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​HIDS/MKD – Hyper-IgD syndrome / Mevalonate Kinase Deficiency

MKD is a rare genetic autoinflammatory disorder.  Hyper-IgD syndrome is the less severe and more common form of MKD, characterized by recurrent episodes of unexplained fever. HIDS is caused by mutations in the gene MVK which encodes the enzyme mevalonate kinase. The first flare usually takes place during infancy. There is often an abrupt onset of fever with no associated infection. Most flares occur approximately every four to six weeks, lasting from three to seven days, and occur periodically throughout life. The frequency of episodes and their severity vary greatly from person to person.

Characteristics of Hyper-IgD syndrome / Mevalonate Kinase Deficiency

Symptoms

These episodes/flares are accompanied by:

  • fever

  • rash

  • chills

  • joint inflammation (arthritis)

  • abdominal pain

  • fatigue

  • swelling of affected lymph nodes (lymphadenopathy)

            

Additional symptoms include:

  • nausea

  • mouth ulcers

  • diarrhoea

  • enlargement of the liver & spleen

  • vomiting                                    

                                                                     

 The rash consists of reddish (erythematous) spots (macules) or bumps (papules). Some individuals have a cough and inflammation of the back of the throat (pharyngitis).

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HIDS is often more severe in children. Affected children often have a high spiking fever that, in some instances, can cause convulsions. Children are also more likely to have an abnormally enlarged spleen. Flares can occur spontaneously or be triggered by vaccinations, infections, and/or emotional or physical stress. Growth and development are usually not affected, unlike in patients with more severe disease mevalonic aciduria (MVA). Adults may have mood and psychiatric features, including depression.

Most people with the disorder are individuals of western European heritage, with approximately 60% occurring in Dutch or French individuals.

Diagnosis

A diagnosis is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., recurrent fevers not caused by infection), and a variety of tests including blood tests to determine the levels of immunoglobulin D (IgD) in the blood, urine tests to detect the presence of mevalonate kinase, and DNA analysis to detect the genetic mutation associated with the disorder.

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High levels of immunoglobulin D (IgD) is indicative of mevalonate kinase deficiency, but does not confirm a diagnosis. Some individuals do not show this finding and their IgD levels may be normal. Also, other periodic fever syndromes may have high levels of IgD in the blood.

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A blood test of the inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid protein A (SAA), and a complete blood count & fibrinogen can be performed during a flare to determine the extent of the inflammation. When the flare is over, the blood test can be done again to see if the inflammatory markers ​​have returned to normal or almost back to normal.

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A urine sample is also examined to detect the presence of protein and red blood cells. During flares, these may temporarily increase significantly. Patients with amyloidosis, however, have permanently elevated protein concentrations in the urine.

Triggers

Acute episodes may be triggered by:

  • Vaccinations – more than 50% report at least one episode in childhood following an immunization

  • Infection

  • Physical and emotional stress

  • Trauma, including surgery

Treatments

  • Canakinumab

  • Anakinra

  • Corticosteroids

  • Colchicine

  • NSAIDs

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