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BackgroundDifferent diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.MethodsStep 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.ResultsThe panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).ConclusionEurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.

Mevalonate kinase deficiency (MKD), a rare auto-inflammatory disorder, arises from mutations in the MVK gene, disrupting isoprenoid biosynthesis, and affecting cellular processes. This comprehensive review provides an updated perspective on MKD, including its aetiology, pathogenesis, diagnostic modalities, and therapeutic strategies. Based on recent research and clinical advances, our objective is to bridge the knowledge gaps in the 2015 SHARE guidelines. By describing molecular mechanisms, diagnostic dilemmas, and emerging therapies, this article should serve as a resource for clinicians and researchers, promoting a deeper understanding of MKD and guiding optimal patient care.

Mevalonate kinase deficiency (MKD) is an inherited autoinflammatory syndrome resulting from impaired isoprenoid biosynthesis due to biallelic mevalonate kinase ( MVK ) mutations. This metabolic defect leads to dysregulated innate immunity, particularly excessive interleukin-1β release. While typically presenting in childhood with periodic fevers, expanding evidence links MKD to heterogeneous adult phenotypes with immune-mediated end-organ damage. We report an adult male presenting with leg pain and finger cyanosis followed by acute ischemic stroke, macular rash, and lymphadenopathies. He exhibited classical markers of innate immune activation, including persistent elevation of C-reactive protein. Genetic testing identified compound heterozygosity for the known MVK pathogenic variant c.1129G>A (V377I) and a novel missense variant, c.1049A>C (Q350P). Structural modeling of Q350P revealed disruption of the GHMP kinase domain, predicted to destabilize mevalonate kinase conformation and impair its function. The measurement of mevalonate kinase activity in lymphocytes was at 55% (normal >60%). Interleukin-1β blockade with canakinumab was initiated, and the blood markers of inflammation normalized, further supporting a central role for innate immune dysregulation. This case highlights a novel MVK missense variant (Q350P) with subnormal mevalonate kinase activity. The patient’s compound heterozygous state with partially preserved mevalonate kinase activity may explain the attenuated systemic features and the delayed clinical onset. Remarkably, ischemic stroke was part of the initial presentation, suggesting that mevalonate kinase deficiency can manifest primarily through thrombo-inflammatory complications in adulthood, even in the absence of recurrent febrile episodes. This expands the phenotypic spectrum of MKD and underscores the need to consider adult-onset autoinflammatory syndromes in the differential diagnosis of cryptogenic ischemic strokes with markers of systemic inflammation. It also supports the utility of cytokine-targeted therapies in such contexts.

Pyrin is a cytosolic protein encoded by the MEFV gene, predominantly expressed in innate immune cells. Upon activation, it forms an inflammasome, a multimolecular complex that enables the activation and secretion of IL-1β and IL-18. In addition, the Pyrin inflammasome activates Gasdermin D leading to pyroptosis, a highly pro-inflammatory cell death. Four autoinflammatory syndromes are associated with Pyrin inflammasome dysregulation: familial Mediterranean fever, hyper IgD syndrome/mevalonate kinase deficiency, pyrin-associated autoinflammation with neutrophilic dermatosis, and pyogenic arthritis, pyoderma gangrenosum, and acne syndrome. In this review, we discuss recent advances in understanding the molecular mechanisms regulating the two-step model of Pyrin inflammasome activation. Based on these insights, we discuss current pharmacological options and identify a series of existing molecules with therapeutic potential for the treatment of pyrin-associated autoinflammatory syndromes.

