RARE DISEASE
Hyperimmunoglobulinemia D with periodic fever
Hyperimmunoglobulinemia D with periodic fever
Hyperimmunoglobulinemia D with periodic fever
Synonyms: HIDS, Hyper-IgD syndrome, Hyperimmunoglobinemia D with recurrent fever, Hyperimmunoglobulinemia D syndrome, Partial mevalonate kinase deficiency
Synonyms: HIDS, Hyper-IgD syndrome, Hyperimmunoglobinemia D with recurrent fever, Hyperimmunoglobulinemia D syndrome, Partial mevalonate kinase deficiency
Synonyms: HIDS, Hyper-IgD syndrome, Hyperimmunoglobinemia D with recurrent fever, Hyperimmunoglobulinemia D syndrome, Partial mevalonate kinase deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Hyperimmunoglobulinemia D with periodic fever (HIDS) is a rare autosomal recessive autoinflammatory disorder caused by MVK gene mutations, leading to partial mevalonate kinase deficiency. It manifests in infancy with recurrent fever episodes (3–7 days), systemic inflammation (abdominal pain, vomiting, diarrhea, lymphadenopathy, arthralgia, and maculopapular rash), and elevated IgD/IgA [1][3][9]. Attacks are triggered by stress, infections, or vaccinations [1][11]. Diagnosis involves genetic testing, urinary mevalonic acid, and exclusion of similar syndromes (e.g., FMF, PFAPA) [1][3][9]. First-line therapies include IL-1 inhibitors (anakinra, canakinumab) [3][7][8].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare immunological diseases, rare inborn errors of metabolism, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
164 drug discovery papers about Hyperimmunoglobulinemia D with periodic fever, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
164 drug discovery papers about Hyperimmunoglobulinemia D with periodic fever, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-28 | The role of mevalonate pathway metabolites in immune homeostasis 2308615
Abstract Introduction The mevalonate pathway is a crucial metabolic pathway responsible for synthesizing key intermediates, including steroids and non-steroidal isoprenoids. Isoprenoid metabolites such as geranylgeranyl pyrophosphate (GGPP) are essential for protein prenylation, a post-translational modification that regulates the localization and function of numerous signaling and structural proteins. The importance of this pathway in immune homeostasis is underscored by the fact that rare inborn errors in enzymes of the pathway such as mevalonate kinase deficiency (MKD), are linked to a spectrum of autoinflammatory syndromes. Mild form of MKD results in hyper-IgD syndrome (HIDS), characterized by recurrent fever episodes, joint pain, abdominal pain, and lymphadenopathy. Current treatments for HIDS are primarily symptomatic and do not target the underlying metabolic deficiency. Methods To gain deeper insights into the immunometabolic crosstalk in HIDS, we conducted a comprehensive metabolomic and proteomic analysis of patient plasma. Additionally, to investigate the therapeutic potential of isoprenoid supplementation, we conducted a pilot study assessing the impact of geranylgeraniol, a GGPP surrogate, on inflammatory status of HIDS patients. Results The analysis identified disease-specific proteomic and metabolic plasma signatures and revealed processes dysregulated by mevalonate pathway dysfunction, including isoprenoids and other lipid species in the plasma of HIDS patients. Geranylgeraniol supplementation impacted global protein and metabolic signatures, confirmed by targeted measurements of inflammatory markers, suggesting potential therapeutic benefit and warranting further study. Conclusion In summary, our study deepens the understanding of the metabolic-immune interface in the context of mevalonate pathway dysfunctions and isoprenoid deficiency and suggests that targeting isoprenoid deficiency may offer a strategy to modulate disease-specific changes and inflammation in HIDS. Funding Source 1) Washington University Institute of Clinical and Transitional Sciences; 2) Longer Life Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-05-02 | NK cell dysfunction and interferon-γ production underlie autoinflammation in mevalonate kinase deficiency.
Prenylopathies such as mevalonate kinase deficiency (MKD) are an emerging family of monogenic autoinflammatory diseases with an underlying defect in isoprenoid lipid synthesis and protein prenylation. The mechanisms linking defective protein prenylation to systemic inflammation remain unclear. We revealed that mice and humans with MKD had significant decreases in the frequency of mature natural killer (NK) cells, impaired trafficking of cytolytic granules, reduced cytotoxic activity, and increased production of the cytokine interferon γ (IFN-γ). Mice with MKD failed to clear murine cytomegalovirus (MCMV) infections and had elevated serum IFN-γ and inflammatory pathology, likely the result of decreased and dysregulated cytotoxic cells. Finally, we describe the beneficial effect of cytokine signaling blockade with a Janus kinase (JAK) inhibitor in an infant with severe MKD. Together, these findings reveal a fundamental role for dysregulated cytotoxic cells and IFN-γ production in MKD and likely other prenylopathies. Importantly, this work provides a rationale for the use of JAK inhibitors in the treatment of MKD.
2026-03-12 | Pyrin inflammasome activation triggers an IL-18-driven IFN-γ response in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to a lowering of the threshold for pyrin inflammasome activation. A cellular model of MKD was established to discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and IFN-γ signaling. Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harboring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses after stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived peripheral blood mononuclear cells were performed to validate in vitro findings. MVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD peripheral blood mononuclear cells hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and natural killer cells were characterized by enhanced IL-18-driven IFN-γ production. Elevated IFN-γ and IL-18 binding protein levels in MKD plasma as well as transcriptomic data of MKD peripheral blood mononuclear cells further confirmed the presence of an IFN-γ signature in MKD. A pyrin inflammasome-driven IL-18/IFN-γ axis is a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.
