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HIDS/MKD: Hyperimmunoglobulinemia D syndrome/Mevalonate Kinase Deficiency

What is it?

HIDS (hyperimmunoglobulinemia D syndrome), also known as Mevalonate Kinase Deficiency (MKD) is a very rare autoinflammatory condition that usually starts in early childhood.[1-4]

This is caused by a genetic mutation in the MVK (mevalonate kinase) gene in MKD syndromes, the level of deficiency of mevalonate kinase is associated with the severity of chronic and systemic inflammation, and organ involvement. There is another MKD syndrome, called mevalonate aciduria (MA) that has more severe, chronic inflammation due to an extreme deficiency of mevalonate kinase.

In most people with HIDS/MKD, the blood levels of an antibody called immunoglobulin D (IgD) are higher than those in healthy people, which gives the condition its name. However, it is now known that there are other conditions where IgD levels are sometimes raised, so measuring IgD is no longer considered the best way to confirm a diagnosis of HIDS/MKD[5].

How common is it?

So far, only about 200 cases have been reported worldwide,[6] although there are likely to be other affected people who remain undiagnosed. Among the known cases, Europeans are most commonly affected.[1]

What are the symptoms?

HIDS/MKD flares tend to occur every 2-8 weeks and last for 3-7 days.[7] The condition usually becomes apparent in the first year of life and consists of recurrent attacks of fever along with other symptoms.[7]

HIDS/MKD flares can involve the following symptoms:[3,4,5]

  • Fever
  • Rash
  • Headache
  • Abdominal pain, vomiting, diarrhoea
  • Some patients can have colitis from infancy
  • Enlarged liver and spleen
  • Joint pain, joint inflammation
  • Swollen lymph nodes
  • Cutaneous vasculitis
  • Some cases of retinitis pigmentosa, conjunctivitis

HIDS/MKD flares can occur spontaneously or can be triggered by:[7]

  • Vaccinations
  • Infections
  • Emotional or physical distress
  • Travel

Click for full-size image

Image showing possible symptoms of HIDS/MKD[1, 3-4, 7-8]

What typically happens over the course of the illness?

Growth and development of children who have HIDS/MKD are usually not affected.[1] With age, the frequency and severity of HIDS/MKD flares decreases in some patients.[6]

A long-term complication, amyloidosis, occasionally develops in some people with HIDS/MKD.[1] Amyloidosis is a condition in which proteins build up in the kidneys leading to kidney damage. Improved diagnostics and treatment greatly reduce the risk for developing amyloidosis.

How is it caused?

It is not clear what triggers the activation of the innate immune system in HIDS/MKD. However, it is known that those with HIDS/MKD have a change (called a mutation) in the MVK gene, which codes for mevalonate kinase (MVK), a protein involved in the production of cholesterol in the body.[1,7] This genetic change, which is thought to be the main underlying problem in HIDS, causes a drop in the levels of mevalonate kinase in the body. This deficiency creates a chain reaction that leads to an overproduction of cytokines, most prominently interleukin-1 beta (IL-1β).[12] In fact, it has been suggested that the term “mevalonate kinase deficiency” should replace HIDS as the name of the condition.[9,10]

The change in the MVK gene is usually inherited recessively.[1] This means that a person must inherit the altered gene from both their mother and their father in order to develop HIDS/MKD. However, some cases of HIDS/MKD have been reported in people who have inherited the altered gene from just one parent.[11]

Hereditary transmission of HIDS/MKD

Status: 2016-01-04

[1] Samuels J, Ozen S. Curr Opin Rheumatol. 2006;18:108–17.
[2] Lachmann HJ, Hawkins PN. Arthritis Res Ther. 2009;11:212.
[3] Savic S, Dickie LJ, Battellino M, et al. Curr Opin Rheumatol. 2012;24:103–12.
[4] Gattorno M, Federici S, Pelagatti MA, et al. J Clin Immunol. 2008;28(suppl 1):S73–83.
[5] Auto Inflammatory Alliance, Hyperimmunoglobulinemia D with Periodic Fever Syndrome. Available from: (accessed March 2016)
[6] Frenkel J, Simon A: Hyperimmunoglobulinemia D with periodic fever.
[7] Orphanet. Hyperimmunoglobulinemia D with periodic fever. Available from: (accessed November 2015).
[8] Drenth JPH, van der Meer JWM. N Engl J Med. 2001;345:1748–1757.
[9] Bader-Meunier B, Florkin B, Jean Sibilia J. Pediatrics 2011;128;e152-9.
[10] Mulders-Manders CM, Simon A. Semin Immunopathol. 2015;37:371–376.
[11] Barron KS, Ombrello AK, Goldsmith, DP et al. Arthritis Rheum 2010;62 Suppl 10:2105.
[12] Mulders-Manders, C et al. Semin Immunopathol (2015) 37:371. doi:10.1007/s00281-015-0492-6.

Kids Corner

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Kids Corner

June 2016 - GLDEIM/ACZ885/0075