023. Autoinflammatory bone disease: Majeed syndrome- description of a novel mutation and therapeutic response to Bisphosphonates and IL-1 blockade

Abstract

Background: Majeed syndrome is a rare autoinflammatory disease of the bone with autosomal recessive inheritance due to mutations in the LPIN2 gene on chromosome 18. It constitutes CRMO (Chronic Recurrent Multifocal Osteomyelitis), congenital dyserythropoeitic anaemia with/without inflammatory cutaneous lesions and recurrent fevers. Longterm prognosis is unknown but afflicted individuals can have significant disability and consequences of uncontrolled inflammation. Treatment modalities include supportive management although IL-1 blockade has been successfully described in a handful of severe cases. Aims: Recognition of extra-osseous manifestations of CRMO and to be aware of genetic/autoinflammatory associations to enable targeted therapy Methods: We describe an 8year old girl, one of 5 siblings, born into a consanguineous family of Pakistani ethnicity. She presented in late infancy with failure to thrive, recurrent fevers, irritability, limb pains, severe microcytic anaemia & high inflammatory markers (CRP 110, ESR 90). An extensive immunology/infectious diseases workup was inconclusive or normal. Empiric treatment for TB was initiated. MRI scans confirmed multiple tibial lesions consistent with CRMO (MRI images available if accepted). A bone marrow and a bone biopsy showed reactive changes. The mother had similar limb pains and congenital dyserythropoetic anaemia was established on her bone marrow. The conglomeration of features was suggestive of Majeed syndrome and a novel missense mutation was confirmed on genetic testing LPIN2 p.R736H. Results: Over the course of a few years, the child had 4 brief courses of oral steroids with transient partial response. Due to spontaneous resolution of episodes, aggressive treatment was not pursued. She was maintained on regular high-dose NSAIDs (Naproxen). Due to ongoing bone lesions on follow-up MRI scans, a trial of Pamidronate infusions for a year was given as per protocol followed for sporadic CRMO patients. This resulted in transient improvement in bone pain and resolution of a majority of bone lesions. Cessation of Pamidronate was followed by resurgence of bone lesions and reintroduction did not prevent new lesions. Due to ongoing nocturnal bone pain, new lesions on MRI, synovitis adjacent to bone lesions, intermittent high inflammatory markers (ESR highest 190, CRP highest 134, Hb lowest 69) and poor growth (0.4th centile for weight & height), IL-1 blockade with daily subcutaneous Anakinra (1mg/kg) was initiated. This resulted in resolution of bone pain, improved appetite with weight gain, normalisation of inflammatory markers (ESR 2, CRP 0.2, Hb 107) significant improvement in CHAQ & Pain scores and negated the need for regular NSAIDs. Conclusions: A high index of suspicion needs to be maintained to diagnose genetic CRMO, especially with atypical presentations. We describe a novel mutation in Majeed syndrome, LPIN2 p.R736H, previously not described in literature. Given our patient's partial response to Pamidronate, we could hypothesise that bisphosphonates might potentially be of some value in mild cases (not described previously in Majeed but akin to sporadic CRMO) or if biologics are contraindicated. Our patient had an excellent response to IL-1 blockade. Duration of therapy and long-term prognosis remains undefined.