Hyper-IgD syndrome is a rare autosomal recessive disorder in which recurring attacks of chills and fever begin during the first year of life. Episodes usually last 4 to 6 days and may be triggered by physiologic stress, such as vaccination or minor trauma. Diagnosis is mainly clinical but includes serum IgD level and possibly genetic testing. Attacks can be prevented with interleukin-1 inhibitors (anakinra or canakinumab). Symptoms can be treated with nonsteroidal anti-inflammatory drugs, glucocorticoids, and anakinra.
Hyper-IgD syndrome is caused by:
Mutations in the MVK gene coding mevalonate kinase, an enzyme important for cholesterol synthesis (1, 2)
Reduction in the synthesis of anti-inflammatory isoprenylated proteins may trigger dysregulated innate immune responses and excessive production of pro-inflammatory cytokines, particularly interleukin (IL)-1 beta but also IL-6 and tumor necrosis factor (TNF).
Hyper-IgD syndrome clusters in children of Dutch, French, and other Northern European ancestry.
General references
1. Touitou I. Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review. Genes Dis. 2021;9(4):1000-1007. doi:10.1016/j.gendis.2021.05.002
2. Drenth JP, Cuisset L, Grateau G, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999;22(2):178-181. doi:10.1038/9696
Symptoms and Signs of Hyper-IgD Syndrome
In addition to chills and fever, symptoms of hyper-IgD syndrome may include abdominal pain, vomiting or diarrhea, headache, and arthralgias.
Signs of hyper-IgD syndrome include cervical lymphadenopathy, splenomegaly, arthritis, skin lesions (maculopapular rash, petechiae, or purpura), and orogenital aphthous ulcers.
Diagnosis of Hyper-IgD Syndrome
History and physical examination
Serum IgD levels
Sometimes genetic testing
Diagnosis of hyper-IgD syndrome is based on history, examination, and a serum IgD level of > 100 units/L; however, up to 20% of patients have normal serum IgD levels (1). Nonspecific abnormalities include leukocytosis and elevated acute-phase reactants during fever; elevated urinary mevalonic acid during attacks helps confirm the diagnosis.
Genetic testing is available but is negative in approximately 25% of patients (2).
Diagnosis references
1. Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019;78(8):1025–1032. doi:10.1136/annrheumdis-2019-215048
2. Simon A, Cuisset L, Vincent MF, et al. Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med. 2001;135(5):338-343. doi:10.7326/0003-4819-135-5-200109040-00010
Treatment of Hyper-IgD Syndrome
For preventing attacks, canakinumab or anakinra
For symptoms, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and anakinra
Canakinumab every 4 weeks is considered first-line therapy and is proved to prevent attacks (Canakinumab every 4 weeks is considered first-line therapy and is proved to prevent attacks (1). Anakinra is an alternative but requires daily dosing. Patients can expect to have recurrent bouts of fever throughout their life, although episodes tend to become less frequent after adolescence.). Anakinra is an alternative but requires daily dosing. Patients can expect to have recurrent bouts of fever throughout their life, although episodes tend to become less frequent after adolescence.
NSAIDs and glucocorticoids may help relieve symptoms during attacks. On-demand treatment of symptoms with anakinra has also been used successfully (2).
Treatment references
1. De Benedetti F, Gattorno M, Anton J, et al: Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378(20):1908–1919, 2018. doi: 10.1056/NEJMoa1706314
2. Ashari KA, Hausmann JS, Dedeoglu F: Update on autoinflammatory diseases. Curr Opin Rheumatol 35(5):285-292, 2023. doi: 10.1097/BOR.0000000000000953
Drugs Mentioned In This Article
