Periodic Fever Syndrome and Developmental Delay

  • Per Wekell
  • Stefan Berg
  • Anders Fasth


The key to diagnosis of mevalonate kinase deficiency, hyper-IgD syndrome (MKD/HIDS) is recurrent fever attacks of 4–6 days, associated with aphthous stomatitis, enlargement of lymph nodes, splenomegaly, abdominal pain, diarrhea, and rash

MKD is a rare autosomal recessive disease caused by mutations in the MVK gene leading to reduced mevalonate kinase activity

Extremely low MVK activity leads to mevalonic aciduria (complete MKD or MVA) associated with developmental delay, progressive ataxia and decreased life expectancy in addition to febrile attacks

Treatment depends on the severity of the condition and includes:

 on demand treatment with glucocorticoids

 on demand or continuous treatment with IL-1 blockade

 allogeneic hematopoietic stem cell transplantation in mevalonic aciduria

In partial MKD/HIDS, episodes often decrease in severity with age


Mevalonate kinase deficiency Hyper-IgD syndrome Mevalonic aciduria 


  1. 1.
    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. 1994;73(3):133–44.CrossRefGoogle Scholar
  2. 2.
    Ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M, Cattalini M, Anton J, Modesto C, Quartier P, Hoppenreijs E, Martino S, Insalaco A, Cantarini L, Lepore L, Alessio M, Calvo Penades I, Boros C, Consolini R, Rigante D, Russo R, Pachlopnik Schmid J, Lane T, Martini A, Ruperto N, Frenkel J, Gattorno M, Paediatric Rheumatology International Trials O, Eurofever P. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever registry. Arthrit Rheumatol (Hoboken, NJ). 2016;68(11):2795–805.CrossRefGoogle Scholar
  3. 3.
    van der Burgh R, Ter Haar NM, Boes ML, Frenkel J. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clinical immunology (Orlando, Fla). 2013;147(3):197–206.CrossRefGoogle Scholar
  4. 4.
    Hoffman G. Mevalonic aciduria. Hepatology. 1988;8(1):197.PubMedGoogle Scholar
  5. 5.
    Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis. 2006;1:13.CrossRefGoogle Scholar
  6. 6.
    Simon A, Kremer HP, Wevers RA, Scheffer H, De Jong JG, Van Der Meer JW, Drenth JP. Mevalonate kinase deficiency: evidence for a phenotypic continuum. Neurology. 2004;62(6):994–7.CrossRefGoogle Scholar
  7. 7.
    Jeyaratnam J, Ter Haar NM, de Sain-van der Velden MG, Waterham HR, van Gijn ME, Frenkel J. Diagnostic value of urinary mevalonic acid excretion in patients with a clinical suspicion of mevalonate kinase deficiency (MKD). JIMD Rep. 2016;27:33–8.CrossRefGoogle Scholar
  8. 8.
    Stoffels M, Simon A. Hyper-IgD syndrome or mevalonate kinase deficiency. Curr Opin Rheumatol. 2011;23(5):419–23.CrossRefGoogle Scholar
  9. 9.
    Ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, Kone-Paut I, Cantarini L, Insalaco A, Neven B, Hofer M, Rigante D, Al-Mayouf S, Touitou I, Gallizzi R, Papadopoulou-Alataki E, Martino S, Kuemmerle-Deschner J, Obici L, Iagaru N, Simon A, Nielsen S, Martini A, Ruperto N, Gattorno M, Frenkel J. Treatment of autoinflammatory diseases: results from the Eurofever registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.CrossRefGoogle Scholar
  10. 10.
    Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, Richer O, Farber CM, Fischbach M, Hentgen V, Jego P, Laroche C, Neven B, Lequerre T, Mathian A, Pellier I, Touitou I, Rabier D, Prieur AM, Cuisset L, Quartier P, Sofremip C. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 2011;128(1):e152–9.CrossRefGoogle Scholar
  11. 11.
    Neven B, Valayannopoulos V, Quartier P, Blanche S, Prieur AM, Debre M, Rolland MO, Rabier D, Cuisset L, Cavazzana-Calvo M, de Lonlay P, Fischer A. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med. 2007;356(26):2700–3.CrossRefGoogle Scholar
  12. 12.
    Frenkel J, Houten SM, Waterham HR, Wanders RJ, Rijkers GT, Duran M, Kuijpers TW, van Luijk W, Poll-The BT, Kuis W. Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D. Rheumatology (Oxford). 2001;40(5):579–84.CrossRefGoogle Scholar
  13. 13.
    van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, Simon A, International HSG. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine. 2008;87(6):301–10.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Per Wekell
    • 1
    • 2
  • Stefan Berg
    • 2
    • 3
  • Anders Fasth
    • 2
    • 3
  1. 1.Department of PediatricsNU Hospital GroupUddevallaSweden
  2. 2.Department of PediatricsSahlgrenska Academy, University of GothenburgGothenburgSweden
  3. 3.Department of Rheumatology and ImmunologyQueen Silvia Children’s HospitalGothenburgSweden

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