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Objective: To identify the molecular basis of a severe systemic autoinflammatory disorder (SAID) and define its main phenotypic features, and to functionally assess the sequence variations identified in LYN, a gene encoding a nonreceptor tyrosine kinase. Methods: We used targeted next‐generation sequencing and in vitro functional studies of Lyn phosphorylation state and Lyn‐dependent NF‐κB activity after expression of recombinant Lyn isoforms carrying different sequence variations. Results: We identified a de novo LYN variation (p.Tyr508His) in a patient presenting since birth with recurrent fever, chronic urticaria, atopic dermatitis, arthralgia, increased inflammatory biomarkers, and elevated plasma cytokine levels. We studied the consequences on Lyn phosphorylation state of the p.Tyr508His variation and of the 2 LYN variations reported so far (p.Tyr508Phe and p.Tyr508*), and found that all 3 variations prevent phosphorylation of residue 508 and lead to autophosphorylation of Tyr397. Additionally, these 3 LYN variations activate the NF‐κB pathway. These results show a gain‐of‐function effect of the variations involving Tyr508 on Lyn activity. Conclusion: This study demonstrates the pathogenicity of the first 3 LYN variations identified in SAID patients and delineates the phenotypic spectrum of a disease entity characterized by severe, early‐onset, systemic inflammatory disease affecting neonates with no family history of SAID. All 3 LYN variations affect the same tyrosine residue located in the C‐terminus of Lyn, thereby demonstrating the critical role of this residue in the proper regulation of Lyn activity in humans. [ABSTRACT FROM AUTHOR]

TCF4 haploinsufficiency by deletions, truncating variants or loss‐of‐function missense variants within the DNA‐binding and protein interacting bHLH domain causes Pitt‐Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N‐terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non‐specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator‐recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype–phenotype correlation for TCF4‐related NDDs. [ABSTRACT FROM AUTHOR]

Background: Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. Methods: We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide‐based array‐CGH analysis. Results: The common clinical features were abnormal maternal serum screening during first‐trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio‐facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. Conclusion: Combined haploinsufficiency of GALNTL5 (alias GalNAc‐T5L), CUL1, SSPO (aliases SCO‐spondin, KIAA0543, and FLJ36112), AOC1(alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient. [ABSTRACT FROM AUTHOR]

Background & Aims: Secondary to tumour necrosis factor‐alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family. Methods: We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*). Results: The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4+/CD8+ T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF‐κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies. Conclusions: This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement. [ABSTRACT FROM AUTHOR]

Introduction: Familial Mediterranean Fever (FMF), the most common monogenic auto‐inflammatory disease, is characterized by recurrent febrile abdominal pain. Helicobacter pylori infection (HPI), one of the most frequent infections worldwide, can mimic an FMF attack. Objectives: Identify FMF patients with HPI in a cohort of French FMF patients and the literature and identify features allowing to distinguish HPI from an FMF attack. Methods: A retrospective study of all HPI cases was performed on the cohort of FMF patients fulfilling the Livneh criteria from the French Reference Center for rare Auto‐Inflammatory Diseases and Amyloidosis (CEREMAIA). A systematic literature review of HPI in FMF patients was conducted according to the PRISMA guidelines. Results: Eight French patients developed HPI, whose symptoms of epigastralgia, diarrhea, anorexia/weight loss, and nausea/vomiting differed from their typical abdominal FMF attacks. A total of 112 FMF patients with HPI have been described in the literature, including 61 adults. Diagnosis of HPI was made by gastroscopy (n = 43), labelled urea test (n = 55) or IgG serology by ELISA (n = 12). When performed, C‐reactive protein was always elevated. Ten cases of interaction between colchicine and antibiotic therapy for HPI (clarithromycin (n = 9) and azithromycin (n = 1)) were reported. Conclusion: We described a total of 120 patients with typical FMF and HPI. When FMF patients develop atypical abdominal symptoms, upper gastrointestinal endoscopy with biopsies is essential to eliminate underlying HPI. Untreated HPI can lead to misdiagnosis of colchicine resistance with inappropriate prescription of an interleukin‐1 inhibitor at a non‐negligible cost. [ABSTRACT FROM AUTHOR]

