(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself.

Variants of uncertain significance (VUS) are a major obstacle in genetic diagnosis, particularly when involving gain-of-function (GoF) mutations that are poorly predicted in silico. MEFV, which encodes the inflammasome sensor pyrin, is mutated in two autoinflammatory diseases, familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Here, we developed SpeckSeq, a method that combines DNA bar-coding, ASC speck–based single-cell sorting and next-generation sequencing to systematically identify hypermorphic MEFV variants in response to different stimuli. SpeckSeq identified 49 GoF mutations separated into two distinct groups containing either PAAND variants or FMF variants. SpeckSeq was validated using patients’ cells and supported a reclassification of MEFV variant pathogenicity, leading to novel diagnoses. As a large-scale mutagenesis approach, using human genetics as a guide, SpeckSeq revealed structural and functional pyrin features, including a putative ligand-accommodating cavity in the B30.2 domain. Altogether, SpeckSeq classifies VUS to refine molecular diagnostics and improve our knowledge on the pyrin inflammasome.

TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly) syndrome is a rare, life‐threatening inflammatory condition linked to infections, neoplasms, and idiopathic multicentric Castleman disease. Interleukin (IL)‐6 inhibitors are the primary treatment, but refractory cases require alternatives. This study reports the first two pediatric TAFRO cases successfully treated with anakinra, an IL‐1 receptor antagonist. Both patients had severe, rapidly progressing disease with multiorgan involvement. Anakinra, combined with corticosteroids, led to significant improvement and remission. We provide a literature review of pediatric TAFRO, confirming its rarity and the partial efficacy of IL‐6 inhibitors in many cases.

Introduction: Syndrome of undifferentiated recurrent fever (SURF) refers to a group of recurrent fevers without a clear monogenic cause. Clinical spectrum, treatment response predictors and management strategies remain unclear. Objective: This study aims to longitudinally analyse a homogeneously selected cohort of 101 SURF patients, to identify factors associated with colchicine resistance and to evaluate the efficacy of interleukin-1 (IL-1) inhibitors. Methods: Patients were enrolled in the Eurofever Registry, carefully excluding those with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA); familial Mediterranean fever and other known monogenic recurrent fevers. Demographic, clinical and treatment data were analysed to identify predictors of colchicine resistance and define subgroups through cluster analysis. Results: Common symptoms included fever, arthralgia, abdominal pain and myalgia, with PFAPA-like features (lymphadenopathy, tonsillitis, oral aphthae) observed in one-third of cases, sporadically. Colchicine efficacy, assessed in 77 patients, revealed complete response in the majority of patients (61%). Univariable analysis identified PFAPA-like features, including aphthous stomatitis (p=0.001), cervical lymphadenopathy (p=0.012) and exudative tonsillitis (p=0.004), as associated with colchicine resistance. Multivariable analysis confirmed aphthous stomatitis as an independent predictor of resistance (p=0.014). Tonsillectomy was ineffective. IL-1 inhibitors (anakinra, canakinumab) were beneficial in refractory cases. Cluster analysis revealed three distinct subgroups with varying symptoms and colchicine responses. Conclusions: These findings provide new insights into SURF, identifying predictors of colchicine resistance and supporting the efficacy of IL-1 blockade. Cluster analysis suggests the heterogeneity within SURF, reinforcing the need for refined diagnostic criteria and personalised treatment strategies.

Objectives: H syndrome is a rare autosomal recessive disorder caused by mutations in SLC29A3, encoding the nucleoside transporter hENT3. Its heterogeneous clinical presentation often includes skin hyperpigmentation, systemic inflammation, endocrinopathies and sensorineural hearing loss. However, typical cutaneous signs may be absent, leading to diagnostic challenges. The objective was to describe a patient with H syndrome misdiagnosed until adulthood as having cryopyrin-associated periodic syndrome (CAPS), due to overlapping clinical and functional features. Methods: We conducted clinical, immunological, genetic and functional assessments in a 24-year-old male with a complex history of early-onset urticarial rash, fever, hearing loss, oral ulcers, colitis and episodic inflammation. Genetic analyses included whole-exome sequencing (WES) and segregation study by quantitative PCR (qPCR). Functional assays evaluated IL-1β secretion, ASC speck formation, reactive oxygen species (ROS) production and type I interferon signature. Results: The patient showed enhanced and accelerated IL-1β secretion and increased ASC speck formation in CD14+ cells after lipopolysaccharide (LPS) stimulation, indicating NLRP3 inflammasome hyperactivation, hallmark features of CAPS. ROS production was significantly elevated in both granulocytes and monocytes, even at baseline. A type I interferon signature was intermittently positive. Genetic testing ultimately revealed a homozygous deletion of exon 2 in the SLC29A3 gene, confirming H syndrome. Conclusion: This case highlights the phenotypic overlap between H syndrome and CAPS, including shared inflammasome dysregulation. Absence of typical skin hyperpigmentation delayed diagnosis despite early-onset systemic inflammation and partial response to IL-1 blockade. Functional assays may support diagnostic refinement in autoinflammatory syndromes with atypical features or inconclusive genetics.