The presentation of mevalonate kinase deficiency depends on the residual activity of the enzyme [1]. At one end of the spectrum, there is HIDS, characterized by recurrent episodes of fever, chills, and headaches, mainly cervical lymphadenopathy, hepatosplenomegaly, vomiting and diarrhea, maculopapular skin rash, urticaria, mucosal sores, arthralgia, and other inflammatory symptoms. Mevalonic aciduria marks the other end of the spectrum and is associated with facial dysmorphism, psychomotor retardation, and failure to thrive [2] [3]. Transitions are fluent; patients may show signs and symptoms of either or both entities, and any tentative diagnosis should be secured by means of genetic studies.

With regard to HIDS, bouts of inflammation are first observed during the first year of life and typically last a few days [4]. The patient may subsequently go through a symptom-free period of several weeks before experiencing another acute episode [5]. Symptom-free periods tend to extend with age, so attack rates are highest in childhood and bouts of HIDS become increasingly rare throughout adolescence and adulthood. Symptomatic episodes may be triggered by infections or vaccinations, by physical or psychological strains. It may not always be possible, though, to associate any trigger to the onset of symptoms. Some patients are able to anticipate an imminent attack, mainly due to prodromal headaches.

HIDS does not usually affect the patient's mental and physical development.

• Abdominal Pain

  The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers and varying degree of skin involvement. [doi.org]

  We report a new case of hyper-IgD syndrome, a recently described disease characterized by recurrent episodes of fever with headache, bilateral cervical lymphadenopathy and, more rarely, abdominal pain and diarrhoea. [ncbi.nlm.nih.gov]

• Episodic Abdominal Pain

  Abdominal pain as by Acute abdomen Splenomegaly (large spleen at 50%) Polyartralgi (joint pain) (80%) during fever episodes Eczema: macular with transition to papules, urticaria, EN or petechia Diarrhea Family history. [bindevevssykdommer.no]

• Blue Sclera

  These symptoms include hyptonia, psychomotor retardation, failure to thrive, ataxia, and congenital malformations such as microcephaly, dolichocephaly, blue sclerae and central cataracts. [preventiongenetics.com]

• Corneal Opacity

  On exam, both eyes had clear conjunctiva, the central corneal opacities had resolved, and despite residual corneal scarring, his uncorrected visual acuity had returned to 20/20 in both eyes [see Additional file 1, 2]. [ped-rheum.biomedcentral.com]

• Conjunctival Injection

  His exam routinely consisted of photophobia, conjunctival injection and nummular keratitis which occurred in conjunction with arthritis and fever. [ped-rheum.biomedcentral.com]

• Eruptions

  Hyperimmunoglobulin D and periodic fever syndrome (HIDS) is an autosomal recessive auto-inflammatory disorder characterized by recurrent febrile attacks with lymphadenopathy, abdominal distress, skin eruptions and joint involvement. [ncbi.nlm.nih.gov]

  Retention of primary (or baby) teeth even after the permanent teeth have erupted is a consistent finding. [primaryimmune.org]

  It is accompanied by bouts of abdominal pain, hepatosplenomegaly, pancreatitis, and eruptive xanthomas; autosomal recessive inheritance. See: familial lipoprotein lipase inhibitor. [m.kmle.co.kr]

  A number of skin eruptions or rashes have been described in this syndrome, and these resolve slowly after the febrile episode settles. [de.slideshare.net]

• Arthralgia

  The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. [ncbi.nlm.nih.gov]

  The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers and varying degree of skin involvement. [doi.org]

• Dolichocephaly

  These symptoms include hyptonia, psychomotor retardation, failure to thrive, ataxia, and congenital malformations such as microcephaly, dolichocephaly, blue sclerae and central cataracts. [preventiongenetics.com]

• Headache

  We report a new case of hyper-IgD syndrome, a recently described disease characterized by recurrent episodes of fever with headache, bilateral cervical lymphadenopathy and, more rarely, abdominal pain and diarrhoea. [ncbi.nlm.nih.gov]

