M van Gijn

Guidelines for the genetic diagnosis of hereditary recurrent fevers

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.

Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report

Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3–7 days and recurring every 4–6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C‐reactive protein are elevated during the episode, and in addition, high levels of interleukine‐1 (IL‐1), IL‐6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF‐alpha inhibitor, and three children with anakinra, IL‐1 receptor antagonist.

Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4‐related autoinflammatory disease, expansion of the phenotype

DEAR EDITOR, Autoinflammatory disorders (AID) are a heterogeneous group of diseases, characterized by an unprovoked innate immune response, resulting in recurrent or ongoing systemic inflammation and fever. Inflammasomes are protein complexes with an essential role in pyroptosis and the caspase1-mediated activation of the proinflammatory cytokines interleukin (IL)-1b, IL-17 and IL-18 (reviewed in Mariathasan and Monack and Lamkanfi and Dixit). Excessive activation of inflammasomes results in systemic autoinflammatory disease. Various inflammasomes have been identified, of which the NLRP3 inflammasome is most widely studied. Gain-of-function mutations in the NLRP3 gene are associated with cryopyrinassociated periodic syndromes (CAPS), with urticarial skin rash as one of the hallmarks. Recently, gain-of-function mutations in NLRC4 (IPAF/CARD12) were found to associate with a clinically heterogeneous AID, characterized by recurrent episodes of fever, periodic urticarial rash, enterocolitis, splenomegaly and macrophage activation syndrome. Five different mutations in NLRC4 have been reported (reviewed in Vance). Gastrointestinal symptoms and haemophagocytosis distinguish the NLRC4-associated phenotype from CAPS. In this study, we describe the phenotype and skin histology of a large pedigree with 13 affected family members due to a novel mutation in NLRC4 (pedigree in Supplementary Fig. S1). Disease onset occurred in infancy in all patients. Symptoms could be triggered by changes in weather conditions, emotional stress and infection. Disease episodes were characterized by skin lesions, conjunctivitis, arthralgias and – in two patients – colitis. Skin lesions, the predominant feature, varied in severity and localization. In contrast to previous reports, we observed different skin phenotypes between the paediatric and adult patients. The adult patients had painful erythematous nodes on their lower legs and feet, either isolated or in combination with urticarial patches on arms, legs, trunk and face. In two patients, the soles were involved, which had not been reported before in AIDs. Remarkably, the paediatric cases in our cohort suffered from urticarial rash only (Fig. 1a). One patient had enterocolitis with histological signs of inflammatory bowel disease, a feature that was previously described. Histological evaluation of colon biopsies revealed active inflammation, with moderate infiltration of neutrophilic granulocytes and a submucosal mononuclear infiltrate. In contrast to the other reports where neonatal-onset enterocolitis spontaneously resolved after the age of 1 year, the onset of enterocolitis in our patient was in adulthood, with a chronic course. The low number of patients with gastrointestinal symptoms in this family is remarkable, as enterocolitis was thought to distinguish the NLRC4-associated AID from CAPS. Haemophagocytosis was not observed. Response to treatment with an IL-1 receptor antagonist (anakinra) varied (Table 1). A detailed description of the methods is given in Supplementary Methods S1. Whole exome sequencing revealed the novel heterozygous c.1333T>C (p.Ser445Pro) variant in NLRC4 in all affected family members. This variant is absent in the dbSNP or ExAC databases. Prediction software programs (Sift score 0 01, Polyphen-2 score 0 997) indicate that this mutation is probably damaging. The mutation is located next to the recently described pathogenic c.1328A>C (p.His443Pro) mutation and segregated with the disease phenotype (LOD score 3 58). Serum analysis of IL-1b, IL-6, IL-10, IL-18, tumour necrosis factor (TNF)-a and interferon-c showed extremely elevated IL-18 concentrations in eight studied patients (median 4324 pg mL , range 3097–13 984 pg mL , normal 0–34 pg mL ). Concentrations of the other cytokines were in the normal range. Skin biopsies were taken from nodes on the shins and/or calf of three adult patients. Histopathological examination in patient V5 showed a deep dermal and subcutaneous lymphocytic–histiocytic infiltrate with (para)septal and lobular panniculitis. In patient VI5, a perivascular infiltrate of lymphocytes and perivascular oedema was observed. Patient VI1 showed a perivascular and interstitial infiltrate of lymphocytes, and in the deep dermis an infiltrate of lymphocytes, histiocytes and a few mast cells (Fig. 1b). Vasculitis was absent in all samples. Skin biopsies of clinically uninvolved skin (V5 and VI1) showed no abnormalities (not shown). Skin biopsies in CAPS and in the related Schnitzler syndrome mostly show a neutrophilic dermal infiltrate without vasculitis. The absence of a neutrophilic infiltrate in the skin biopsies of our patients is remarkable. Immunofluorescence studies did not detect IL-1b in the skin biopsies, whereas it was found in mast cells in a skin biopsy from a patient with Schnitzler syndrome (data not shown). NLRC4 could not be detected in affected or unaffected skin (not shown), whereas it was present in the positive control (spleen).

Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.

Deficiency of adenosine deaminase-2 (ADA2) is a recently described autoinflammatory disorder with cutaneous inflammatory disease, febrile episodes, cytopenias, splenomegaly and early-onset stroke. Several homozygous and compound heterozygous mutations in CECR1 have been reported in these patients; however, pathogenesis is still poorly understood.

The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: from PAPA to PAMI syndrome and beyond

Mutations in the PSTPIP1 gene encoding proline-serine-threonine-phosphatase interactive protein 1 were first identified in an autosomal dominant syndrome called PAPA associated with pyogenic sterile arthritis, pyoderma gangrenosum (PG) and cystic acne.1,2 . We report a patient with an autoinflammatory syndrome called PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome.3 A 23-year-old man had a 3-year-history of skin ulcerations. This article is protected by copyright. All rights reserved.

Targeted NGS based hereditary autoinflammatory disorder screening in routine diagnostics, two year experience in the Netherlands

Hereditary autoinflammatory diseases (AID) are characterized by recurrent bouts of systemic inflammation caused by dysregulation of the innate immunity system. The genotype-phenotype correlation can be highly variable which makes a genetic diagnosis in AID patients complex and laborious. A clear and definitive diagnosis cannot be provided for up to 80% of AID patients, which can be important for treatment options. To date, over 20 causal genes have been identified for monogenic AIDs.

A novel mutation in NLRC4 in a large pedigree with an anakinra responsive autoinflammatory disease

Autoinflammatory disorders (AID) are characterized by chronic or recurrent systemic inflammation associated with various clinical presentations. It is a genetically heterogeneous group of diseases. Recently, gain of function mutations in NLRC4 have been described to be associated with autoinflammatory disease. Here, we report a novel NLRC4 mutation in a large pedigree with an anakinra responsive autoinflammaotry disease.

PW03-007 - NLRP3 genetic variants in Schnitzler’s syndrome

Schnitzler’s syndrome (SchS) is an autoinflammatory disorder, characterized by chronic urticaria, fever, gammopathy and bone pain. The etiology is unknown, but interleukin-1 (IL-1) inhibition is very effective, like in the cryopyrin associated periodic syndrome (CAPS), that is caused by activating NLRP3 mutations. Previously, a V198M mutation in NLRP3 was reported in one patient with SchS, but this is a prevalent variation in the general healthy population.

PW02-034 - NLRP3 mosaicism detection in CAPS using NGS

Heterozygous germline mutations in NLRP3 are a known cause of Cryopyrin associated periodic syndrome (CAPS). However, in a considerable number of these patients mutations cannot be detected by conventional genetic analyses. Somatic mosaicism has been detected in several mutation-negative patients, and is suggested to be a major cause of CAPS in these patients.

OR7-002 – Pyrin 577 mutations in dominant autoinflammation

Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome.