Hyper-IgD syndrome




Hyper IgD syndrome (HIDS) is an inflammatory genetic where high levels of the immunoglobulin D cause disorder characterized by periodic episodes of fever associated with additional symptoms including joint pain, skin rash and abdominal pain. Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from case to case. It is originally described in 1984 by the Prof. Jos van der Meer at Leiden University Medical Centre.


Symptoms of HIDS are noted by the first year of life in most patients. Bouts of HIDS symptoms or attacks usually begin with chills, then a quick rise in temperature that causes a fever for 3-7 days. HIDS patients may (but not always) have a diffuse erythematous maculpapular rash, urticaria, headaches, joint pain, large joint arthritis, enlarged cervical lymph nodes, vomiting and diarrhea during the flares. Some patients have petechiae or purpura, and even painful aphthous mouth or vaginal ulcers. As with all other autoinflammatory diseases, these conditions are not infectious, and are generally caused by having a genetic mutation that causes this disease. Even during flares of fever with the accompanying symptoms, these patients are not infectious if they are suffering from a HIDS flare.

Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from case to case. The first attack usually takes place during infancy. Patients may have no symptoms between attacks. However, in some patients, the attacks may be so frequent that the symptoms persist

The intensity of HIDS symptoms begins to taper off after a few days of the flare. The attacks can occur with great frequency, often every two to six weeks, and are often triggered by vaccinations, minor trauma, stress, surgery or unknown causes.

Hyper IgD Syndrome presents with longer episodes of flare-ups than CAPS, and a different rash. Once the attack is over, patients are free of symptoms, but it may take awhile for the joint pain and skin rash to fully disappear. Patients can have attacks off and on throughout their life, and patients can sometimes be free of symptoms for many months or even years in some cases. Generally, patients have the greatest frequency of HIDS attacks during childhood through adolescence.

Common Symptoms:

  • Abdominal pain
  • Abnormality of temperature regulation
  • Arthralgia
  • Gastrointestinal hemorrhage
  • Hepatomegaly
  • Lymphadenopathy
  • Myalgia
  • Fever
  • Chills
  • Lymph gland swelling in neck
  • Vomiting
  • Diarrhea


MKD (HIDS) is an inherited auto inflammatory disease that is most often caused by an inherited autosomal recessive gene mutation of the mevalonate kinase gene (MVK), from both parents. The mutations lead to a decrease in the enzymatic activity of the gene. The gene is located at chromosome 12q24. However, there are cases of single-mutation dominant HIDS. Also, there are some that are clinically diagnosed with HIDS, where the patient has all the symptoms and findings associated with this disease, but the genetic mutation(s) have not been found with the current genetic testing.

HIDS is caused by the inherited MVK gene mutation. Clinical symptoms of HIDS, and the finding of MVK mutation(s)and elevated inflammatory markers during flares of symptoms, such as high C-reactive protein and ESR are helpful in diagnosing a patient with this disease. HIDS is a lifelong disease in many cases, but some patients have greatly reduced,or infrequent symptoms as adults.

Amyloidosis is not often seen in HIDS. There is a more severe condition, known as Mevalonate Aciduria (MA) that also involves a mutation in the MVK gene, but it is associated with significant, chronic inflammation, dysmorphic facial features, failure to thrive,systemic organ involvement and neurocognitive delays. 

Hyper IgD syndrome is inherited in an autosomal recessive manner, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. About one half of patients have a positive family history.


Continuously high IgD values (more than 100 IU per milliliter) on 2-IgD lab tests done one month apart can help doctors to consider the diagnosis of HIDS in many patients. But this test is not accurate in children under 2-3 years of age, plus 20% of HIDS patients never have elevated IgD, and elevated IgD is noted at times with other autoinflammatory diseases (but not as often as it is with HIDS) so doctors should not rely on the IgD testing alone for a diagnosis. Over 80% of HIDS patients also have high IgA levels along with high IgD levels. During an attack, leukocytosis, high levels of C-reactive protein (CRP) and serum amyloid A are noted. Mevalonate aciduria is also noted in many cases. Nonspecific abnormalities include leukocytosis and elevated acute-phase reactants during fever; specific but insensitive findings include elevated urinary neopterin and mevalonic acid.


atients with hyper IgD syndrome have a good prognosis because amyloidosis has not been reported in any patient with this syndrome. No apparent neurologic or morphologic abnormalities occur, and, between fever attacks, patients are generally free of symptoms. Attacks do continue throughout the lifetime, although there may be a slight decrease following adolescence.


There is no cure for hyper IgD syndrome and currently no established treatment. Management is focused on supportive care. Some patients have responded to high-dose prednisone. Simvastatin, Anakinria (an IL-1 receptor antagonist) and TNF inhibitors have recently shown some success in controlling inflammatory attacks.

Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and infectious disease specialist (to evaluate periodic fever). Patients can expect to have recurrent bouts of fever throughout their lives, although episodes tend to diminish in frequency after adolescence.


  • NIH