Hyperimmunoglobulin D syndrome (HIDS) or mevalonate kinase deficiency belongs to the spectrum of autoinflammatory syndromes. In fact, HIDS is an autosomal recessive disease where the MVK gene encoding mevalonate kinase is mutated. To clarify, mevalonate kinase is an enzyme important for the biosynthesis of cholesterol, so it's classified as a "metabolic" disease. Consequently, the reduction in the products of the pathway leads to interleukin (IL)-1β secretion and autoinflammation. Besides, MVK gene has a wide range of 100 mutations, but the most common variant is V377I.
Above all, starting since infancy, this syndrome leads to recurrent episodes of fever and more that lasts around 4 days each month. Fortunately, because of the advancement in medicine, it's possible to reduce the patients' symptoms drastically. Besides, usually this syndrome doesn't stick around until adulthood.
What causes hyperimmunoglobulin D syndrome (HIDS):
In general, it's still unclear why this genetic disease occurs. However, it's mostly inherited from carrier parents where they both give two mutated genes. Afterall it is an autosomal recessive disease. This suggests that the parents don't have to carry the disease, but maybe someone from the family had it. If parents give birth to a child with HIDS, there's a 25% possibility that they give birth to another with the same genetic defect.
As to why hyperimmunoglobulin D syndrome causes fever, it could be the reduction of molecules important for inflammation regulation. Mostly, the episodes start due to a stimulant that triggers fever. For example, such stimulants are vaccines, infections, surgeries, stress and trauma.
Symptoms of HIDS:
Indeed, HIDS is intense when the enzymatic function is low. As a matter of fact, the severe form of hyperimmunoglobulin D syndrome is called " Mevalonic aciduria". For instance, while the MVK enzymatic activity is below 1% for mevalonic aciduria (MA), the enzymatic activity is reduced to 1%-8% in the case of MVK-HIDS.
-For 1-8% MVK enzymatic activity (mild symptoms):
- Fever episodes that lasts 3-7 days
- Skin-rashes that are non specific
- Enlargement of neck and head lymph nodes "Cervical lymphadenitis"
- Joint pain "Arthritis or arthralgia"
- Abdominal pain
- Nausea and vomiting
- Loss of appetite
- Flu-like symptoms
- 72% has persistently high polyclonal serum immunoglobulin D and A
- Recurrence of symptoms every 4-6 weeks
-For less than 1% MVK enzymatic activity (severe symptoms):
- Chronic febrile episodes
- Mental retardation
- Dysmorphic features
- Rarely, the disability to thrive
Diagnosis of hyperimmunoglobulin D syndrome:
Hyperimmunoglobulin D syndrome targets all ethnic groups, but it mostly affects Western Europians.
Diagnosis is as follows:
Genetic test: The presence of pathogenic or likely pathogenic mevalonate kinase variants (homozygous or trans-heterozygous) is one criterion for diagnosis of 98% efficiency.
Physical test: Another criterion of diagnosis is based on the enlarged cervical lymphadenitis, aphthous stomatitis and gastrointestinal symptoms of 100% efficiency. Furthermore, although enlarged cervical lymphadenitis is one of the clinical findings of hyperimmunoglobulin D, it is sometimes misdiagnosed as PFAPA syndrome.
Blood test: Inflammation can be detected by a blood test during an episode.
Serum test: The presence of elevation in immunoglobulins A and D levels suggests the presence of HIDS.
Treatment of hyperimmunoglobulin D syndrome:
Frankly speaking, there exist no therapy to prevent the inflammation but corticosteroids are effective to reduce the severity of symptoms such as fever episodes. Besides, nonsteroidal anti-inflammatory drugs such as naproxen and ibuprofen can help reduce symptoms. Also, in case corticosteroids aren’t helping, treatment with anti interleukin (IL) -1 agents (1 mg/kg/day) or anti-tumor necrosis factor (TNF) agents must solve the problem. Thus, anakinra is a good interleukin-1 blocker medicine to minimize the fever episodes, but it doesn’t end them exclusively. When the symptoms are severe, an anti-TNF called entacercept (Enbrel) can help with episodes.
Amyloidosis is a complication of hyperimmunoglobulin D syndrome that involves the kidneys. To illustrate, abnormal (misfolded) amyloid builds up in the body tissues, organs and nerves which causes them damage and diseases including an enlarged heart, kidney issues, etc...
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-Rigante D, Ansuini V, Bertoni B, Pugliese AL, Avallone L, Federico G, Stabile A. Treatment with anakinra in the hyperimmunoglobulinemia D/periodic fever syndrome. Rheumatol Int. 2006 Nov;27(1):97-100. doi: 10.1007/s00296-006-0164-x. Epub 2006 Jul 27. PMID: 16871408.
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