2024-07-18 | Geranylgeraniol supplementation leads to an improvement in inflammatory parameters and reversal of the disease specific protein signature in patients with hyper-IgD syndrome
Abstract Mevalonate kinase (MVK) deficiency, a rare autosomal recessive disease, significantly impacts metabolism and immunity, leading to mevalonic aciduria in severe cases and hyper-IgD syndrome (HIDS) in partial deficiency. These conditions arise due to disruptions in the mevalonate pathway, which is essential metabolic pathway responsible for the synthesis of non-sterol isoprenoids and other molecules. The resulting metabolic blockade triggers autoinflammatory responses, primarily due to deficient isoprenoid intermediates such as geranylgeranyl pyrophosphate (GGPP). This first reported pilot study evaluates the safety and efficacy of dietary geranylgeraniol supplementation (GG) in three patients with HIDS. Over three months, GG supplementation showed no liver toxicity and did not alter lipid profiles. Although GG did not rise the plasma levels of GGPP, the plasma proteomics showed significant changes induced by GG. Proteomic analysis further revealed that GG supplementation can reverse some of the features of HIDS-specific plasma protein signature, highlighting its potential to modulate inflammation and protein prenylation pathways. These findings suggest that GG supplementation could be a promising metabolic intervention to mitigate inflammation in HIDS, warranting further, more targeted investigation in larger clinical trials.
2023-12-25 | Recent Insights in Pyrin Inflammasome Activation: Identifying Potential Novel Therapeutic Approaches in Pyrin-Associated Autoinflammatory Syndromes.
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.
proteins
2026-07-30 | Novel compound heterozygous MVK variants cause early-onset mevalonic aciduria in a Chinese infant.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder caused by mevalonate kinase (MVK) gene mutations, with phenotypes ranging from mild hyper-IgD syndrome (HIDS) to severe mevalonic aciduria (MA). Here, we report a 7-month-old Chinese male infant presenting with neonatal-onset MA. The proband presented with growth retardation, intractable diarrhea, recurrent fever, generalized rash, progressive hepatosplenomegaly, and persistent systemic inflammation. Laboratory tests revealed marked leukocytosis, elevated C-reactive protein, hyper-IgD and increased urinary mevalonic acid. Whole-exome sequencing identified two novel compound heterozygous MVK variants: c.64G > A (p.Val22Met) and c.1063G > C (p.Ala355Pro). Both variants were absent in global population databases. In silico analyses, including cross-species conservation, structural modeling, and pathogenicity prediction, confirmed significant structural perturbations. The patient achieved sustained remission with canakinumab. This is the first worldwide report of the MVK c.1063G > C variant causing severe MA, expanding the MVK mutational spectrum in Chinese populations.
2026-03-16 | Phenotype-genotype correlation and treatment outcomes in mevalonate kinase deficiency: A large Turkish cohort.
This study aimed to comprehensively assess the clinical spectrum, genotype-phenotype correlations, and treatment responses in a large cohort of Turkish pediatric patients with genetically confirmed mevalonate kinase deficiency (MKD). This retrospective, multicenter cohort study included 107 genetically confirmed MKD patients followed between 2010 and 2024 across 25 pediatric rheumatology centers in Turkey. Demographic characteristics, clinical features, laboratory parameters, genotypic data, and treatment outcomes were recorded and analyzed. Of the 107 patients, 48 (44.9%) were female. The median age at symptom onset was 7 (3-24) months, and the median age at diagnosis was 71 (27-115) months. The most frequent clinical features included fever in 105 (98.1%) patients, abdominal pain in 92 (86%), arthralgia in 74 (69.2%), diarrhea in 73 (68.2%), lymphadenopathy in 64 (59.8%), vomiting in 52 (48.6%), and oral aphthae in 50 (46.7%). Less frequent findings included pancreatitis in 2 (1.9%), genital aphthae in 2 (1.9%), neurosensory hearing loss in 3 (2.8%), and hidradenitis suppurativa in 1 (0.9%) patients. Amyloidosis and MAS were reported in 4 (3.7%) and 4 (3.7%) patients, respectively. Among the 107 patients, 45 (42%) had a homozygous V377I mutation (Group 1), 28 (26.2%) had a compound heterozygous mutation involving V377I and a non-V377I allele (Group 2), 15 (14%) had two non-V377I alleles (Group 3), and 19 (17.8%) had a single heterozygous mevalonate kinase gene mutation (Group 4). No statistically significant differences were observed between the groups in demographic features, attack characteristics, clinical manifestations, laboratory findings, or treatment outcomes. IL-1 antagonists were the primary therapeutic agents. Anakinra yielded no clinical response in 14 (13.1%), partial response in 17 (15.9%), and complete response in 13 (12.1%) patients. Canakinumab treatment resulted in no response in 2 (1.9%) patients, partial response in 34 (31.8%), and complete response in 56 (52.3%). The variability in clinical manifestations and treatment responses across genotypes highlights the complexity and heterogeneity of MKD, suggesting that factors beyond genotype may influence disease expression and therapeutic outcomes. We also confirm that heterozygous individuals may express the disease phenotype.
2026-02-04 | A Diagnostic Challenge: Recurrent Uveitis Leading to the Diagnosis of Hyper-IgD Syndrome in a 28-Year-Old Patient.
Mevalonate Kinase Deficiency (MKD), which includes the clinical phenotype known as Hyperim munoglobulin D Syndrome (HIDS), is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene. While typically characterized by childhood-onset recurrent febrile episodes and systemic symptoms like lymphadenopathy and abdominal pain, ocular involvement is usually limited to conjunctivitis. Uveitis is a rare manifestation, often associated with more severe forms of the disease. This report describes a 28-year-old male who presented with bilateral, recurrent anterior uveitis and vitritis. Although the patient reported self-limiting febrile episodes during childhood, the presentation of ocular inflammation in adulthood as the primary symptom posed a significant diagnostic challenge. Initial treatment with topical and systemic corticosteroids provided only temporary relief, with the patient developing cystoid macular edema and further recurrences. A multidisciplinary evaluation and genetic testing confirmed the diagnosis of HIDS. Following the diagnosis, the patient was started on targeted anti-IL-1 therapy (anakinra or canakinumab). This intervention led to a significant improvement in symptoms and was essential in halting recurrences and preventing chronic ocular damage. Recurrent uveitis, even in adult patients, should prompt the investigation of rare autoinflammatory syndromes. A timely genetic diagnosis and a multidisciplinary approach are crucial for initiating targeted biological treatments, which offer a superior visual and systemic prognosis compared to conventional therapies.