  The most frequent symptoms are fever, diarrhoea, arthralgias, cold shivers, abdominal pain, vomiting and headache. Physical examination often reveals lymphadenopathy, skin lesions, arthritides, splenomegaly and serositis. [ntvg.nl]

  These include painful swelling of lymph nodes (especially in the neck), skin rash, headache, sore throat, ulcers in the mouth, abdominal pain, vomiting, diarrhoea, joint pain and joint swelling. [printo.it]

• Poor Coordination

  coordination (ataxia), and seizures. [rarediseases.org]

The diagnosis of HIDS is based on clinical and biochemical findings as well as the molecular biological confirmation of mutations in the MVK gene. A positive family history may narrow down the list of differential diagnoses but does not replace either of the diagnostic procedures described below.

Laboratory analyses may yield important clues as to the nature of the disease:

• Mevalonate kinase deficiency results in the accumulation of mevalonic acid, and increased levels of this compound may be detected in blood and urine samples. Still, HIDS is generally associated with mild increases of mevalonic acid, and it may be necessary to perform repeated measurements to achieve reliable results. Also, highly sensitive techniques should be used to this end [6].
• Hyperimmunoglobulinemia D is often named as a permanent feature of HIDS but should not be understood as an exclusion criterion. Some patients, especially children, may have normal levels of immunoglobulin D [5]. Physiological values may also be obtained when patients are free of symptoms.
• Hyperimmunoglobulinemia A is encountered in the majority of patients.
• During symptomatic episodes, inflammatory parameters, such as erythrocyte sedimentation rate, levels of C-reactive protein, interleukin-1, interleukin-6, and TNFα, are increased. Leukocytosis and neutrophilia are common findings, too [7].

Finally, the tentative diagnosis of HIDS should be confirmed by means of genetic studies. All patients reported to date have carried pathogenic mutations of the MVK gene, so negative results should prompt clinical reassessment and lead to the revision of the diagnosis. Measurements of mevalonate kinase enzyme may be considered in this context but are not part of the conventional workup of HIDS cases.

In mild cases with less than one episode per month and normalization of biochemical parameters between bouts of HIDS, short courses of non-steroidal anti-inflammatory drugs or corticosteroids may suffice to alleviate symptoms [2] [4].

Otherwise, more potent drugs should be administered, and the respective HIDS patients largely benefit from anti-IL-1β-treatment. IL-1 receptor antagonists like anakinra have been proven to effectively limit the inflammatory response, thereby contributing to a sustained improvement of both clinical and biochemical parameters. Unless daily applications are required due to frequent febrile episodes and/or severe symptoms, anakinra is administered on-demand. The major drawback of this type of therapy are painful reactions at the injection sites, an unpleasant side effect less frequently observed under treatment with canakinumab. Indeed, the spectrum of therapeutic possibilities has been broadened substantially upon the treatment approval of this long-acting human anti-IL-1β monoclonal antibody, which has been shown to be superior to anakinra in its efficacy to reduce both the frequency and severity of HIDS-related signs and symptoms [3]. Current literature suggests that a complete response can be achieved in about half of all patients [2] [7].

Resistance to IL-1β-targeting drugs has been described in isolated cases. Some of these patients have been treated with tocilizumab, a humanized monoclonal antibody targeting interleukin-6, which is another cytokine presumably involved in the pathogenesis of HIDS. And indeed, tocilizumab treatment resulted in decreased inflammation [8] [9]. Mevalonate kinase deficiency may similarly result in impaired TNFα-signaling, but data regarding the efficacy of anti-TNFα-treatment in HIDS are scarce and less promising. Nevertheless, this option may be considered if resistance to all of the aforementioned therapies is encountered [5] [10].

In any case, suppressing inflammation merely constitutes symptomatic treatment. Further studies are required to assess the long-term effects of anti-inflammatory therapy in HIDS patients, to evaluate its effect on their risk of long-term complications as described in the following paragraph [2].

