Rare Monogenic Autoinflammatory Diseases Research Articles

Periodic Fever in Children: A Report of Three Unusual Cases

Introduction: Periodic fever syndrome (PFS) is a rare monogenic autoinflammatory disease group. The innate immune system abnormalities have a characteristic onset and spontaneous inflammation without any infectious or autoimmune trigger. It differs from autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) occurring due to a defect in the adaptive immune system with auto-antibodies. Case Presentation: The clinical features of three patients presented with a periodic pattern of fever and a different constellation of symptoms were investigated. The final diagnosis of Periodic fever syndrome was reached based on standard diagnostic criteria and genetic testing. All three cases were observed to present with recurrent fever episodes at an interval of 6 - 12 weeks, 3 - 4 weeks, and one month, respectively. The first patient, presenting with a diffuse erythematous plaque-like lesion along the calf with severe calf pain and tenderness with signs of meningeal irritation, was diagnosed with a tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) like phenotype. The genetic panel was negative in this case. The second patient presenting with recurrent pharyngitis, cervical adenitis, and tonsillitis unresponsive to antibiotics was diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. The last patient presenting with recurrent monoarthritis, hepatosplenomegaly, and a positive Mediterranean fever (MEFV) gene mutation was diagnosed with familial Mediterranean fever (FMF). All three patients had normal growth and development. Conclusions: Although periodic fever syndrome was an uncommon entity, it was recommended that this syndrome should be considered when a patient presented with recurring fever episodes with a characteristic constellation of symptoms.

NOD2-associated granulomatous autoinflammatory syndromes – a short update for clinicians

NOD2 (nucleotide-binding oligomerization domain-2), a pattern recognition receptor, is involved in innate immune defense against pathogens, intestinal mucosal barrier integrity, gut microbiota composition, autophagy, immune homeostasis and inflammation. NOD2 mutations have been associated primarily with childhood diseases (Blau syndrome and sarcoidosis with early-onset, monogenic Crohn’s disease), but also with adult diseases (NOD2-associated autoinflammatory syndrome – NAID, also called Yao syndrome etc.). Intermediate forms between Blau syndrome and NAID have also been described. Blau’s disease and early-onset sarcoidosis are the familial and the sporadic forms respectively of a dominantly inherited rare monogenic autoinflammatory disease. Blau’s syndrome starts in early childhood, evolving with non-caseating granulomatous arthritis with prominent tenosynovitis, dermatitis with a “bronzed”, maculo-papular or scaly skin rash, and intermittent fever. Periodic fever, generalized lymphadenopathy, and granulomatous visceral involvement may be present. Therapy consists in systemic steroids, immunosuppressants and biologic drugs. In adults the NAID or Yao’s syndrome evolves with bouts of systemic inflammation with lower limbs swelling, tenosynovitis and non-erosive arthritis, fever and dermatitis. We discuss the differential diagnosis with other granulomatous diseases. Increased awareness is necessary regarding these rare diseases which may alter the quality of life or lead to disability, in order to improve their prognosis.

Genetic Landscape of Rare Autoinflammatory Disease Variants in Qatar and Middle Eastern Populations Through the Integration of Whole-Genome and Exome Datasets.

Rare monogenic autoinflammatory diseases are a group of recurrent inflammatory genetic disorders caused due to genetic variants in over 37 genes. While a number of these disorders have been identified and reported in Middle Eastern populations, the carrier frequency of these genetic variants in the Middle Eastern population is not known. The availability of whole-genome and exome datasets of over 1,000 individuals from Qatar persuaded us to explore the genetic epidemiology of rare autoinflammatory genetic variants. We have systematically analyzed genetic variants in genome-scale datasets from Qatar with a compendium of variants associated with autoinflammatory diseases. The variants were systematically reclassified according to the American College of Medical Genetics and Genomics guidelines for interpretation of variant pathogenicity. Our analysis identified seven pathogenic and likely pathogenic variants with significant differences in their allele frequencies compared to the global population. The cumulative carrier frequency of these variants was found to be 2.58%. Furthermore, our analysis revealed that five genes, implicated in rare autoinflammatory diseases, were under natural selection. To the best of our knowledge, this is the first and most comprehensive study on the population-scale analysis and genetic epidemiology of genetic variants that cause rare autoinflammatory disease in Middle Eastern populations.

The expanding pathways of autoinflammation: a lesson from the first 100 genes related to autoinflammatory manifestations.