2026-02-01 | Targeting cytokine pathways: the role of biologics in autoinflammatory disorders.
Autoinflammatory diseases are inherited disorders of innate immunity, broadly classified into inflammasomopathies, interferonopathies, and complement-mediated disorders. They are characterized by dysregulated cytokine signaling - particularly IL-1, IL-6, TNF, type I interferon, and the JAK-STAT pathway-and are increasingly managed with molecular targeted therapies. Prototypical entities include familial Mediterranean fever (FMF), TNF receptor - associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndromes (CAPS). Other conditions - notably mevalonate kinase deficiency (MKD/HIDS), deficiency of adenosine deaminase 2 (DADA2), haploinsufficiency of A20 (HA20), OTULIN-related autoinflammatory syndromes, and proteasome-associated autoinflammatory syndromes (PRAAS) - are now recognized as biologic-responsive diseases. This review summarizes molecular mechanisms and therapeutic strategies, focusing on IL-1 blockade with anakinra, canakinumab, and rilonacept, as well as IL-6 and TNF inhibitors, integrating evidence from clinical trials and real-world studies. IL-1 inhibition has transformed the management of inflammasome-mediated diseases, enabling glucocorticoid-free remission and reducing amyloidosis risk. TNF inhibitors remain standard for vasculopathic disorders such as DADA2, while IL-6 blockade and JAK inhibitors are options in selected refractory cases. The recognition of novel syndromes, including HA20, OTULIN deficiency, and PRAAS, has broadened the therapeutic landscape, and next-generation biologics may further enable personalized treatment.
2025-12-22 | Skin involvement in classic monogenic autoinflammatory diseases. Part 1
Autoinflammatory diseases (AIDs) represent a heterogeneous group of conditions pathogenetically associated with dysregulation of innate immunity and clinically characterized by recurrent episodes of sterile inflammation in affected organs in the absence of infection, allergy, and high titers of circulating autoantibodies or autoreactive T cells. The overwhelming majority of monogenic AIDs (mAIDs) are accompanied by skin rashes, the type of which is determined by the specific disease and, to some extent, by differing pathogenetic mechanisms. The first part of the article presents the cutaneous characteristics of the most common mAIDs: Familial Mediterranean fever (FMF), cryopyrinassociated periodic syndromes (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodic syndrome with hyperimmunoglobulinemia D / mevalonate kinase deficiency (HIDS/MKD). Skin involvement in these diseases reflects systemic inflammation associated with hyperproduction of the key pro-inflammatory cytokine interleukin (IL)-1β. In other AIDs, symptoms mainly depend on increased levels of cytokines such as IL-18, IL-36, etc. (NLRC4-associated autoinflammatory disease; deficiency of the IL-36 receptor antagonist – DITRA), as well as activation of interferon signaling pathways (interferonopathies). Different pathogenetic mechanisms determine the diversity of clinical phenotypes, including cutaneous manifestations. Knowledge of these features helps establishing a correct diagnosis, obtaining genetic confirmation (without which accurate identification of these rare conditions is impossible today) and selecting appropriate therapy. Pathological examination plays a special auxiliary role and should be used in diagnostically challenging situations.
cell therapies
2022-08-02 | The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency.
Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment. This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office. We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications. In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy.
2021-01-07 | Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency
Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first.Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs.Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
2015-03-05 | Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype that may be expressed as a spectrum of disease phenotypes, from those with prevailing autoinflammatory syndrome and variable response to anti-inflammatory therapies, to mevalonic aciduria, which is associated with dysmorphic features, severe neurologic involvement, and the worst prognosis. We describe a boy, aged 2 years, 10 months, with severe phenotype of mevalonate kinase deficiency who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical unrelated cord blood because his condition had failed to improve with antiinflammatory treatment as first-line therapy and an anticytokine drug as second-line therapy. The child had a sustained remission of febrile attacks and inflammation after transplant, and during a 5-year follow-up period, psychomotor and neurologic development were normal, without signs of underlying disease or late transplant-related effects. This case confirms that allogeneic HSCT is a safe and effective cure for patients affected by MKD in whom anticytokine drugs alone are insufficient for the management of autoinflammatory syndrome and for the unfavorable outcome of the disease.
2006-07-11 | Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency
Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene resulting in deficient activity of mevalonate kinase (MK). Depending on the clinical severity, MKD may present as hyper-IgD and periodic fever syndrome (HIDS) or the more severe mevalonic aciduria (MA). We analyzed the MVK gene in 57 patients with MKD and found 39 different mutations including 15 novel mutations, expanding the total mutational spectrum of MKD to 63 mutations. To get more insight into the genotype–phenotype correlation in MKD, we studied the effect of selected missense mutations on MK protein stability and activity in various patient fibroblast cell lines. All MKD cell lines showed markedly decreased MK activities that correlated well with the clinical severity and, for most of the cell lines, with the amount of MK protein. When fibroblasts of MKD patients were cultured under conditions known to promote a more controlled protein folding, all cell lines of patients with the HIDS phenotype and few cell lines of patients with the MA phenotype showed an increase in the residual MK activity. This increase in enzyme activity correlates well with an increase in the MK protein levels in these cell lines, indicating that most of the mutations in MKD affect stability and/or folding of the MK protein rather than affecting the catalytic properties of the enzyme. The finding that the residual activity in MKD can be manipulated by environmental conditions may offer therapeutic options to alleviate or prevent the clinical symptoms associated with MKD. Hum Mutat 27(8), 796–802, 2006. © 2006 Wiley-Liss, Inc.
antibodies
2026-08-13 | Autoinflammatory Syndromes of Hidradenitis Suppurativa: Updates in Clinical Features, Emerging Associations, and Management.
To summarize and critically evaluate recent literature on autoinflammatory syndromes of hidradenitis suppurativa (HS). HS-associated autoinflammatory syndromes traditionally encompass pyoderma gangrenosum (PG), acne, and HS (PASH); pyogenic arthritis, PG, acne, and HS (PAPASH); psoriatic arthritis, PG acne, and HS (PsAPASH); and PG, acne, HS and ankylosing spondylitis (PASS). However, this spectrum continues to expand, with recent literature considering the inclusion of additional autoinflammatory diseases such as HS associated with SAPHO, including synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO); and Hyperimmunoglobulin D Syndrome (HIDS). HS-associated autoinflammatory syndromes are thought to be driven by dysregulation of the innate immune system and the subsequent overexpression of key inflammatory cytokines such as IL-1, and targeted IL-1 therapies have demonstrated particularly brisk and efficacious response. Multiple genes related to follicular keratinization or inflammatory regulation have been implicated, and sequencing methods such as whole-exome sequencing and variant enrichment analysis continue to identify novel genetic variants and are being used to further elucidate genotype-phenotype correlations. HS-associated autoinflammatory syndromes are an evolving spectrum of rare, severe, diseases in which HS coexists with other autoinflammatory conditions, most commonly PASH and related syndromes. They are driven by innate immune dysregulation and pathogenic genetic variants, with whole-exome sequencing aiding diagnosis and genotype-phenotype correlation. Management is often challenging and highly individualized, with targeted biologic therapies such as IL-1 inhibitors showing the most consistent and rapid clinical benefit.
2026-05-22 | Effective interleukin-6 inhibition in a pediatric patient with mevalonate kinase deficiency and chronic nonbacterial osteomyelitis-like bone lesions under interleukin-1 blockade.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease. Chronic nonbacterial osteomyelitis (CNO) represents another autoinflammatory disorder characterized by sterile bone inflammation. Although musculoskeletal pain is common in MKD, CNO-like bone lesions have rarely been described. Tocilizumab has been used separately in MKD / hyper-IgD syndrome (HIDS) and in CNO; however, pediatric cases showing both conditions together and responding completely to IL-6 blockade have not been previously reported. We present a 16-year-old boy born to consanguineous parents who experienced early-onset recurrent fever episodes with abdominal pain, maculopapular rash, oral ulcers, and conjunctival injection. He was initially misdiagnosed with FMF and IgA vasculitis and treated with colchicine with partial improvement. Persistent systemic inflammation prompted referral to our tertiary center at age 9. A periodic fever gene panel revealed a homozygous MVK p.V377I mutation, confirming MKD. Anakinra therapy was initiated. Although no attacks occurred during the first month, flares characterized by fever, abdominal pain, rash, and elevated acute-phase reactants recurred in the second and third months, reflecting a partial response. Consequently, treatment was switched to canakinumab. Toward the end of the second year of IL-1 blockade, attack frequency increased to once every three months, and at age 12 he developed diffuse musculoskeletal pain. Whole-body magnetic resonance imaging demonstrated multifocal metaphyseal bone marrow edema compatible with CNO-like lesions. Sulfasalazine was added but discontinued after drug-induced pancreatitis. Given persistent systemic inflammation and inadequate response to IL-1 inhibitors, canakinumab was replaced with weekly subcutaneous tocilizumab, resulting in rapid improvement in bone pain and systemic inflammation. Since the third month of tocilizumab therapy, he has remained clinically stable with normalized inflammatory markers and only a single mild flare over the last year. This case highlights the potential role of IL-6 inhibition in complicated MKD presenting with autoinflammatory bone disease refractory to standard therapies.
2026-02-20 | A nephritic puzzle: C3-dominant glomerulonephritis as a sentinel of hidden autoinflammatory disease.
Membranoproliferative glomerulonephritis (MPGN) is among the most challenging glomerulonephritides to diagnose and manage, given its clinico-immunopathologic heterogeneity. Although recent advances have introduced new therapies for complement-mediated and immune-complex MPGN, a substantial subset of cases remains poorly understood and lacks effective treatment. We report a pediatric case of biopsy-confirmed C3-dominant MPGN without evidence of complement dysregulation, with disease flares triggered by febrile episodes. Genetic testing identified underlying hyper-IgD syndrome (HIDS), a rare autoinflammatory disorder characterized by recurrent fevers and immune dysregulation. The patient's MPGN was refractory to conventional immunosuppressive therapy but achieved remission with IL-1β blockade that targets HIDS. This case highlights the importance of considering alternative etiologies-including autoinflammatory diseases-in patients with MPGN when complement dysregulation is not evident.
2025-10-20 | Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke-characterization of a novel genetic variant.
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.
2025-08-18 | Atypical cutaneous manifestations in hyperimmunoglobulin D syndrome: A case report
Hyperimmunoglobulin D syndrome (HIDS) is a rare autosomal recessive autoinflammatory disorder caused by mutations in the mevalonate kinase (MVK)gene. It is characterized by recurrent fever episodes, abdominal pain, elevated serum IgD levels, and systemic inflammation. We report a 5-year-old boy presenting with recurrent fever, abdominal pain, diarrhea, and hyperpigmented skin lesions. Physical examination revealed abdominal distension and multiple café-au-lait like spots on the lower extremities, with no lymphadenopathy or organomegaly. Whole-exome sequencing revealed a homozygous missense pathogenic variant (c.1129G>A; p.Val377Ile) in MVK gene. Abdominal CT revealed colonic wall thickening with mucosal hyperenhancement. However, the lower GI endoscopy was unremarkable. Skin biopsy was consistent with café-au-lait spots. Despite the inadequate response to colchicine and anakinra, the patient showed significant clinical improvement with canakinumab. This case underscores the diagnostic complexity of HIDS and suggests a potential novel association with café-au-lait macules. Early genetic testing is crucial for timely diagnosis and targeted therapy. • This case describes a rare presentation of Hyper IgD Syndrome (HIDS) with persistent café-au-lait–like macules. • The patient exhibited gastrointestinal involvement with poor response to colchicine and anakinra, improved on canakinumab. • This case expands the clinical spectrum of HIDS and highlights the importance of early genetic testing.
