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
161 drug discovery papers related to Hyperimmunoglobulinemia D with periodic fever, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
161 drug discovery papers related to Hyperimmunoglobulinemia D with periodic fever, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-03-16 | 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.
2026-03-12 | 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.
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.
2026-03-16 | 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.
2026-03-12 | 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.
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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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