Objective: To determine the molecular and cellular bases of autoinflammatory syndromes in a multigenerational French family with Muckle‐Wells syndrome and in a patient originating from Portugal with familial cold autoinflammatory syndrome. Methods: Sequencing of NLRP3 exon 3 was performed in all accessible patients. Microsatellite and whole‐genome single nucleotide polymorphism genotyping was used i) to test the intrafamilial segregation of the identified variant and ii) to look for a founder effect. Functional analyses included the study of i) apoptosis‐associated speck‐like protein containing a CARD (ASC) speck formation in HEK293T cells (stably expressing ASC–green fluorescent protein and pro‐caspase 1‐FLAG) transiently expressing the wild‐type or mutated NLRP3 protein, ii) levels of IL‐1β secreted from transfected THP‐1 cells, and iii) inflammasome‐related gene expression and cytokine secretion from monocytes isolated from patients in crisis (probands from the two families), related patients out of crisis, and from controls. Results: The same heterozygous mutation (c.1322C>T, p.A441V) located in the NACHT domain, segregating with the disease within the first family, was identified in the two families. This mutation was found to be associated with different core haplotypes. NLRP3‐A441V led to increased ASC speck formation and high levels of secreted IL‐1β. Monocyte inflammasome‐related gene expression and cytokine secretion, which were within the normal range in patients out of crisis, were found to be differentially regulated between the two probands, correlating with their phenotypic status. Conclusion: These molecular and cellular findings, which indicate a recurrent mutational event, clearly demonstrate the pathogenicity of the p.A441V missense mutation in NLRP3‐associated autoinflammatory disease and point to the interest of studying patients' primary cells to assess disease activity. [ABSTRACT FROM AUTHOR]

Pitt‐Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care. [ABSTRACT FROM AUTHOR]

These data prompted us to assess the contribution of I NLRP3 i and I UBA1 i somatic mutations, as well as of the main genes so far involved in SAID patients with cutaneous lesions in SchS pathophysiology. Absence of NLRP3 somatic mutations and VEXAS-related UBA1 mutations in a large cohort of patients with Schnitzler syndrome Schnitzler's syndrome (SchS) is an extremely rare systemic autoinflammatory disease (SAID) characterized by a late onset of urticarial rash, recurrent fever, bone pain, arthralgia, elevated acute-phase reactants, and a monoclonal gammopathy involving IgM chains (classical type) and rarely IgG (variant type). [Extracted from the article]

Acute pancreatitis (AP) rarely complicates the clinical course of systemic lupus erythematosus (SLE). AP as the initial manifestation of SLE is exceptional, but its outcome is often fatal. Corticosteroids have been suspected to play a role in the development of AP, but the therapeutic benefit seems to be far above the risk of exacerbation of pancreatic lesions. We report a 13-y-old girl presenting with arthralgia and malaise, followed by abdominal pain, generalized oedema and haemodynamic instability. Increased CRP (325  ng/ml), serum amylase (14 000  IU/l) and lipase (2500  IU/l) levels suggested AP. Acute anuric renal failure required haemodialysis. Multiorgan involvement suggested SLE, which was confirmed 3  d later by increased anti-ds-DNA levels. Three methylprednisolone pulses were administered promptly, followed by oral prednisone (1.5  mg/kg/d) and six pulses of cyclophosphamide (500  mg/1.73  m 2 /2  wk). Mycophenolate mofetil was introduced for long-term disease control. Amylase and lipase levels decreased over 4  wk. Renal function was normal after 3  wk and proteinuria negative after 6  wk. This case suggests that steroid pulse therapy should be promptly administered if clinical and biochemical investigations suggest SLE to be responsible for AP. Aggressive treatment may be life saving. [ABSTRACT FROM AUTHOR]