other
2025-07-03 | Treatment advances in mevalonate kinase deficiency: A comprehensive review
Mevalonate kinase deficiency (MKD) is a rare auto-inflammatory disease caused by mutations in the mevalonate kinase gene. This leads to problems with isoprenoid production and cell function. Individuals with MKD usually experience repeated fever episodes, along with stomach issues, mouth sores, swollen neck lymph nodes, and skin rashes. In addition, the severity of MKD varies markedly among individuals. The most severe and rarest form of MKD is called mevalonic aciduria, while the most typical type is referred to as hyperimmunoglobulinemia-D syndrome. Based on new research and clinical progress, this review explores more treatment options for MKD.
small molecules
2026-07-28 | The role of mevalonate pathway metabolites in immune homeostasis 2308615
Abstract Introduction The mevalonate pathway is a crucial metabolic pathway responsible for synthesizing key intermediates, including steroids and non-steroidal isoprenoids. Isoprenoid metabolites such as geranylgeranyl pyrophosphate (GGPP) are essential for protein prenylation, a post-translational modification that regulates the localization and function of numerous signaling and structural proteins. The importance of this pathway in immune homeostasis is underscored by the fact that rare inborn errors in enzymes of the pathway such as mevalonate kinase deficiency (MKD), are linked to a spectrum of autoinflammatory syndromes. Mild form of MKD results in hyper-IgD syndrome (HIDS), characterized by recurrent fever episodes, joint pain, abdominal pain, and lymphadenopathy. Current treatments for HIDS are primarily symptomatic and do not target the underlying metabolic deficiency. Methods To gain deeper insights into the immunometabolic crosstalk in HIDS, we conducted a comprehensive metabolomic and proteomic analysis of patient plasma. Additionally, to investigate the therapeutic potential of isoprenoid supplementation, we conducted a pilot study assessing the impact of geranylgeraniol, a GGPP surrogate, on inflammatory status of HIDS patients. Results The analysis identified disease-specific proteomic and metabolic plasma signatures and revealed processes dysregulated by mevalonate pathway dysfunction, including isoprenoids and other lipid species in the plasma of HIDS patients. Geranylgeraniol supplementation impacted global protein and metabolic signatures, confirmed by targeted measurements of inflammatory markers, suggesting potential therapeutic benefit and warranting further study. Conclusion In summary, our study deepens the understanding of the metabolic-immune interface in the context of mevalonate pathway dysfunctions and isoprenoid deficiency and suggests that targeting isoprenoid deficiency may offer a strategy to modulate disease-specific changes and inflammation in HIDS. Funding Source 1) Washington University Institute of Clinical and Transitional Sciences; 2) Longer Life Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-05-02 | NK cell dysfunction and interferon-γ production underlie autoinflammation in mevalonate kinase deficiency.
Prenylopathies such as mevalonate kinase deficiency (MKD) are an emerging family of monogenic autoinflammatory diseases with an underlying defect in isoprenoid lipid synthesis and protein prenylation. The mechanisms linking defective protein prenylation to systemic inflammation remain unclear. We revealed that mice and humans with MKD had significant decreases in the frequency of mature natural killer (NK) cells, impaired trafficking of cytolytic granules, reduced cytotoxic activity, and increased production of the cytokine interferon γ (IFN-γ). Mice with MKD failed to clear murine cytomegalovirus (MCMV) infections and had elevated serum IFN-γ and inflammatory pathology, likely the result of decreased and dysregulated cytotoxic cells. Finally, we describe the beneficial effect of cytokine signaling blockade with a Janus kinase (JAK) inhibitor in an infant with severe MKD. Together, these findings reveal a fundamental role for dysregulated cytotoxic cells and IFN-γ production in MKD and likely other prenylopathies. Importantly, this work provides a rationale for the use of JAK inhibitors in the treatment of MKD.
2026-03-12 | Pyrin inflammasome activation triggers an IL-18-driven IFN-γ response in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to a lowering of the threshold for pyrin inflammasome activation. A cellular model of MKD was established to discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and IFN-γ signaling. Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harboring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses after stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived peripheral blood mononuclear cells were performed to validate in vitro findings. MVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD peripheral blood mononuclear cells hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and natural killer cells were characterized by enhanced IL-18-driven IFN-γ production. Elevated IFN-γ and IL-18 binding protein levels in MKD plasma as well as transcriptomic data of MKD peripheral blood mononuclear cells further confirmed the presence of an IFN-γ signature in MKD. A pyrin inflammasome-driven IL-18/IFN-γ axis is a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.
2024-07-18 | Geranylgeraniol supplementation leads to an improvement in inflammatory parameters and reversal of the disease specific protein signature in patients with hyper-IgD syndrome
Abstract Mevalonate kinase (MVK) deficiency, a rare autosomal recessive disease, significantly impacts metabolism and immunity, leading to mevalonic aciduria in severe cases and hyper-IgD syndrome (HIDS) in partial deficiency. These conditions arise due to disruptions in the mevalonate pathway, which is essential metabolic pathway responsible for the synthesis of non-sterol isoprenoids and other molecules. The resulting metabolic blockade triggers autoinflammatory responses, primarily due to deficient isoprenoid intermediates such as geranylgeranyl pyrophosphate (GGPP). This first reported pilot study evaluates the safety and efficacy of dietary geranylgeraniol supplementation (GG) in three patients with HIDS. Over three months, GG supplementation showed no liver toxicity and did not alter lipid profiles. Although GG did not rise the plasma levels of GGPP, the plasma proteomics showed significant changes induced by GG. Proteomic analysis further revealed that GG supplementation can reverse some of the features of HIDS-specific plasma protein signature, highlighting its potential to modulate inflammation and protein prenylation pathways. These findings suggest that GG supplementation could be a promising metabolic intervention to mitigate inflammation in HIDS, warranting further, more targeted investigation in larger clinical trials.
2023-12-25 | Recent Insights in Pyrin Inflammasome Activation: Identifying Potential Novel Therapeutic Approaches in Pyrin-Associated Autoinflammatory Syndromes.
