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Hyperimmunoglobulinaemia D with periodic fever syndrome

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, 2011.


What is hyperimmunoglobulinaemia D with periodic fever syndrome?

Hyperimmunoglobulinaemia D with periodic fever syndrome (MIM 260920) is more commonly known as hyper-IgD syndrome or HIDS. It is a rare inherited autoinflammatory syndrome that presents with recurrent episodes of fever, skin rash, abdominal pain, headaches and enlarged lymph glands that begin in infancy.

Mevalonic aciduria is a severe variant of HIDS.

Who gets HIDS and why?

HIDS is predominantly identified in populations from two northern European areas, The Netherlands (over 50% of cases) and northern France. However approximately 200 cases have been reported in various ethnic groups.

Typically symptoms of HIDS begin before the age of 1 year with the median age of onset being 6 months. However making the diagnosis is challenging and can often take many years.

HIDS is inherited as an autosomal recessive condition, meaning two copies of the defective gene are inherited, one from each of the unaffected carrier parents.

Molecular biology and genetics

The MVK gene involved in HIDS is located on chromosome 12 (12q24) and produces the enzyme mevalonate kinase. Mutations in this gene have been reported in 75% of typical cases. V377I is the most common disease-linked mutation reported. In HIDS, the gene mutations result in reduced enzyme activity, approximately 5-10% of normal. Mevalonic aciduria is a more severe and fatal form of this deficiency in which enzyme activity is virtually undetectable. (see below)

The enzyme mevalonate kinase is involved in the isoprenoid pathway of cholesterol biosynthesis. The enzyme deficiency results accumulation of mevalonic acid and increased interleukin 1.

Clinical features of HIDS

The acute febrile episodes of HIDS begin in infancy. The clinical features are:

  • fever
  • non-migratory maculopapular skin rash
  • headache
  • painful enlarged lymph nodes in the neck
  • abdominal and joint pain.

The attacks last for up to one week, longer than those of familial Mediterranean fever. They may recur every 1-2 months.

The characteristics of the recurrent acute episodes of HIDS are described in the table below.

Symptom Features
  • over 40C
  • preceding chills and malaise
Skin rash
  • affects up to 80%
  • various presentations (see below)
  • nonspecific
Enlarged lymph nodes in neck
  • characteristic
  • bilateral
  • painful
Abdominal pain
  • severe
  • diarrhoea and vomiting
  • peritonitis
Joint pain
  • arthralgia (pain) or arthritis (swelling)
  • most common in young patients
  • affects large joints
  • symmetrical, polyarticular, non-destructive
  • symptoms occur with abdominal pain and settle slowly
Enlarged liver and spleen (hepatosplenomegaly)
  • affects 50% of children

Cutaneous signs of HIDS

Skin rash affects up to 80% of patients. A number of skin eruptions or rashes have been described in this syndrome, and these resolve slowly after the febrile episode settles.

The rashes seen in HIDS are most commonly described as follows:

  • small flat spots (macules)
  • raised bumps (small papules or larger nodules)
  • measles-like rash (morbilliform)
  • hive-like rash (urticarial).

Less common or rare skin presentations include:

Oral and/or vaginal aphthous ulcers affect 50% of patients.

What triggers attacks?

Acute episodes may be triggered by:

  • Vaccinations – more than 50% report at least one episode in childhood following an immunisation
  • Infection
  • Physical and emotional stress
  • Trauma, including surgery

What is the likely outcome for patients?

There is a tendency to improve with age, with less frequent and less severe attacks by adulthood. Between episodes, health is normal.

A small subgroup of affected patients develop neurologic abnormalities in adulthood, similar to mevalonic aciduria (see below).

Unlike familial Mediterranean fever, amyloidosis is rarely seen in HIDS, affecting less than 3%.

Life expectancy is usually normal, however this can be affected by renal failure due to amyloidosis or severe infections.

How is HIDS diagnosed?

The characteristic recurrent acute febrile attacks without a clear infectious or autoimmune cause, suggest the need for investigation.

Clinical criteria

In addition to the the of febrile attacks outlined above, clinical diagnostic criteria should include:

  • Onset before the age of 5 years
  • Episodes last less than 14 days

MVK gene mutations are unlikely if these features are not present.

IgD levels

Raised levels of IgD can be found in many but not all patients, especially in children under 3 years of age. Levels are raised not only during an attack but between attacks. Elevations of IgD levels can occur in other periodic fever syndromes such as familial Mediterranean fever and TRAPS, and other chronic inflammatory conditions, so it should be interpreted with caution.

Other useful tests

Urine organic acids measured during an acute attack usually show raised levels of mevalonic acid.

During an attack, there are also increases in white cell count (leukocytosis), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA). Serum IgA levels may also be increased.

Radiometric assay testing can demonstrate reduced mevalonate kinase activity in white blood cells or cultured fibroblasts.

Skin biopsy may show a mild vasculitis which may extend deeply. Changes may resemble Sweet disease or cellulitis.

DNA analysis

DNA analysis showing two disease-linked mutations in the MVK gene is used to confirm the diagnosis of HIDS. In most cases the patient has two different mutations, called compound heterozygosity.

Treatment of HIDS

Many treatments have been tried in HIDS, none with uniform success:

  • Colchicine – is generally unhelpful although there are case reports of its successful use
  • Non-steroidal anti-inflammatory drugs (NSAID)
  • Statins – such as simvastatin, inhibit HMGCoA-reductase resulting in reduced production of mevalonic acid
  • Systemic corticosteroids – a single dose at the start of an attack may reduce the severity and duration (1mg/kg)
  • Dapsone
  • Ciclosporin
  • Thalidomide
  • Intravenous immunoglobulin (IVIG)
  • Biologic agents – including anakinra (interleukin-1 receptor antagonist) and etanercept (tumour necrosis factor alfa inhibitor) have been reported to reduce the frequency and/or severity of attacks in 80%. However there have also been cases where these agents have increased the frequency and/or prolonged attacks.

Mevalonic aciduria

Mevalonic aciduria (MIM 610377) involves the same gene and enzyme as HIDS, however the resulting enzyme deficiency is virtually complete. The condition is also called mevalonate kinase deficiency. The gene mutations so far identified have been localised to one end of the enzyme. Mevalonic aciduria results in neurological effects that mainly arise because of inadequate cholesterol, which is required for brain and nerve development.

Patients with mevalonic aciduria suffer the same febrile episodes as in HIDS, but in addition develop profound developmental delay, retinal dystrophy (visual defects) and cataracts, mild facial deformities, and liver/spleen enlargement. Those less severely affected have intellectual disability, failure to thrive, progressive cerebellar ataxia (unsteadiness) and anaemia. In childhood and adolescence, eye problems develop, including cataracts and uveitis. Myopathy (muscle weakness) can occur. In those severely affected, mevalonic aciduria is commonly fatal in infancy/childhood.

High levels of mevalonic acid are detected in the urine at all times.

Genetic counselling should be performed for families with an affected child and prenatal testing should be considered.



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