Mevalonate Kinase Deficiency (MKD)/Hyperimmunoglobulin D Syndrome (HIDS)

  • Olga PetrynaEmail author
  • Neha Purat


Mevalonate kinase deficiency (MKD) and its milder spectrum hyper IgD syndrome (HIDS) is a rare monogenic disease with multiple organ manifestations. HIDS patients most commonly present with recurrent febrile attacks, gastrointestinal symptoms (abdominal pain, nausea, and vomiting), inflammatory arthritis, and arthralgia as well as mucocutaneous manifestations. Disease usually manifests in childhood, although adult cases of HIDS have been described in literature.

The most common mutation in MKD is pV377I (G1129A) and is primarily observed among heterozygous individuals with HIDS. Other genetic mutations have also been described in literature, but not all of them seem to correlate with clinical manifestations.

Increased levels of immunoglobulin D (IgD) as well as high levels of IL-1, IL-6, and tumor necrosis factor-α (TNFα) are usually observed in majority of the patients during febrile attacks.

New treatment modalities have been developed based on recent advances in pathogenesis of MKD/HIDS. Stemming from the proposed mechanism of inflammasome activation, IL-1 pathway appears to be the most effective therapeutic target to date.

Early diagnosis and treatment are crucial in MKD/HIDS as it can prevent irreversible organ damage and improve quality of life of patients, whose daily activities, education, and employment are often affected by frequent febrile attacks.


Hyper IgD syndrome Mevalonate kinase deficiency Mevalonic aciduria 


  1. 1.
    Rowe DS, Fahey JL. A New Class of Human Immunoglobulins. I. A Unique Myeloma Protein. J Exp Med. 1965;121:171–84.CrossRefGoogle Scholar
  2. 2.
    Drenth JP, et al. Location of the gene causing hyperimmunoglobulinemia D and periodic fever syndrome differs from that for familial Mediterranean fever. International Hyper-IgD Study Group. Hum Genet. 1994;94(6):616–20.CrossRefGoogle Scholar
  3. 3.
    Church LD, et al. Hereditary auto-inflammatory disorders and biologics. Springer Semin Immunopathol. 2006;27(4):494–508.CrossRefGoogle Scholar
  4. 4.
    Durel CA, et al. Observational study of a French and Belgian multicenter cohort of 23 patients diagnosed in adulthood with mevalonate kinase deficiency. Medicine (Baltimore). 2016;95(11):e3027.CrossRefGoogle Scholar
  5. 5.
    Toplak N, et al. Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey. Pediatr Rheumatol Online J. 2010;8:29.CrossRefGoogle Scholar
  6. 6.
    Stoffels M, Simon A. Hyper-IgD syndrome or mevalonate kinase deficiency. Curr Opin Rheumatol. 2011;23(5):419–23.CrossRefGoogle Scholar
  7. 7.
    Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med. 2001;345(24):1748–57.CrossRefGoogle Scholar
  8. 8.
    Caso F, et al. Working the endless puzzle of hereditary autoinflammatory disorders. Mod Rheumatol. 2014;24(3):381–9.CrossRefGoogle Scholar
  9. 9.
    Simon A, et al. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am J Med. 2003;114(2):148–52.CrossRefGoogle Scholar
  10. 10.
    Houten SM, et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003;11(2):196–200.CrossRefGoogle Scholar
  11. 11.
    Hospach T, et al. Pseudodominant inheritance of the hyperimmunoglobulinemia D with periodic fever syndrome in a mother and her two monozygotic twins. Arthritis Rheum. 2005;52(11):3606–10.CrossRefGoogle Scholar
  12. 12.
    van der Hilst JC, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87(6):301–10.CrossRefGoogle Scholar
  13. 13.
    Ter Haar NM, et al. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever registry. Arthritis Rheumatol. 2016;68(11):2795–805.CrossRefGoogle Scholar
  14. 14.
    Edwards PA, Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem. 1999;68:157–85.CrossRefGoogle Scholar
  15. 15.
    Nagashima T, et al. Apoptosis of rheumatoid synovial cells by statins through the blocking of protein geranylgeranylation: a potential therapeutic approach to rheumatoid arthritis. Arthritis Rheum. 2006;54(2):579–86.CrossRefGoogle Scholar
  16. 16.
    Simon A, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther. 2004;75(5):476–83.CrossRefGoogle Scholar
  17. 17.
    Henneman L, et al. Compromised geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency. J Inherit Metab Dis. 2010;33(5):625–32.CrossRefGoogle Scholar
  18. 18.
    Kostjukovits S, et al. Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. Eur J Pediatr. 2015;174(6):707–14.CrossRefGoogle Scholar
  19. 19.
    Stoffels M, et al. TLR2/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome. Rheumatology (Oxford). 2015;54(2):363–8.CrossRefGoogle Scholar
  20. 20.
    Bader-Meunier B, et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 2011;128(1):e152–9.CrossRefGoogle Scholar
  21. 21.
    Balgobind B, Wittebol-Post D, Frenkel J. Retinitis pigmentosa in mevalonate kinase deficiency. J Inherit Metab Dis. 2005;28(6):1143–5.CrossRefGoogle Scholar
  22. 22.
    Obici L, et al. First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 2004;50(9):2966–9.CrossRefGoogle Scholar
  23. 23.
    Damian LO, et al. Ultrasonographic findings in hyperimmunoglobulin D syndrome: a case report. Med Ultrason. 2017;19(2):224–7.CrossRefGoogle Scholar
  24. 24.
    Tsimaratos M, et al. Crescentic glomerulonephritis in hyper IgD syndrome. Pediatr Nephrol. 1999;13(2):132–4.CrossRefGoogle Scholar
  25. 25.
    de Hullu JA, et al. Hyper-IgD syndrome and pregnancy. Eur J Obstet Gynecol Reprod Biol. 1996;68(1–2):223–5.CrossRefGoogle Scholar
  26. 26.
    Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore). 1994;73(3):133–44.CrossRefGoogle Scholar
  27. 27.
    Houten SM, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22(2):175–7.CrossRefGoogle Scholar
  28. 28.
    Schneiders MS, et al. Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency. Arthritis Rheum. 2006;54(7):2306–13.CrossRefGoogle Scholar
  29. 29.
    Ter Haar N, et al. Treatment of autoinflammatory diseases: results from the Eurofever registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.CrossRefGoogle Scholar
  30. 30.
    Ozen S, Demir S. Monogenic periodic fever syndromes: treatment options for the pediatric patient. Paediatr Drugs. 2017;19(4):303–11.CrossRefGoogle Scholar
  31. 31.
    Bodar EJ, et al. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med. 2005;63(7):260–4.PubMedGoogle Scholar
  32. 32.
    Arostegui JI, et al. Open-label, phase II study to assess the efficacy and safety of Canakinumab treatment in active Hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheumatol. 2017;69(8):1679–88.CrossRefGoogle Scholar
  33. 33.
    Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014;20(2):103–5.CrossRefGoogle Scholar
  34. 34.
    Musters A, et al. Anti-interleukin 6 receptor therapy for hyper-IgD syndrome. BMJ Case Rep. 2015;2015. ISSN 1757-790X.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.NYU School of Medicine, Rheumatology Division/Department of Internal MedicineNew YorkUSA
  2. 2.New York Presbyterian Hospital, Department of Internal MedicineBrooklynUSA

Personalised recommendations