Residual enzyme activity largely determines the patient's prognosis [1]. The complete deficiency of mevalonate kinase, which gives rise to mevalonic aciduria, may be lethal, but HIDS is generally related to a favorable outcome. While HIDS is a lifelong, as-of-yet incurable disease, both the frequency and severity of inflammatory episodes tend to diminish with age. The majority of patients aged 20 years and older have 6-12 attacks per year, with data regarding older patients not yet being available [4].

In isolated cases, though, systemic amyloidosis leading to nephrotic syndrome, abdominal adhesions, and joint contractures have been described as late sequelae, and these conditions significantly reduce life quality and/or expectancy [4] [5] [11]. HIDS patients also have an increased risk of severe, possibly life-threatening bacterial infections and sepsis, and they should be treated aggressively when presenting with complicated infectious disorders [2].

Both HIDS and mevalonic aciduria are caused by mutations in the MVK gene, which is located on the long arm of chromosome 12 and encodes for the peroxisomal enzyme mevalonate kinase. Patients may be homozygous or compound heterozygous for gene defects that result in mevalonate kinase deficiency. While residual enzyme activity of up to 8% is characteristic of HIDS, it falls below detection levels in mevalonic aciduria [1].

Four mutations, namely V377I, I268T, H20P/N, and P167L, account for more than 70% of cases of HIDS [4]. Variants V377I and P167L have exclusively been observed in HIDS patients. Mutations I268T and H20P, however, have also been identified in patients with mevalonic aciduria, suggesting the genotype of the second allele to be critical for the phenotype displayed by the individual. Moreover, environmental factors may affect the residual activity of mevalonate kinase [1].

On a global scale, about 300 patients are known to suffer from mevalonate kinase deficiency in any degree of severity. Although the true number is likely greater, and no specific data can be provided on the incidence and prevalence of HIDS, it is generally assumed to be a rare disease. The majority of patients described to date are Caucasian, but HIDS may occur in any ethnic and racial group [7]. Males and females are affected alike.

Mevalonate kinase plays a key role in early cholesterol and non-sterol isoprenoid synthesis. This enzyme catalyzes the phosphorylation of mevalonic acid to mevalonate 5-phosphate, a reaction lying immediately downstream of the reduction of HMG-CoA by HMG-CoA reductase. Although the latter is considered the rate-limiting step in the mevalonate pathway, mevalonate kinase deficiency necessarily results in a shortage of intermediate compounds and end products of this important metabolic pathway [3].

Cholesterol is an essential component of cell membranes and serves as a precursor of steroid hormones, vitamin D, and bile acids. Non-sterol isoprenoids, on the other hand, are involved in the prenylation of numerous proteins, and these proteins' trafficking, distribution, binding behavior, and function may be adversely affected in the absence of the corresponding prenyl groups. According to current hypotheses on the pathogenesis of HIDS, prenylation may ameliorate the inflammatory response. Mevalonate kinase deficiency may favor the exacerbation of inflammation over its resolution, and this assumption is well supported by the fact that HIDS patients do show an overproduction of the pro-inflammatory cytokine interleukin-1β. Of note, further cytokine abnormalities may be detected in HIDS patients, which is why treatment with IL-1β antagonists and related compounds is insufficient to terminate the inflammatory process [3].

The impairment of other cell functions most likely contributes to the development of signs and symptoms. In this context, mitochondrial dysfunction and imbalances between programmed cell death and survival have been proposed as part of the pathophysiological cascade leading to clinical HIDS.

Affected families may benefit from genetic counseling. The prenatal diagnosis of HIDS is feasible but rarely requested.

