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:
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.
2026-07-30 | 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.
2026-07-28 | 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)
2026-05-22 | 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.
2026-05-02 | 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.
2026-08-13 | 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.
2026-07-30 | 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.
2026-07-28 | 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)
2026-05-22 | 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.
2026-05-02 | 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.
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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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