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.
proteins
2026-07-30 | Novel compound heterozygous MVK variants cause early-onset mevalonic aciduria in a Chinese infant.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder caused by mevalonate kinase (MVK) gene mutations, with phenotypes ranging from mild hyper-IgD syndrome (HIDS) to severe mevalonic aciduria (MA). Here, we report a 7-month-old Chinese male infant presenting with neonatal-onset MA. The proband presented with growth retardation, intractable diarrhea, recurrent fever, generalized rash, progressive hepatosplenomegaly, and persistent systemic inflammation. Laboratory tests revealed marked leukocytosis, elevated C-reactive protein, hyper-IgD and increased urinary mevalonic acid. Whole-exome sequencing identified two novel compound heterozygous MVK variants: c.64G > A (p.Val22Met) and c.1063G > C (p.Ala355Pro). Both variants were absent in global population databases. In silico analyses, including cross-species conservation, structural modeling, and pathogenicity prediction, confirmed significant structural perturbations. The patient achieved sustained remission with canakinumab. This is the first worldwide report of the MVK c.1063G > C variant causing severe MA, expanding the MVK mutational spectrum in Chinese populations.
2026-03-16 | Phenotype-genotype correlation and treatment outcomes in mevalonate kinase deficiency: A large Turkish cohort.
This study aimed to comprehensively assess the clinical spectrum, genotype-phenotype correlations, and treatment responses in a large cohort of Turkish pediatric patients with genetically confirmed mevalonate kinase deficiency (MKD). This retrospective, multicenter cohort study included 107 genetically confirmed MKD patients followed between 2010 and 2024 across 25 pediatric rheumatology centers in Turkey. Demographic characteristics, clinical features, laboratory parameters, genotypic data, and treatment outcomes were recorded and analyzed. Of the 107 patients, 48 (44.9%) were female. The median age at symptom onset was 7 (3-24) months, and the median age at diagnosis was 71 (27-115) months. The most frequent clinical features included fever in 105 (98.1%) patients, abdominal pain in 92 (86%), arthralgia in 74 (69.2%), diarrhea in 73 (68.2%), lymphadenopathy in 64 (59.8%), vomiting in 52 (48.6%), and oral aphthae in 50 (46.7%). Less frequent findings included pancreatitis in 2 (1.9%), genital aphthae in 2 (1.9%), neurosensory hearing loss in 3 (2.8%), and hidradenitis suppurativa in 1 (0.9%) patients. Amyloidosis and MAS were reported in 4 (3.7%) and 4 (3.7%) patients, respectively. Among the 107 patients, 45 (42%) had a homozygous V377I mutation (Group 1), 28 (26.2%) had a compound heterozygous mutation involving V377I and a non-V377I allele (Group 2), 15 (14%) had two non-V377I alleles (Group 3), and 19 (17.8%) had a single heterozygous mevalonate kinase gene mutation (Group 4). No statistically significant differences were observed between the groups in demographic features, attack characteristics, clinical manifestations, laboratory findings, or treatment outcomes. IL-1 antagonists were the primary therapeutic agents. Anakinra yielded no clinical response in 14 (13.1%), partial response in 17 (15.9%), and complete response in 13 (12.1%) patients. Canakinumab treatment resulted in no response in 2 (1.9%) patients, partial response in 34 (31.8%), and complete response in 56 (52.3%). The variability in clinical manifestations and treatment responses across genotypes highlights the complexity and heterogeneity of MKD, suggesting that factors beyond genotype may influence disease expression and therapeutic outcomes. We also confirm that heterozygous individuals may express the disease phenotype.
2026-02-04 | A Diagnostic Challenge: Recurrent Uveitis Leading to the Diagnosis of Hyper-IgD Syndrome in a 28-Year-Old Patient.
Mevalonate Kinase Deficiency (MKD), which includes the clinical phenotype known as Hyperim munoglobulin D Syndrome (HIDS), is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene. While typically characterized by childhood-onset recurrent febrile episodes and systemic symptoms like lymphadenopathy and abdominal pain, ocular involvement is usually limited to conjunctivitis. Uveitis is a rare manifestation, often associated with more severe forms of the disease. This report describes a 28-year-old male who presented with bilateral, recurrent anterior uveitis and vitritis. Although the patient reported self-limiting febrile episodes during childhood, the presentation of ocular inflammation in adulthood as the primary symptom posed a significant diagnostic challenge. Initial treatment with topical and systemic corticosteroids provided only temporary relief, with the patient developing cystoid macular edema and further recurrences. A multidisciplinary evaluation and genetic testing confirmed the diagnosis of HIDS. Following the diagnosis, the patient was started on targeted anti-IL-1 therapy (anakinra or canakinumab). This intervention led to a significant improvement in symptoms and was essential in halting recurrences and preventing chronic ocular damage. Recurrent uveitis, even in adult patients, should prompt the investigation of rare autoinflammatory syndromes. A timely genetic diagnosis and a multidisciplinary approach are crucial for initiating targeted biological treatments, which offer a superior visual and systemic prognosis compared to conventional therapies.
2026-02-01 | Targeting cytokine pathways: the role of biologics in autoinflammatory disorders.
Autoinflammatory diseases are inherited disorders of innate immunity, broadly classified into inflammasomopathies, interferonopathies, and complement-mediated disorders. They are characterized by dysregulated cytokine signaling - particularly IL-1, IL-6, TNF, type I interferon, and the JAK-STAT pathway-and are increasingly managed with molecular targeted therapies. Prototypical entities include familial Mediterranean fever (FMF), TNF receptor - associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndromes (CAPS). Other conditions - notably mevalonate kinase deficiency (MKD/HIDS), deficiency of adenosine deaminase 2 (DADA2), haploinsufficiency of A20 (HA20), OTULIN-related autoinflammatory syndromes, and proteasome-associated autoinflammatory syndromes (PRAAS) - are now recognized as biologic-responsive diseases. This review summarizes molecular mechanisms and therapeutic strategies, focusing on IL-1 blockade with anakinra, canakinumab, and rilonacept, as well as IL-6 and TNF inhibitors, integrating evidence from clinical trials and real-world studies. IL-1 inhibition has transformed the management of inflammasome-mediated diseases, enabling glucocorticoid-free remission and reducing amyloidosis risk. TNF inhibitors remain standard for vasculopathic disorders such as DADA2, while IL-6 blockade and JAK inhibitors are options in selected refractory cases. The recognition of novel syndromes, including HA20, OTULIN deficiency, and PRAAS, has broadened the therapeutic landscape, and next-generation biologics may further enable personalized treatment.
