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, corticosteroids, and anakinra.
Hyper-IgD syndrome clusters in children of Dutch, French, and other Northern European ancestry and is caused by
Mutations in the gene coding mevalonate kinase, an enzyme important for cholesterol synthesis (1)
Reduction in the synthesis of anti-inflammatory isoprenylated proteins may account for the clinical syndrome.
General reference
1. Touitou I: Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review. Genes Dis 9(4):1000-1007, 2021. doi: 10.1016/j.gendis.2021.05.002
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
Clinical evaluation
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. Nonspecific abnormalities include leukocytosis and elevated acute-phase reactants during fever; elevated urinary mevalonic acid during attacks helps confirm the diagnosis (1).
Genetic testing is available but is negative in 25% of patients.
Diagnosis reference
1. Gattorno M, Hofer M, Federici S, et al; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO): Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78(8):1025–1032, 2019. doi: 10.1136/annrheumdis-2019-215048
Treatment of Hyper-IgD Syndrome
For preventing attacks, anakinra or canakinumab
For symptoms, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and anakinra
1). Patients can expect to have recurrent bouts of fever throughout their life, although episodes tend to become less frequent after adolescence.
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
