Infant-onset mevalonate kinase deficiency with a previously unreported MVK c.827 A > G (p.Glu276Gly) variant presenting as suspected incomplete kawasaki disease with marked hyperinflammation: clinical response to firsekibart and systematic evidence synthesis
- 1Anhui Province Children’s Hospital, Hefei, China
- 2The University of Sydney, Sydney, Australia
Abstract
Background: Mevalonate kinase deficiency (MKD) is an autosomal-recessive autoinflammatory disorder spanning a clinical continuum from the hyperimmunoglobulin-D syndrome/recurrent-fever phenotype to severe mevalonic aciduria. In infants, the first attacks can resemble infection, incomplete Kawasaki disease, or other forms of systemic hyperinflammation. Comparative evidence to guide treatment choice and dose adjustment remains limited.
Case presentation and methods: We describe a female infant with recurrent high fever and a generalized erythematous rash beginning at 1 month and 23 days of age. She was initially treated for suspected incomplete Kawasaki disease because fever, rash, leukocytosis, elevated C-reactive protein, and qualitatively reported mild coronary-artery dilatation were present; segment-specific coronary measurements and z scores were not available. Ferritin 1101.72 ng/mL, soluble CD25 34,200 pg/mL, reduced natural-killer-cell activity, cervical lymphadenopathy, and mild splenomegaly indicated marked hyperinflammation, but the available data were insufficient to diagnose hemophagocytic lymphohistiocytosis or macrophage activation syndrome. Trio whole-exome sequencing identified MVK c.439G > A (p.Ala147Thr), maternally inherited, and c.827 A > G (p.Glu276Gly), paternally inherited. The second variant was not listed in Infevers and was not identified in ClinVar or the peer-reviewed MKD literature searched on 13 July 2026. It was classified as likely pathogenic by the reporting laboratory, but laboratory-specific ACMG/AMP evidence codes and biochemical confirmation were unavailable. We also updated a systematic review of IL-1-targeted treatment in systemic MKD.
Results: Intravenous immunoglobulin and systemic corticosteroids produced transient improvement. An etanercept biosimilar provided only temporary control. Tocilizumab prolonged attack intervals but was discontinued after likely treatment-associated secondary hypogammaglobulinemia requiring intravenous immunoglobulin and subsequent relapse. Firsekibart (Jin Beixin; Changchun GeneScience Pharmaceutical Co., Ltd., Changchun, China), a fully human IgG4λ monoclonal antibody that selectively neutralizes IL-1β, was then given off-label at 40 mg subcutaneously (approximately 4 mg/kg) every 4 weeks; after the second dose, the interval was extended to 40 days. At the latest documented follow-up, five doses had been given and no typical fever-rash attacks or new treatment-related adverse events had been reported. The original database search identified 876 records and 7 eligible reports; a targeted update added 3 full-text studies, including the RELIANCE registry, for 10 reports in the final descriptive synthesis. Trial, extension, cohort, post-marketing, registry, and case-based evidence consistently supported IL-1 pathway inhibition. Dose escalation, interval modification, and individualized treat-to-target adjustment were frequent across the published reports.
Conclusions: This case supports early MVK testing when recurrent infantile inflammation persists after treatment for suspected incomplete Kawasaki disease. The patient had marked hyperinflammation with several HLH-associated abnormalities, but not enough evidence for a formal HLH/MAS diagnosis. Her response is consistent with the established therapeutic rationale for IL-1 blockade in systemic MKD; however, the c.827 A > G variant requires fuller laboratory documentation, and the firsekibart observation remains a single-patient, short-term, agent-specific experience.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12969-026-01262-z.