2025-12-22 | Skin involvement in classic monogenic autoinflammatory diseases. Part 1
Autoinflammatory diseases (AIDs) represent a heterogeneous group of conditions pathogenetically associated with dysregulation of innate immunity and clinically characterized by recurrent episodes of sterile inflammation in affected organs in the absence of infection, allergy, and high titers of circulating autoantibodies or autoreactive T cells. The overwhelming majority of monogenic AIDs (mAIDs) are accompanied by skin rashes, the type of which is determined by the specific disease and, to some extent, by differing pathogenetic mechanisms. The first part of the article presents the cutaneous characteristics of the most common mAIDs: Familial Mediterranean fever (FMF), cryopyrinassociated periodic syndromes (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodic syndrome with hyperimmunoglobulinemia D / mevalonate kinase deficiency (HIDS/MKD). Skin involvement in these diseases reflects systemic inflammation associated with hyperproduction of the key pro-inflammatory cytokine interleukin (IL)-1β. In other AIDs, symptoms mainly depend on increased levels of cytokines such as IL-18, IL-36, etc. (NLRC4-associated autoinflammatory disease; deficiency of the IL-36 receptor antagonist – DITRA), as well as activation of interferon signaling pathways (interferonopathies). Different pathogenetic mechanisms determine the diversity of clinical phenotypes, including cutaneous manifestations. Knowledge of these features helps establishing a correct diagnosis, obtaining genetic confirmation (without which accurate identification of these rare conditions is impossible today) and selecting appropriate therapy. Pathological examination plays a special auxiliary role and should be used in diagnostically challenging situations.
cell therapies
2022-08-02 | The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency.
Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment. This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office. We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications. In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy.
2021-01-07 | Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency
Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first.Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs.Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
2015-03-05 | Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype that may be expressed as a spectrum of disease phenotypes, from those with prevailing autoinflammatory syndrome and variable response to anti-inflammatory therapies, to mevalonic aciduria, which is associated with dysmorphic features, severe neurologic involvement, and the worst prognosis. We describe a boy, aged 2 years, 10 months, with severe phenotype of mevalonate kinase deficiency who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical unrelated cord blood because his condition had failed to improve with antiinflammatory treatment as first-line therapy and an anticytokine drug as second-line therapy. The child had a sustained remission of febrile attacks and inflammation after transplant, and during a 5-year follow-up period, psychomotor and neurologic development were normal, without signs of underlying disease or late transplant-related effects. This case confirms that allogeneic HSCT is a safe and effective cure for patients affected by MKD in whom anticytokine drugs alone are insufficient for the management of autoinflammatory syndrome and for the unfavorable outcome of the disease.
2006-07-11 | Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency
Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene resulting in deficient activity of mevalonate kinase (MK). Depending on the clinical severity, MKD may present as hyper-IgD and periodic fever syndrome (HIDS) or the more severe mevalonic aciduria (MA). We analyzed the MVK gene in 57 patients with MKD and found 39 different mutations including 15 novel mutations, expanding the total mutational spectrum of MKD to 63 mutations. To get more insight into the genotype–phenotype correlation in MKD, we studied the effect of selected missense mutations on MK protein stability and activity in various patient fibroblast cell lines. All MKD cell lines showed markedly decreased MK activities that correlated well with the clinical severity and, for most of the cell lines, with the amount of MK protein. When fibroblasts of MKD patients were cultured under conditions known to promote a more controlled protein folding, all cell lines of patients with the HIDS phenotype and few cell lines of patients with the MA phenotype showed an increase in the residual MK activity. This increase in enzyme activity correlates well with an increase in the MK protein levels in these cell lines, indicating that most of the mutations in MKD affect stability and/or folding of the MK protein rather than affecting the catalytic properties of the enzyme. The finding that the residual activity in MKD can be manipulated by environmental conditions may offer therapeutic options to alleviate or prevent the clinical symptoms associated with MKD. Hum Mutat 27(8), 796–802, 2006. © 2006 Wiley-Liss, Inc.
antibodies
2026-08-13 | Autoinflammatory Syndromes of Hidradenitis Suppurativa: Updates in Clinical Features, Emerging Associations, and Management.
To summarize and critically evaluate recent literature on autoinflammatory syndromes of hidradenitis suppurativa (HS). HS-associated autoinflammatory syndromes traditionally encompass pyoderma gangrenosum (PG), acne, and HS (PASH); pyogenic arthritis, PG, acne, and HS (PAPASH); psoriatic arthritis, PG acne, and HS (PsAPASH); and PG, acne, HS and ankylosing spondylitis (PASS). However, this spectrum continues to expand, with recent literature considering the inclusion of additional autoinflammatory diseases such as HS associated with SAPHO, including synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO); and Hyperimmunoglobulin D Syndrome (HIDS). HS-associated autoinflammatory syndromes are thought to be driven by dysregulation of the innate immune system and the subsequent overexpression of key inflammatory cytokines such as IL-1, and targeted IL-1 therapies have demonstrated particularly brisk and efficacious response. Multiple genes related to follicular keratinization or inflammatory regulation have been implicated, and sequencing methods such as whole-exome sequencing and variant enrichment analysis continue to identify novel genetic variants and are being used to further elucidate genotype-phenotype correlations. HS-associated autoinflammatory syndromes are an evolving spectrum of rare, severe, diseases in which HS coexists with other autoinflammatory conditions, most commonly PASH and related syndromes. They are driven by innate immune dysregulation and pathogenic genetic variants, with whole-exome sequencing aiding diagnosis and genotype-phenotype correlation. Management is often challenging and highly individualized, with targeted biologic therapies such as IL-1 inhibitors showing the most consistent and rapid clinical benefit.
