Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS).

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.

Can early-onset acquired demyelinating syndrome (ADS) hide pediatric Behcet's disease? A case report.

Behcet's disease (BD) is a rare vasculitis characterized by multisystemic inflammation. Central nervous system (CNS) involvement is rare and heterogeneous, particularly in the pediatric population. A diagnosis of neuro-Behcet could be highly challenging, especially if neurological manifestations precede other systemic features; however, its timely definition is crucial to prevent long-term sequelae. In this study, we describe the case of a girl who, at 13 months of age, presented with a first episode of encephalopathy compatible with acute disseminated encephalomyelitis, followed, after 6 months, by a neurological relapse characterized by ophthalmoparesis and gait ataxia, in association with new inflammatory lesions in the brain and spinal cord, suggesting a neuromyelitis optica spectrum disorder. The neurological manifestations were successfully treated with high-dose steroids and intravenous immunoglobulins. In the following months, the patient developed a multisystemic involvement suggestive of Behcet's disease, characterized by polyarthritis and uveitis, associated with HLA-B51 positivity. The challenge presented by this unique case required a multidisciplinary approach involving pediatric neurologists, neuro-radiologists, and pediatric rheumatologists, with all of these specialists creating awareness about early-onset acquired demyelinating syndromes (ADSs). Given the rarity of this presentation, we performed a review of the literature focusing on neurological manifestations in BD and differential diagnosis of patients with early-onset ADS.

Development of a score for early identification of children with Kawasaki disease requiring second-line treatment in multi-ethnic populations in Europe: A multicentre retrospective cohort study.

Background: Early identification of high-risk patients is essential to stratify treatment algorithms of Kawasaki disease (KD) and to appropriately select patients at risk for complicated disease who would benefit from intensified first-line treatment. Several scores have been developed and validated in Asian populations but have shown low sensitivity in predicting intravenous immunoglobulin (IVIG) resistance in non-Asian populations. We sought methods to predict the need for secondary treatment after initial IVIG in non-Asian populations. Methods: We conducted a retrospective, multicenter study including consecutive patients with KD admitted to two tertiary pediatric hospitals in France and Italy from 2005 to 2019. We evaluated the performance of the Kawanet-score and compared it with the performances of initial echocardiography findings, and of a newly proposed score combining the Kawanet-score and initial echocardiography findings. For each score, we assessed the AUC, sensitivity and specificity for predicting the need for second-line treatment. Findings: We included 363 children with KD, 186 from France and 177 from Italy, of whom 57 (16%) required second-line therapy after the first IVIG dose. The Kawanet score, coronary artery dilation or aneurysm with maximal Z-score ≥2.0 at baseline, and abnormal initial echocardiography had a sensitivity of 43%, 55% and 65% and a specificity of 73%, 78%, 73%, respectively, for predicting the need for second-line treatment. The Kawanet-score was significantly improved by combining it with initial echocardiography findings. The best predictive performance (Sensitivity 76%, Specificity 54%) was obtained by combining the Kawanet-score with abnormal initial echocardiography, defined by the presence of either coronary artery maximal Z-score ≥2.0, pericarditis, myocarditis and/or ventricular dysfunction. This score predicted the need for second-line treatment in European, African/Afro-Caribbean and Asian ethnicity with a sensitivity of 80%, 65% and 100%, respectively, and a specificity of 56%, 51% and 61%, respectively. Interpretation: Our study proposes a score that we named the Kawanet-echo score, which allows early identification of children with KD who require a second-line treatment in multi-ethnic populations in Europe. Funding: None.

Infection-Triggered Hyperinflammatory Syndromes in Children.

An association between infectious diseases and macrophage activation syndrome (MAS) has been reported, yet the exact role of infection in MAS development is still unclear. Here, a retrospective analysis of the clinical records of patients with rheumatic diseases complicated with MAS who were treated in a pediatric tertiary care center between 2011 and 2020 was performed. Any infection documented within the 30 days preceding the onset of MAS was reported. Out of 125 children in follow-up for systemic rheumatic diseases, 12 developed MAS, with a total of 14 episodes. One patient experienced three episodes of MAS. Clinical and/or laboratory evidence of infection preceded the onset of MAS in 12 events. Clinical features, therapeutic strategies, and patient outcomes were described. The aim of this study was to evaluate the possible role of infection as a relevant trigger for MAS development in children with rheumatic conditions. The pathogenetic pathways involved in the cross-talk between uncontrolled inflammatory activity and the immune response to infection deserve further investigation.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies: CANDLE/PRAAS, SAVI, and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.

Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation.

Gain-of-function mutations in STING1 cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel STING1 variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations.

Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.

BACKGROUND: Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. OBJECTIVES: We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). METHODS: In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. RESULTS: Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. CONCLUSIONS: CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

When neonatal inflammation does not mean infection: an early-onset mevalonate kinase deficiency with interstitial lung disease.

Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value <0.1). Next-generation sequencing showed a rare c.709A > T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease.

Progressive pseudorheumatoid dysplasia: a rare childhood disease.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic bone disorder characterised by the progressive degeneration of articular cartilage that leads to pain, stiffness and joint enlargement. As PPRD is a rare disease, available literature is mainly represented by single case reports and only a few larger case series. Our aim is to review the literature concerning clinical, laboratory and radiological features of PPRD. PPRD is due to a mutation in Wnt1-inducible signalling protein 3 (WISP3) gene, which encodes a signalling factor involved in cartilage homeostasis. The disease onset in childhood and skeletal changes progresses over time leading to significant disability. PPRD is a rare condition that should be suspected if a child develops symmetrical polyarticular involvement without systemic inflammation, knobbly interphalangeal joints of the hands, and gait abnormalities. A full skeletal survey, or at least a lateral radiograph of the spine, can direct towards a correct diagnosis that can be confirmed molecularly. More than 70 WISP3 mutations have so far been reported. Genetic testing should start with the study of genomic DNA extracted from blood leucocytes, but intronic mutations in WISP3 causing splicing aberrations can only be detected by analysing WISP3 mRNA, which can be extracted from cultured skin fibroblasts. A skin biopsy is, therefore, indicated in patients with typical PPRD findings and negative mutation screening of genomic DNA.

Lung involvement in childhood onset granulomatosis with polyangiitis.

Granulomatosis with polyangiitis is an ANCA-associated systemic vasculitis with a low incidence in the pediatric population. Lung involvement is a common manifestation in children affected by granulomatosis with polyangiitis, both at disease's onset and during flares. Its severity is variable, ranging from asymptomatic pulmonary lesions to dramatic life-threatening clinical presentations such as diffuse alveolar haemorrhage. Several radiologic findings have been described, but the most frequent abnormalities detected are nodular lesions and fixed infiltrates. Interstitial involvement, pleural disease and pulmonary embolism are less common. Histology may show necrotizing or granulomatous vasculitis of small arteries and veins of the lung, but since typical features may be patchy, the site for lung biopsy should be carefully chosen with the help of imaging techniques such as computed tomography. Bronchoalveolar lavage is helpful to confirm the diagnosis of alveolar haemorrhage. Pulmonary function tests are frequently altered, showing a reduction in the diffusion capacity for carbon monoxide, which can be associated with obstructive abnormalities related to airway stenosis. Nodular lung lesions tend to regress with immunosuppressive therapy, but lung disease may also require second line treatments such as plasmapheresis. In cases of massive diffuse alveolar haemorrhage, ventilator support is crucial in the management of the patient.

Recurrent Fever in Children.

Children presenting with recurrent fever may represent a diagnostic challenge. After excluding the most common etiologies, which include the consecutive occurrence of independent uncomplicated infections, a wide range of possible causes are considered. This article summarizes infectious and noninfectious causes of recurrent fever in pediatric patients. We highlight that, when investigating recurrent fever, it is important to consider age at onset, family history, duration of febrile episodes, length of interval between episodes, associated symptoms and response to treatment. Additionally, information regarding travel history and exposure to animals is helpful, especially with regard to infections. With the exclusion of repeated independent uncomplicated infections, many infective causes of recurrent fever are relatively rare in Western countries; therefore, clinicians should be attuned to suggestive case history data. It is important to rule out the possibility of an infectious process or a malignancy, in particular, if steroid therapy is being considered. After excluding an infectious or neoplastic etiology, immune-mediated and autoinflammatory diseases should be taken into consideration. Together with case history data, a careful physical exam during and between febrile episodes may give useful clues and guide laboratory investigations. However, despite a thorough evaluation, a recurrent fever may remain unexplained. A watchful follow-up is thus mandatory because new signs and symptoms may appear over time.

Chorea, a little-known manifestation in systemic lupus erythematosus: short literature review and four case reports.

Chorea is a movement disorder that may be found in children due to several causes. Here we focus especially on Systemic Lupus Erythematosus associated chorea. First we outline its epidemiology, hypothesized pathogenesis, clinical presentation and treatment, then we report four significant clinical cases, which represent well the extreme variability of set of symptoms that may accompany lupus chorea. Our experience, according to literature, suggests that choreic movements in a child should alert the pediatrician and lead him to investigate a potential neurological involvement of Systemic Lupus Erythematosus.