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BibTeX
@article{shen2026infantonset,
title = {{Infant-onset mevalonate kinase deficiency with a previously unreported MVK c.827 A > G (p.Glu276Gly) variant presenting as suspected incomplete kawasaki disease with marked hyperinflammation: clinical response to firsekibart and systematic evidence synthesis}},
author = {Yang Shen and Yutong Gao and Jing Shan and Xiaoliang He and Denghuan Chen and Shouwei Hang and Xinrong Wang and Dingyun Chen and Na Li and Daliang Xu},
journal = {Pediatric Rheumatology},
year = {2026},
month = aug,
doi = {10.1186/s12969-026-01262-z},
url = {https://doi.org/10.1186/s12969-026-01262-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Infant-onset mevalonate kinase deficiency with a previously unreported MVK c.827 A > G (p.Glu276Gly) variant presenting as suspected incomplete kawasaki disease with marked hyperinflammation: clinical response to firsekibart and systematic evidence synthesis
AU - Yang Shen
AU - Yutong Gao
AU - Jing Shan
AU - Xiaoliang He
AU - Denghuan Chen
AU - Shouwei Hang
AU - Xinrong Wang
AU - Dingyun Chen
AU - Na Li
AU - Daliang Xu
PY - 2026
DA - 2026/08/08
JO - Pediatric Rheumatology
DO - 10.1186/s12969-026-01262-z
UR - https://doi.org/10.1186/s12969-026-01262-z
AB - Background: Mevalonate kinase deficiency (MKD) is an autosomal-recessive autoinflammatory disorder spanning a clinical continuum from the hyperimmunoglobulin-D syndrome/recurrent-fever phenotype to severe mevalonic aciduria. In infants, the first attacks can resemble infection, incomplete Kawasaki disease, or other forms of systemic hyperinflammation. Comparative evidence to guide treatment choice and dose adjustment remains limited. Case presentation and methods: We describe a female infant with recurrent high fever and a generalized erythematous rash beginning at 1 month and 23 days of age. She was initially treated for suspected incomplete Kawasaki disease because fever, rash, leukocytosis, elevated C-reactive protein, and qualitatively reported mild coronary-artery dilatation were present; segment-specific coronary measurements and z scores were not available. Ferritin 1101.72 ng/mL, soluble CD25 34,200 pg/mL, reduced natural-killer-cell activity, cervical lymphadenopathy, and mild splenomegaly indicated marked hyperinflammation, but the available data were insufficient to diagnose hemophagocytic lymphohistiocytosis or macrophage activation syndrome. Trio whole-exome sequencing identified MVK c.439G > A (p.Ala147Thr), maternally inherited, and c.827 A > G (p.Glu276Gly), paternally inherited. The second variant was not listed in Infevers and was not identified in ClinVar or the peer-reviewed MKD literature searched on 13 July 2026. It was classified as likely pathogenic by the reporting laboratory, but laboratory-specific ACMG/AMP evidence codes and biochemical confirmation were unavailable. We also updated a systematic review of IL-1-targeted treatment in systemic MKD. Results: Intravenous immunoglobulin and systemic corticosteroids produced transient improvement. An etanercept biosimilar provided only temporary control. Tocilizumab prolonged attack intervals but was discontinued after likely treatment-associated secondary hypogammaglobulinemia requiring intravenous immunoglobulin and subsequent relapse. Firsekibart (Jin Beixin; Changchun GeneScience Pharmaceutical Co., Ltd., Changchun, China), a fully human IgG4λ monoclonal antibody that selectively neutralizes IL-1β, was then given off-label at 40 mg subcutaneously (approximately 4 mg/kg) every 4 weeks; after the second dose, the interval was extended to 40 days. At the latest documented follow-up, five doses had been given and no typical fever-rash attacks or new treatment-related adverse events had been reported. The original database search identified 876 records and 7 eligible reports; a targeted update added 3 full-text studies, including the RELIANCE registry, for 10 reports in the final descriptive synthesis. Trial, extension, cohort, post-marketing, registry, and case-based evidence consistently supported IL-1 pathway inhibition. Dose escalation, interval modification, and individualized treat-to-target adjustment were frequent across the published reports. Conclusions: This case supports early MVK testing when recurrent infantile inflammation persists after treatment for suspected incomplete Kawasaki disease. The patient had marked hyperinflammation with several HLH-associated abnormalities, but not enough evidence for a formal HLH/MAS diagnosis. Her response is consistent with the established therapeutic rationale for IL-1 blockade in systemic MKD; however, the c.827 A > G variant requires fuller laboratory documentation, and the firsekibart observation remains a single-patient, short-term, agent-specific experience. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12969-026-01262-z.
SN - 1546-0096
ER -