AutoInflammatory Diseases (AIDs) are a group of innate immune system disorders characterized by sterile inflammation without evidence of pathogenic autoantibodies or auto-reactive T lymphocytes. An expanding spectrum of genes and molecular pathways are associated with AIDs. Inflammasomopathies are secondary to dysregulation of multi-protein complexes, called inflammasomes, leading to an excessive maturation and secretion of IL1β and IL18. Patients present with persistent or recurrent systemic inflammation, abdominal and chest pain, skin rashes and are sensible to IL1 inhibitors. Unfolded proteins response causes a small number of AIDs that we propose to call immuno-proteinopathies, characterized by recurrent fevers and deep tissues inflammation. Other inflammatory conditions can occur in case of abnormalities of actin polymerization and the term of immuno-actinopathies is proposed. Generalized pustular psoriasis is a marker of autoinflammation mainly affecting the keratinocytes. Specific treatment targeting the p40 subunit of IL12 and IL23 or IL-17 are usually effective. Granulomatous inflammation characterizes AIDs related to NOD2 signaling defects. Defects in the ubiquitin-proteasome system cause a group of relopathies and some interferonopathies related to defect of the proteasome function (CANDLE syndrome). Gain of function of proteins regulating the production of type I interferons lead to severe inflammatory conditions, called interferonopathies. The JAK/STAT inhibitors are usually effective in these latter conditions. In conclusions, the identification of the main intracellular pathways involved in rare monogenic AIDs allows not only the proper classification of different conditions, but also highlight a pivotal role of possible novel therapeutic targets for the future.

Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome.

Blau syndrome (BS) is a rare monogenic autoinflammatory disease caused by NOD2 mutations. BS classically presents in early childhood as a triad of granulomatous polyarthritis, uveitis and skin involvement. Joint and ocular involvement have been characterized by several cohort studies but only very little data are available on skin lesions. We aimed to provide a detailed clinical and microscopic analysis of skin manifestations and to study whether they may contribute to an early diagnosis. We conducted a retrospective multicentre study in a French cohort of 21 patients diagnosed with genetically confirmed BS. Skin involvement was the first clinical manifestation of BS in 15/16 patients with dermatological manifestations. The presence of skin lesions was associated with significant shorter age at diagnosis (P=0.03) and diagnostic delay (P=0.04). Dermatological assessment allowed an earlier diagnosis (P=0.001) and reduces the diagnostic delay (P=0.007). Early skin lesions had a homogeneous, stereotypical clinical presentation, namely non-confluent erythematous or pigmented millimetric papules in 13/14(93%) patients. In contrast, skin lesions occurring during later disease stages had a more heterogeneous clinical presentation, including ichthyosiform dermatosis, panniculitis, livedoid lesions and vasculitis. Whatever their time of occurrence and the clinical aspect, all biopsied showed histologically presence of granuloma. Skin involvement in BS is the earliest clinical manifestation of the BS in the large majority of patients. The recognition of dermatological manifestations as granulomatous skin lesions and early dermatological expertise are the key to an early diagnosis of BS. In view of our results, it seems reasonable to propose a simplified view of skin lesions of BS in which the granuloma is the key structure.

Polymyalgia rheumatica: an autoinflammatory disorder?

Polymyalgia rheumatica (PMR) is an elderly onset syndrome characterised by aching and stiffness in the shoulders and the pelvic girdle associated to increased levels of acute phase reactants and rapid...

Muckle–Wells Syndrome in a Child With Recurrent Urticaria

Cryopyrin associated periodic syndromes (CAPS) are rare monogenic autoinflammatory diseases from the group of hereditary periodic syndromes caused by a regulation defect of inflammatory cytokines, in particular interleukin 1 β . They include familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (CINCA/NOMID). Previously, Muckle–Wells syndrome was considered as a triad of symptoms — urticaria, deafness, and reactive amyloidosis. Today, the spectrum of symptoms is constantly expanding: it includes fever, fatigue, conjunctivitis, arthralgia, arthritis, myalgia, irritability, headache, abdominal pain, mouth ulcers, pericarditis, which involves doctors of different specialties in the diagnostic and treatment process, who are not always familiar with this disease. In Russia, single observations of this disease have been described. We present the clinical case of Muckle–Wells syndrome in a 5-year-old child, whose first symptoms appeared at the age of 2 months. This observation underscores the complexity of diagnosing the syndrome in children.

