家族性地中海熱

Amyloidosis is a systemic clinical condition characterised by the extracellular deposition of misfolded proteins in various organs, most frequently involving the heart, kidneys, gastrointestinal tract, and bone marrow. Among its types, AA amyloidosis accounts for approximately 15% of cases and is mainly secondary to chronic infectious or inflammatory conditions. The association between Familial Mediterranean Fever (FMF) and AA amyloidosis is well-established, with the MEFV gene's M694V mutation being the most recognised risk factor. However, the role of other genetic variants often remains underestimated. This case series presents a spectrum of AA amyloidosis patients harbouring various MEFV gene variants. By emphasizing the clinical presentations and diagnostic challenges encountered, this report aims to highlight the clinical significance of heterozygous and less common variants that are frequently overlooked in the progression to AA amyloidosis.

Background/Objectives: Autoinflammatory syndromes are defined by episodes of recurrent fever driven by innate immune dysregulation, yet their long-term organ consequences remain largely underestimated, mostly in children. Renal AA amyloidosis represents the most perilous complication of sustained, even subclinical, inflammation, capable of progressing silently to irreversible renal failure. In pediatric cohorts, the interval between autoinflammatory disease onset and amyloidosis diagnosis spans nearly a decade, an actionable window that current surveillance frameworks have not adequately addressed. This review examines the pathophysiological continuum linking chronic cytokine overproduction to renal amyloid deposition in children with autoinflammatory syndromes, evaluates emerging subclinical biomarkers of early renal injury, identifies relevant diagnostic pitfalls, and proposes a structured renal surveillance framework for at-risk pediatric populations. Materials and Methods: This comprehensive review has been conducted analyzing studies reporting renal outcomes, biomarker data, or therapeutic interventions in pediatric patients with monogenic or polygenic autoinflammatory conditions. No date restriction was applied, with emphasis placed on publications from 2015 onward reflecting contemporary treatments and diagnostic standards. Results: An overproduction of interleukin (IL)-1β and IL-6 drives serum amyloid-A accumulation that may persist measurably during intercritical periods, preceding overt proteinuria by years in most young patients with autoinflammatory syndromes. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is significantly elevated in attack-free children with familial Mediterranean fever (FMF) compared to healthy controls, representing an early and sensitive marker of tubular stress. Shear wave elastography has demonstrated measurable increases in renal tissue stiffness in pediatric FMF patients, correlating with subclinical inflammatory activity. Critically, nutcracker syndrome has emerged as the leading cause of proteinuria in colchicine-treated FMF cohorts, accounting for up to 67.5% of proteinuria cases and representing a clinically significant confounder. IL-1 inhibition with either anakinra or canakinumab has demonstrated histological regression of established amyloid deposits in different cohorts of pediatric patients, reinforcing the potential therapeutic value of earlier identification and intervention before overt irreversible glomerular damage comes out. Conclusions: Renal amyloidosis in autoinflammatory syndromes is a plausibly preventable outcome when subclinical injury is identified and treated within the pre-amyloid window in the pediatric age. Conventional reliance on 'proteinuria' as the primary surveillance threshold is potentially misleading. A biomarker-guided monitoring approach incorporating serum amyloid-A, urinary NGAL, and renal elastography might offer a clinically actionable pathway toward earlier nephrology referral and targeted IL-1 blockade, with the potential to improve renal prognosis of these children.

Background/Objectives: Interleukin-6 is a key proinflammatory cytokine involved in the pathophysiology of Familial Mediterranean Fever (FMF). This study aimed to evaluate interleukin-6 levels and the interleukin-6 rs1800795 variant in pediatric FMF participants and to investigate their associations with clinical manifestations, laboratory findings, and Mediterranean fever (MEFV) mutation status. Methods: The research involved 69 pediatric FMF participants and 50 healthy children. Interleukin-6 levels, laboratory findings, and genotype distributions of the interleukin-6 rs1800795 variant were compared between FMF and control groups. Moreover, the relationship between interleukin-6 levels and clinical findings, MEFV mutation status, and laboratory parameters were evaluated in the FMF group. Results: In the FMF group, interleukin-6, serum amyloid-A (SAA), white blood cell count (WBC), neutrophil, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) levels were higher compared to the control group. In the FMF group, interleukin-6 levels showed a positive correlation with ISSF score, annual attack frequency, the number of concomitant symptoms, disease duration, SAA, CRP, and ESR. The allele and genotype distribution of the interleukin-6 rs1800795 variant was similar to those in the control and FMF groups. In the FMF group, interleukin-6 values were higher in patients with abdominal pain, fever, chest pain, or arthralgia compared to those without these symptoms. Interleukin-6 levels were higher in both homozygous and compound heterozygous subgroups compared to the heterozygous subgroup. Conclusions: Elevated interleukin-6 levels in symptomatic pediatric FMF patients and those with homozygous or compound heterozygous MEFV mutations suggest that interleukin-6 may reflect both clinical disease severity and MEFV mutation status.

OBJECTIVES: Familial Mediterranean fever (FMF) is highly prevalent in Mediterranean populations, yet data from Azerbaijan remain scarce despite its location within the traditional FMF belt. This study presents the first nationwide characterization of pediatric FMF in Azerbaijan. METHODS: A multicenter retrospective cohort study was conducted across pediatric and genetic referral centers in eleven regions of Azerbaijan. Demographic, clinical, and genetic data were analyzed. Genotype-phenotype associations were evaluated with particular emphasis on exon-based variant distribution, exon 10 allelic burden. RESULTS: A total of 349 pediatric patients (60.45% boys) were enrolled. The median age at symptom onset and diagnosis was 4 (0-18) and 7 (0-23) years, respectively. The most prevalent MEFV variants were M694V (47.3%), V726A (20.1%), and R202Q (19.8%). Zygosity distribution: 18.3% homozygous, 40% heterozygous, and 41.5% compound heterozygous.Genotype-phenotype analyses included 329 patients after excluding isolated R202Q heterozygotes. Fever (79.3%) and abdominal pain (66.6%) were the most frequent manifestations. Compound heterozygous exon 10 genotypes were associated with earlier symptom onset in univariate analyses. In multivariable hierarchical logistic regression analyses, the presence of at least one M694V allele independently increased the likelihood of early-onset disease (OR 2.10, 95% CI 1.29-3.43, p = 0.003), while the zygosity-based model supported an association between biallelic exon 10 involvement and early disease onset. CONCLUSION: This first nationwide pediatric FMF study from Azerbaijan reveals substantial regional genetic heterogeneity, with compound heterozygosity associated with earlier disease onset. These findings advance FMF epidemiology in the Caucasus and support improved genetic counseling and surveillance for high-risk genotypes.

Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.