Background. We aimed to document childhood onset mevalonate kinase deficiency (MKD) and to explore treatment responses and diagnostic challenges in regions endemic to familial Mediterranean fever (FMF). Methods. This retrospective study included patients under 18 years of age, diagnosed with MKD and followed for at least six months at the pediatric rheumatology department of Istanbul University - Cerrahpaşa Medical Faculty between 2016 and 2024. Results. Of 33 patients, 51.5% were female, with a median age of symptom onset at 6 (2-17.3) months. Eight patients had a history of tonsillectomy, and seven exhibited an underlying exon 10 Mediterranean FeVer (MEFV) gene mutation. The mean diagnostic delay was 67.6 months, which was longer for those with exon 10 mutations (95.0 months) and those with a history of tonsillectomy (99.5 months). The median duration of attacks was 5 (4-7) days. The median frequency of attacks was 12 (10-24) per year. The most prevalent clinical findings observed during these attacks included malaise (87.8%), arthralgia (69.6%), abdominal pain (63.6%), cervical lymphadenopathy (63.6%), diarrhea (54.5%), and maculopapular rash (51.5%). A total of 30 patients (90.9%) identified pre-attack triggers. Among the patients evaluated, 19 (57.5%) were homozygous for V377I, and 7 (21.2%) had V377I biallelic heterozygous mutation in MVK gene. Cytopenia was observed in 18 patients (54.5%) during episodes, including anemia (39.3%), lymphopenia (24.2%), leukopenia (12.1%), and neutropenia (9%). Conclusions. Patients presenting with periodic fever suggestive of FMF who exhibit atypical features should be evaluated for MKD. Further genetic testing should be performed when atypical clinical findings are present, even in those carrying pathogenic variants in exon 10 of the MEFV gene.

ObjectiveThe aim of the study was to determine the sensitivity and specificity rates of Eurofever/PRINTO autoinflammatory recurrent fever classification criteria with real-life data in patients with an autoinflammatory disease.MethodsA total of 119 patients were included in the study. Based on clinical symptoms, they were divided into four subgroups: cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and syndrome of undifferentiated recurrent fever (SURF) using the Eurofever/PRINTO clinical classification criteria. In the last step, the patients were re-evaluated in the light of genetic results and their final diagnosis was reached.ResultsA total of 119 patients, including 37 CAPS, 13 TRAPS, 8 MKD, 39 SURF, 14 NLRP12-related autoinflammatory disease (NLRP12-AID), and 8 familial Mediterranean fever (FMF) patients were evaluated in the study. While the sensitivity of the new clinical Eurofever/PRINTO criteria was 48% for CAPS, 77% for TRAPS, 87.5%for MKD, and the specificity of the clinical criteria was 86% for CAPS, 85% for TRAPS, and 60% for MKD. The sensitivity of the new mixed (genetic plus clinical variables) Eurofever/PRINTO criteria was 27% for CAPS, 61% forTRAPS, 85% for MKD, and the specificity of the mixed criteria for each group was 100%.ConclusionWe found the sensitivity of the Eurofever/PRINTO classification criteria to be low as genotypic changes between populations cause phenotypic differences. For this reason, we think that patient-based evaluation is correct rather than standard classification criteria in real life.Key-points• In systemic autoinflammatory diseases, common variants in the populations may alter the phenotype, and making it difficult to classify some patients with the current classification criteria.• In populations with common genetic variants, the classification criteria should be modified according to the clinical phenotype.

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle–Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.

Background Hyperimmunoglobulin D syndrome is a rare autosomal recessive autoinflammatory syndrome caused by mevalonate kinase enzyme deficiency. It is characterized by recurrent febrile attacks beginning in the first year of life. Treatment is mainly supportive, and there are successful reports of trials of novel therapies such as anakinra and canakinumab. Case presentation We present a case of a 3-month-old girl from Tanzania, East Africa, who experienced recurrent febrile attacks, sepsis, and anemia since her first week of life. She also exhibited arthritis, generalized lymphadenopathy, urticaria, dermatitis, and failure to thrive. After multiple hospital admissions for similar symptoms, a diagnosis of primary immunodeficiency was considered and genetic testing revealed two heterozygous-like pathogenic variants in the mevalonate kinase gene. Conclusion This case highlights the importance of clinicians in low-resource settings to have a high index of suspicion for primary immunodeficiencies when managing patients with recurrent febrile infections and to consider genetic studies for accurate diagnosis.