Identification of three ADA2 deficiency families with novel CECR1 mutations

Adenosine desaminase 2 deficiency (DADA2) is a rare monogenic autoinflammatory disease, presenting with systemic inflammation, vascular pathology with possible strokes, and mild immunodeficiency. Recently, the CECR1 gene was found to be responsible for this disease with an autosomal recessive inheritance.

From bench to bedside and back again: translational research in autoinflammation.

Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies. The study of IL-1 and IL-6 in this context led to novel therapies by forward translation. Conversely, effective treatment of sJIA and TRAPS with IL-1 blockade stimulated reverse translational efforts to study the pathophysiology of these cytokines in autoinflammatory diseases. These translational efforts led to the discovery of biomarkers such as S100 proteins, IL-18 or serum amyloid A, which are components of the inflammatory process, support diagnosis and allow for monitoring of disease activity, helping to predict patient outcomes. The ongoing characterization of autoinflammatory diseases in individual patients has led to classification into heterogeneous subgroups. Further characterization of relevant subgroups and the design of tailored treatment regimens, as well as the identification of new therapeutic targets and treatment options, are the major future challenges in the field of autoinflammatory diseases, particularly for paediatric rheumatologists.

The inflammasome and IL-1β: implications for the treatment of inflammatory diseases.

The bioactive form of IL-1β, a key immunoregulatory and proinflammatory cytokine, is produced by the inflammasome - a caspase-1 activating molecular platform - in response to selected danger-associated molecular patterns and pathogen-associated molecular patterns. Advances in understanding the role of IL-1β in inflammatory conditions has resulted in IL-1β becoming a therapeutic target for a number of inflammatory diseases beyond the rare monogenic autoinflammatory diseases characterized by aberrant inflammasome function and enhanced bioactive IL-1β production. In the monogenic autoinflammatory diseases known as cryopyrin-associated periodic syndromes, neutralization of IL-1β results in a rapid and sustained reduction in disease severity without severe side effects, which has consequently driven off-label applications of IL-1β-targeted therapy in other inflammatory diseases. This review summarizes inflammatory diseases for which accumulating evidence suggests a therapeutic potential for IL-1β antagonists.

SP0009 The Expanding Spectrum of Autoinflammation

The term autoinflammation was coined by McDermott and colleagues in 1999 to describe inflammatory conditions with apparently unprovoked inflammation without high titer autoantibodies or antigen-specific T lymphocytes. Unlike autoimmune diseases,...

The expanding spectrum of rare monogenic autoinflammatory diseases

Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle diseases, but we wanted to focus on the most recent rare syndromes. A comprehensive review is thus provided, including taxonomic, genetic, and epidemiological data, along with characteristics defining positive and differential diagnoses and treatment. We believe that this update will assist physicians in correctly naming their patient’s illness. This is an essential step for the effective and targeted management of an orphan disease.

The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation against self

The nucleotide-binding domain, leucine-rich repeat containing family (NLR) network has provided pivotal genetic and molecular insights into diseases that were hitherto regarded as autoimmune. The NLR-related disorders include rare monogenic autoinflammatory diseases collectively termed cryopyrin-associated periodic syndromes, Crohn's disease which is a common polygenic disease and also an association at the mechanistic level with gout and pseudogout. Unlike the classical autoimmune diseases where disease immunopathogenesis is played out primarily in the primary and secondary lymphoid organs, the immunopathogenesis of the NLR-related disorders is played out in the tissues where inflammation arises. As the genetic mutations or molecular cascades associated with the NLR-related disorders have a widespread cellular distribution, it has been somewhat enigmatic why these disorders attack certain territories, but not others. This implies that tissue-specific factors in the target organs themselves contribute to disease expression. Such examples include the high abundance of NOD2 expressing cells in the part of the gut most typically afflicted by Crohn's disease and the preferential deposition of crystals in the joints to where inflammation localises in gout and pseudogout. The NLR network is associated principally with increases in TNF or IL-1 production, both of which are key players in innate immunity. Therefore, the NLR network identifies at the genetic and molecular level a robust paradigm for innate immune activation against self. This tissue-specific-factor-associated inflammation is the diametric opposite of classical autoimmunity. Of note, the MHC class-I-associated diseases including psoriasis (HLA-Cw6) and ankylosing spondylitis (HLA-B27) show striking clinical overlaps with Crohn's disease and also some rare monogenic diseases. Thus, the NLR innate immune pathway allows the full spectrum of inflammation against self to be viewed along an immunological disease continuum with autoantibody-associated disease at one end, innate immune diseases at the other and MHC class-1-related disorders as an intermediate.