In 1984, HIDS has first been described as "hyperimmunoglobulinemia D and periodic fever" [12]. The authors reported a group of Dutch patients with a long history of recurrent attacks of fever of unknown cause, which they related to abnormally high levels of immunoglobulin D. While the clinical picture reminded them of familial Mediterranean fever, the latter is rarely accompanied by hyperimmunoglobulinemia, so Meer and colleagues proposed the existence of a new syndrome. Towards the end of the 20th century, HIDS could finally be linked to loss-of-function mutations in the gene encoding mevalonate kinase [13].

Nowadays it is recognized that HIDS is a rather mild type of mevalonate kinase deficiency. Patients with HIDS still have residual enzyme activity and don't suffer from neurological complications and developmental delays, as do patients with mevalonic aciduria. This disease may be lethal and is caused by a complete loss of mevalonate kinase activity. Accordingly, an individual patient's prognosis largely depends on their genotype and residual activity of mevalonate kinase [1].

Hyper-IgD syndrome (HIDS) is also referred to as hyperimmunoglobulinemia D and periodic fever syndrome. It is a hereditary disease associated with an exacerbated inflammatory response, which is caused by mutations in the MVK gene. This gene encodes for mevalonate kinase, an enzyme that plays a key role in cholesterol and isoprenoid metabolism. In the absence of mevalonate kinase, the regulation of cellular processes and inflammation is disturbed, giving rise to a series of symptoms. The severity of these symptoms largely depends on the degree of mevalonate kinase deficiency: HIDS patients do have residual activity of mevalonate kinase and thus present a relatively mild phenotype.

In detail, HIDS manifests in recurrent episodes of fever, lymphadenopathy, hepatosplenomegaly, vomiting and diarrhea, skin rash and mucosal sores, joint pain and other inflammatory symptoms. These are first observed in infancy, most commonly at the age of 3-9 months. They may last several days, resolve, and recur after a symptom-free period of about one month. In some cases, acute episodes can be related to infections, vaccinations, or stress, but they may occur spontaneously. Both the severity and frequency of bouts of HIDS tend to diminish with age.

The diagnosis of HIDS is based on clinical findings, biochemical results, and genetic studies. With regard to management, HIDS patients benefit from anti-inflammatory treatment. Conventional measures such as the application of NSAIDs or steroids may provide relief in mild cases, while other patients require IL-1β-targeting drugs such as anakinra. In any case, the patient's response to therapy will guide treatment decisions, which generally focus on maintaining or augmenting quality of life. As of to date, there is no cure for HIDS, but symptomatic episodes can often be suppressed and patients likely do have a normal life expectancy.

1. Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat. 2006; 27(8):796-802.
2. Galeotti C, Meinzer U, Quartier P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford). 2012; 51(10):1855-1859.
3. Mulders-Manders CM, Simon A. Hyper-IgD syndrome/mevalonate kinase deficiency: what is new? Semin Immunopathol. 2015; 37(4):371-376.
4. van der Hilst JC, Bodar EJ, Barron KS, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008; 87(6):301-310.
5. Korppi M, Van Gijn ME, Antila K. Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report. Acta Paediatr. 2011; 100(1):21-25.
6. Rodrigues AV, Maggs JL, McWilliam SJ, et al. Quantification of urinary mevalonic acid as a biomarker of HMG-CoA reductase activity by a novel translational LC-MS/MS method. Bioanalysis. 2014; 6(7):919-933.
7. Curtis CD, Fox CC. Treatment of adult hyper-IgD syndrome with canakinumab. J Allergy Clin Immunol Pract. 2015; 3(5):817-818.
8. Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014; 20(2):103-105.
9. Stoffels M, Jongekrijg J, Remijn T, Kok N, van der Meer JW, Simon A. TLR2/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome. Rheumatology (Oxford). 2015; 54(2):363-368.
10. Ter Haar N, Lachmann H, Özen S, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013; 72(5):678-685.
11. Obici L, Manno C, Muda AO, et al. First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 2004; 50(9):2966-2969.
12. van der Meer JW, Vossen JM, Radl J, et al. Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet. 1984; 1(8386):1087-1090.
13. Houten SM, Kuis W, Duran M, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999; 22(2):175-177.