Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis.

OBJECTIVE: To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS: Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS: A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1ß secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/ß, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION: We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency.

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist.

BACKGROUND: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01801449. FUNDING: NIH, NIAMS, and NIAID.

Candida albicans osteomyelitis in an infant: a case report and literature review.

Skeletal infections secondary to Candida albicans are uncommon and described primarily in adults. Nearly all 22 pediatric cases of C. albicans osteomyelitis described to date have occurred in neonates with specific risk factors or in children with a severe immunodeficiency. We report an unusual presentation of C. albicans osteomyelitis and arthritis in a 1-year-old boy without an immunodeficiency, which led to a delayed diagnosis. He most likely developed C. albicans arthritis and osteomyelitis during the neonatal period with a subsequent indolent and subacute presentation. Our literature search found no prior or recent reviews of C. albicans osteomyelitis in pediatric patients. On the basis of this patient and the case reports previously published, we discuss an approach to the evaluation and management of pediatric patients with Candida osteomyelitis.

Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis.

BACKGROUND: Deficiency of interleukin 1 receptor antagonist (DIRA) is a recently described autoinflammatory syndrome of skin and bone caused by recessive mutations in the gene encoding the interleukin 1 receptor antagonist. Few studies have been published about this debilitating condition. Early identification is critical for targeted lifesaving intervention. OBSERVATIONS: A male infant, born to nonconsanguineous Puerto Rican parents, was referred for management of a pustular eruption diagnosed as pustular psoriasis. At 2 months of age, the infant developed a pustular eruption. After extensive evaluation, he was confirmed to be homozygous for a 175-kb genomic deletion on chromosome 2 that includes the IL1RN gene, commonly found in Puerto Ricans. Therapy with anakinra was initiated, with rapid clearance of skin lesions and resolution of systemic inflammation. CONCLUSIONS: Recent identification of DIRA as a disease entity, compounded by the limited number of reported cases, makes early identification difficult. It is critical to consider this entity in the differential diagnosis of infantile pustulosis. Targeted therapy with the recombinant human interleukin 1 receptor antagonist anakinra can be lifesaving if initiated early. A high carrier frequency of the 175-kb DIRA-associated genomic deletion in the Puerto Rican population strongly supports testing infants presenting with unexplained pustulosis in patients from this geographic region.

Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by small airways, alveolar and systemic inflammation and remodeling causing airflow limitation and parenchymal destruction. Mechanisms of oxidative stress include exposure to cigarette smoke and environmental stimuli that activate proinflammatory responses, stimulate alveolar neutrophils and macrophages and lead to apoptosis of endothelial and epithelial cells. COPD may have origins in fetal and neonatal factors that affect intrauterine growth of lungs and airways, lead to low birth weight and impair the development of immune response. Maternal smoking may diminish interferon response secondary to micronutrient deficiency, particularly of Vitamin A, and support persistence of Respiratory Syncytial Virus (RSV), normally a childhood pathogen, into adult life. Muscle wasting and cachexia are systemic features of COPD. Cachexia is associated with systemic inflammation and worsened by Vitamin D deficiency. Nutritional depletion is related to poor survival and is a rational target for therapeutic intervention in advanced and critically ill patients. Preliminary studies and suggest that supplementation with omega-3 polyunsaturated fatty acids and micronutrient repletion with Vitamin A, Vitamin D3, and zinc may have beneficial effects in COPD.

Pediatric asthma: natural history, assessment, and treatment.

Wheezing and childhood asthma are not synonymous but rather comprise a heterogeneous group of conditions that have different outcomes over the course of childhood. Most infants who wheeze have a transient condition associated with diminished airway function at birth and have no increased risk of asthma later in life. However, children with persistent wheezing throughout childhood and frequent exacerbations represent the main challenge today. Studying the natural history of asthma is important for the understanding and accurate prediction of the clinical course of different phenotypes. To date, a great improvement has been achieved in reducing the frequency of asthma symptoms. However, neither decreased environmental exposure nor controller treatment, as recommended by the recent National Asthma Education And Prevention Program, can halt the progression of asthma in childhood or the development of persistent wheezing phenotype. This review focuses on the recent studies that led to the current understanding of asthma phenotypes in childhood and the recommended treatments.

Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature.

Classic rhizomelic chondrodysplasia punctata is a rare, autosomal, recessively inherited disorder that is characterized by proximal shortening of the limbs, punctuate calcifications of the epiphyses, cataracts, developmental delay, and early lethality. A distinctive biochemical profile is characteristic for each of the several defects of peroxisomal metabolism. Recently, cases have been described that were not associated with peroxisomal dysfunction. These cases were found to be secondary to teratogen exposure or maternal conditions. Since 1993, there have been 9 reported cases of neonates with rhizomelic chondrodysplasia punctata who were born to mothers with connective tissue disease. We followed a newborn boy with features suggestive of rhizomelic chondrodysplasia punctata whose biochemical studies failed to demonstrate a defect in either plasmalogen or cholesterol biosynthesis. His mother developed systemic lupus erythematosus 8 months after delivery. This case is compared with the previously reported 9 cases from the literature and is instructive in demonstrating a lesser known effect of maternal autoantibodies on the fetus.