2026-05-22 | Effective interleukin-6 inhibition in a pediatric patient with mevalonate kinase deficiency and chronic nonbacterial osteomyelitis-like bone lesions under interleukin-1 blockade.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease. Chronic nonbacterial osteomyelitis (CNO) represents another autoinflammatory disorder characterized by sterile bone inflammation. Although musculoskeletal pain is common in MKD, CNO-like bone lesions have rarely been described. Tocilizumab has been used separately in MKD / hyper-IgD syndrome (HIDS) and in CNO; however, pediatric cases showing both conditions together and responding completely to IL-6 blockade have not been previously reported. We present a 16-year-old boy born to consanguineous parents who experienced early-onset recurrent fever episodes with abdominal pain, maculopapular rash, oral ulcers, and conjunctival injection. He was initially misdiagnosed with FMF and IgA vasculitis and treated with colchicine with partial improvement. Persistent systemic inflammation prompted referral to our tertiary center at age 9. A periodic fever gene panel revealed a homozygous MVK p.V377I mutation, confirming MKD. Anakinra therapy was initiated. Although no attacks occurred during the first month, flares characterized by fever, abdominal pain, rash, and elevated acute-phase reactants recurred in the second and third months, reflecting a partial response. Consequently, treatment was switched to canakinumab. Toward the end of the second year of IL-1 blockade, attack frequency increased to once every three months, and at age 12 he developed diffuse musculoskeletal pain. Whole-body magnetic resonance imaging demonstrated multifocal metaphyseal bone marrow edema compatible with CNO-like lesions. Sulfasalazine was added but discontinued after drug-induced pancreatitis. Given persistent systemic inflammation and inadequate response to IL-1 inhibitors, canakinumab was replaced with weekly subcutaneous tocilizumab, resulting in rapid improvement in bone pain and systemic inflammation. Since the third month of tocilizumab therapy, he has remained clinically stable with normalized inflammatory markers and only a single mild flare over the last year. This case highlights the potential role of IL-6 inhibition in complicated MKD presenting with autoinflammatory bone disease refractory to standard therapies.
2026-02-20 | A nephritic puzzle: C3-dominant glomerulonephritis as a sentinel of hidden autoinflammatory disease.
Membranoproliferative glomerulonephritis (MPGN) is among the most challenging glomerulonephritides to diagnose and manage, given its clinico-immunopathologic heterogeneity. Although recent advances have introduced new therapies for complement-mediated and immune-complex MPGN, a substantial subset of cases remains poorly understood and lacks effective treatment. We report a pediatric case of biopsy-confirmed C3-dominant MPGN without evidence of complement dysregulation, with disease flares triggered by febrile episodes. Genetic testing identified underlying hyper-IgD syndrome (HIDS), a rare autoinflammatory disorder characterized by recurrent fevers and immune dysregulation. The patient's MPGN was refractory to conventional immunosuppressive therapy but achieved remission with IL-1β blockade that targets HIDS. This case highlights the importance of considering alternative etiologies-including autoinflammatory diseases-in patients with MPGN when complement dysregulation is not evident.
2025-10-20 | Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke-characterization of a novel genetic variant.
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.
2025-08-18 | Atypical cutaneous manifestations in hyperimmunoglobulin D syndrome: A case report
Hyperimmunoglobulin D syndrome (HIDS) is a rare autosomal recessive autoinflammatory disorder caused by mutations in the mevalonate kinase (MVK)gene. It is characterized by recurrent fever episodes, abdominal pain, elevated serum IgD levels, and systemic inflammation. We report a 5-year-old boy presenting with recurrent fever, abdominal pain, diarrhea, and hyperpigmented skin lesions. Physical examination revealed abdominal distension and multiple café-au-lait like spots on the lower extremities, with no lymphadenopathy or organomegaly. Whole-exome sequencing revealed a homozygous missense pathogenic variant (c.1129G>A; p.Val377Ile) in MVK gene. Abdominal CT revealed colonic wall thickening with mucosal hyperenhancement. However, the lower GI endoscopy was unremarkable. Skin biopsy was consistent with café-au-lait spots. Despite the inadequate response to colchicine and anakinra, the patient showed significant clinical improvement with canakinumab. This case underscores the diagnostic complexity of HIDS and suggests a potential novel association with café-au-lait macules. Early genetic testing is crucial for timely diagnosis and targeted therapy. • This case describes a rare presentation of Hyper IgD Syndrome (HIDS) with persistent café-au-lait–like macules. • The patient exhibited gastrointestinal involvement with poor response to colchicine and anakinra, improved on canakinumab. • This case expands the clinical spectrum of HIDS and highlights the importance of early genetic testing.
other
2025-07-03 | Treatment advances in mevalonate kinase deficiency: A comprehensive review
Mevalonate kinase deficiency (MKD) is a rare auto-inflammatory disease caused by mutations in the mevalonate kinase gene. This leads to problems with isoprenoid production and cell function. Individuals with MKD usually experience repeated fever episodes, along with stomach issues, mouth sores, swollen neck lymph nodes, and skin rashes. In addition, the severity of MKD varies markedly among individuals. The most severe and rarest form of MKD is called mevalonic aciduria, while the most typical type is referred to as hyperimmunoglobulinemia-D syndrome. Based on new research and clinical progress, this review explores more treatment options for MKD.
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Drug Discovery Landscape
3 orphan drug designations for Hyperimmunoglobulinemia D with periodic fever, including 1 approved therapy.
3 orphan drug designations for Hyperimmunoglobulinemia D with periodic fever, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
canakinumab [ILARIS] | antibodies | FDA | 2013-12-05 | 2016-09-23 | Novartis Pharmaceuticals Corporation |
Lactic acid | — | FDA | 1999-06-29 | — | Frontier Pharmaceutical, Inc. |
Thalidomide | — | FDA | 1995-05-15 | — | Andrulis Research Corporation |
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