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Hyperimmunoglobulinemia D with periodic fever syndrome

What is hyperimmunoglobulinemia D with periodic fever syndrome?

Hyperimmunoglobulinemia D with periodic fever syndrome (MIM 260920) is more commonly known as hyper-IgD syndrome or HIDS. It is a rare inheritance autoinflammatory syndrome that occurs with recurrent episodes of fever, skin eruption, abdominal pain, headaches, and enlarged lymph nodes that start in childhood.

Mevalonic aciduria is a severe variant of HIDS.

Who gets HIDS and why?

HIDS is predominantly identified in populations in two areas of northern Europe, the Netherlands (more than 50% cases) and northern France. However, approximately 200 cases have been reported in various ethnic groups.

HIDS symptoms usually begin before the age of 1 year with an average age of onset of 6 months. However, making the diagnosis is challenging and can often take many years.

HIDS is inherited as a autosomal recessive condition, i.e. two copies of the faulty gene are inherited, one of each of the unaffected carrier parents

Molecular biology and genetics

The MVK gene involved in HIDS is found in chromosome 12 (12q24) and produces the enzyme mevalonate kinase Mutations In this gene, 75% have been reported in typical cases. V377I is the most common related disease mutation reported. In HIDS, genetic mutations result in reduced enzyme activity, approximately 5-10% from normal. Mevalonic aciduria is a more serious and fatal form of this deficiency in which the enzyme activity is practically undetectable. (look down)

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

HIDS Clinical Features

the acute febrile HIDS episodes begin in childhood. The clinical characteristics are:

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

Attacks last up to a week, longer than those of family Mediterranean fever. They can reappear every 1-2 months.

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

Symptom Characteristics
  • more than 40C
  • previous chills and discomfort
  • affects up to 80%
  • various presentations (see below)
  • unspecific
Enlarged lymph nodes in the neck
  • characteristic
  • bilateral
  • painful
Abdominal pain
  • serious
  • diarrhea and vomiting
  • peritonitis
Joint pain
  • arthralgia (pain) or arthritis (swelling)
  • more 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 children's 50%

Cutaneous hids signs

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

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

  • small flat spots (macules)
  • raised bumps (small papules or bigger nodules)
  • measles-like rashmorbilliform)

  • acneurticarial)

Less common or rare skin presentations include:

  • Henoch-Schönlein purple
  • erythema elevatum diutinum
  • petechiae (small bleeding or purple spots)
  • erythema nodosum

Oral and / or vaginal aphthous ulcers it affects the 50% of the patients.

What triggers the attacks?

Acute episodes can be caused by:

  • Vaccines: More than 50% report at least one episode in childhood after immunization
  • 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 in adulthood. Between episodes, health is normal.

A small subgroup of affected patients develops neurological 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 serious infections.

How is HIDS diagnosed?

Characteristic recurrent acute febrile seizures without an infectious clearing or autoimmune cause, suggest the need for research.

Clinical criteria

In addition to the febrile seizures described above, clinical diagnostic criteria should include:

  • Start before 5 years.
  • Episodes last less than 14 days.

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

IgD levels

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

Other useful tests

Organic acids in the urine measured during an acute attack generally show elevated levels of mevalonic acid.

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

Radiometric assay tests can demonstrate reduced mevalonate kinase activity in white blood cells or in culture fibroblasts.

Skin biopsy may show a slight vasculitis that can extend deeply. The changes may resemble Sweet's disease or cellulite.

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.

HIDS Treatment

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

  • Colchicine: Generally not useful, although there are case reports of its successful use

  • Nonsteroidal anti-inflammatory drugs (NSAID)
  • Statins, like simvastatin, inhibit HMGCoA-reductase resulting in reduced production of mevalonic acid
  • Systemic corticosteroids: a single dose at the beginning of an attack can reduce severity and duration (1 mg / kg)
  • Dapsone
  • Cyclosporine
  • Thalidomide
  • Intravenous immunoglobulin (IVIG)
  • Biological agents, including anakinra (interleukin-1 receiver antagonist) and etanercept (tumor necrosis alpha factor inhibitor) has been reported to reduce the frequency and / or severity of attacks in an 80%. However, there have also been cases where these agents have increased 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 genetic mutations identified so far have been located to one end of the enzyme Mevalonic aciduria produces neurological effects that arise mainly due to inadequate cholesterol, which is required for the development of the brain and nerves.

Patients with mevalonic aciduria suffer the same feverish episodes as in HIDS, but also develop a profound delay in development, the retina dystrophy (visual defects) and waterfalls, mild facial deformities and an enlarged liver / spleen. The least affected have mental retardation, lack of growth, progressive cerebellar ataxia (instability) and anemia. 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 Counseling should be done for families with an affected child and prenatal Evidence must be considered.