemic inflammation. This syndrome named DIRA (Deficiency of the Interleukin-1 Receptor Antagonist) unequivocally implicates the IL-1 pathway in the pathogenesis of sterile osteomyelitis. An update of the genetics and pathogenesis of the autoinflammatory syndromes will be presented. Disclosure of Interest None Declared

SP0039 Immunological and genetic basis of CRMO

Abstract: Chronicnon-bacterial osteomyelitis (CNO) is an inflammatory bone disorder of yet unknown origin. The clinical spectrum ranges from relatively benign, self-limiting, mono-focal symptoms to destructive, multi-focal involvement (known as chronic recurrent multifocal osteomyelitis, CRMO). Secondary to the absence of high-titer autoantibodies and autoreactive T lymphocytes, CNO was classified as an autoinflammatory disorder. The diagnosis is based on the clinical picture, the exclusion of differential diagnoses (including infections and malignancies), and radiographic findings. Treatment options are empiric, including NSAIDs as first line therapy, and steroids, bisphosphonates, or biologicals in more treatment resistant cases. To date, the etiopathology of CNO remains to be elucidated. Linkage analyses point to a susceptibility locus on chromosome 18q. However, conclusive evidence is lacking. A rare syndromal form of CNO, referred to as Majeed syndrome, has been linked to mutations in the LPIN2 gene on chromosome 18p. Further autoinflammatory syndromes, namely deficiency of IL-1 receptor antagonist (DIRA; mutations in IL1RN ) and pyogenic arthritis, pyoderma gangrenosum and acne (PAPA; mutations in CD2BP1 gene), share bone inflammation with CNO, however presenting with a more severe clinical picture. We will discuss 1) animal models, mimicking the phenotype of CRMO, 2) how genetic and immunological findings in related disorders may contribute to a better understanding of the pathophysiology of bone inflammation in CNO, and 3) most recent findings, indicating that monocytes from CNO patients fail to produce IL-10, resulting in a disrupted balance between pro- and anti-inflammatory cytokines. Disclosure of Interest None Declared