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.

• Cervical Lymphadenopathy

  The fever is typically accompanied by abdominal pain, vomiting, diarrhea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. [aai.org.tr]

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Serum IgD and IgA levels are increased during and between attacks. [immunodeficiencysearch.com]

  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]

  An attack is accompanied by cervical lymphadenopathy, abdominal pain and arthralgias. Some patients have a rash, diarrhea and vomiting. In between attacks the patient are asymptomatic. Genetics HIDS is caused by a mutation in the MVK-gene. [jessazh.be]

  Physical examination reveals cervical lymphadenopathy in most cases and, sometimes, splenomegaly. Skin lesions have been observed in isolated cases during attacks. [jamanetwork.com]

• Lymphadenopathy

  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]

  Sie ist klinisch charakterisiert durch rezidivierende Fieber-Attacken, Lymphadenopathie, Hautrötungen und Gelenkschmerzen. Biochemisch findet sich eine deutliche IgD-Erhöhung. b' ' Systematic References: 1. [moldiag.com]

  The fever is typically accompanied by abdominal pain, vomiting, diarrhea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. [aai.org.tr]

• Amyloidosis

  If the amyloidosis aggravates, the next step should be one of the biological drugs discussed above. [njmonline.nl]

  Amyloidosis has been reported only rarely in HIDS. [scielo.isciii.es]

  This case demonstrates that AA amyloidosis does occur in patients with HIDS and can present with intestinal symptoms and proteinuria. Once amyloidosis is diagnosed the goal of treatment is to prevent further complications. [ncbi.nlm.nih.gov]

• Constitutional Symptom

  Forty percent of patients with FMF present with pleurisy and other constitutional symptoms. Unilateral chest pain is more commonly reported. Patients may have decreased breath sounds or pleural friction rub. [emedicine.medscape.com]

• Abdominal Pain

  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 fever is typically accompanied by gastro-intestinal disturbances (abdominal pain, vomiting, and diarrhea), painful red skin rash, muscle pain and periorbital swelling. [ard.bmj.com]

  The fever is typically accompanied by abdominal pain, vomiting, diarrhea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. [aai.org.tr]

   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  affects 50% of children Fever Skin rash Abdominal [de.slideshare.net]

• Diarrhea

  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. [ard.bmj.com]

  Her parents and elder brother had no history of recurrent fever, prolonged abdominal pain or diarrhea of unknown origin. [tandfonline.com]

• Chronic Diarrhea

  Hyper IgM syndrome Immunoglobulin M Specialty Immunology Symptoms Chronic diarrhea[1] Types Hyper-IgM syndrome type 1,2,3,4 and 5[2][3][4][5][6] Diagnostic method MRI, Chest radiography[1] Treatment Allogeneic hematopoietic cell transplantation[7] Hyper [en.wikipedia.org]

  Chronic diarrhea with or without infection has been frequently reported. Neutropenia, anemia, and thrombocytopenia are common. An increased risk of GI tract malignancies has been reported. [emedicine.medscape.com]

  Other findings associated with X-linked hyper-IgM syndrome, some of which may become apparent at as early as six to nine months of age, may include chronic diarrhea that, in some people, may lead to impaired absorption of nutrients by the intestinal tract [rarediseases.org]

  Other systemic features are reported as well as, exophthalmos or eyelid swelling, lymphadenopathy, gastro intestinal symptoms such as chronic diarrhea, pancreatic dysfunction, skeletal abnormalities [ 138, 140 ]. [em-consulte.com]

• Hepatosplenomegaly

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Serum IgD and IgA levels are increased during and between attacks. [immunodeficiencysearch.com]

  We discuss the case of a 15-year-old Japanese girl who had presented with periodic fever, hepatosplenomegaly and intractable diarrhea from seven weeks of age. [tandfonline.com]

  In this case report, a 6-year-old male patient who was presented with a history of attacks of recurrent fever, malaise, aphthous ulcers, cervical lymphadenopathy, macular rash in the lower extremity, severe muscle pain, abdominal pain and hepatosplenomegaly [aai.org.tr]

  Herewe report on the case of a 2 year-old Portuguese boy with recurrent episodes of fever, malaise, massive cervical lymphadenopathy and hepatosplenomegaly since the age of 12 months. [repositorio.chlc.min-saude.pt]

• Oral Ulcers

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Serum IgD and IgA levels are increased during and between attacks. [immunodeficiencysearch.com]

  Here, we report a case series of HIDS from India, which includes ten patients from six families who presented with a wide spectrum of clinical features such as recurrent fever, oral ulcers, rash, arthritis, recurrent diarrhea, hepatosplenomegaly, and [guardian.meragenome.com]

  Her rheumatological review of systems was negative except for cyclical fevers and oral ulceration. It was negative for alopecia, skin changes, photosensitivity, lymphadenopathy, and sicca symptoms, including dry eyes or dry mouth. [cureus.com]

  Severe neutropenia is often associated with oral ulcers, proctitis (inflammation and ulceration of the rectum) and skin infections. Autoimmune disorders may also occur in patients with XHIGM syndrome or CD40 defects. [primaryimmune.org]

  […] was characterized by a primary complaint of Fever, which was brief, recurring in a periodic, timely manner and save associated oral ulcers, pharyngitis, and adenopathy, was without more serious focal or systemic signs of illness. [slideplayer.biz.tr]

• 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]

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Serum IgD and IgA levels are increased during and between attacks. [immunodeficiencysearch.com]

  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]

• Ulcer

  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 ulcers may be biopsied. Biopsy shows superficial ulceration and neutrophilic inflammation. Treatment of PAPA syndrome with etanercept or anakinra may be useful. Acne is treated with oral tetracycline or isotretinoin. [merckmanuals.com]

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Serum IgD and IgA levels are increased during and between attacks. [immunodeficiencysearch.com]

  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]

• Skin Rash

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

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Serum IgD and IgA levels are increased during and between attacks. [immunodeficiencysearch.com]

  We performed biochemical and molecular genetic analyses on 2 girls with periodic episodes of fever, skin rash, abdominal pain, and arthralgia, of whom 1 had elevated levels of serum IgD. [ncbi.nlm.nih.gov]

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

  Skin rashes on all parts of the body—Including the hands and feet and painful sores in the mouth – may occur. One of the most striking features is swelling of the lymph nodes in the neck or other parts of the body. [rheumatology.org]

• 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. [tandfonline.com]

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

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

• Suggestibility

  Our analysis suggests that a limited number of variants account for the majority of the patients with HIDS in South India. [guardian.meragenome.com]

  This triggered a compensatory increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity, suggesting that MVK becomes progressively rate-limiting. [autoinflammatory.uk]

  Our favorable experience with etanercept for the treatment of HIDS suggests that further investigation of this therapy is warranted. [ncbi.nlm.nih.gov]

  The diagnosis of HIDS was suggested clinically by the early age of onset and further supported by a grossly elevated serum IgD level. [onlinelibrary.wiley.com]

  When the diagnosis of HIDS was suggested, the patient was treated with a single dose (12.5 mg) of prednisone at the beginning of the flare up episodes. [ard.bmj.com]

• Headache

  Migraine headache Migraine headaches [ more ] 0002076 Papule 0200034 Recurrent aphthous stomatitis Recurrent canker sores 0011107 Urticaria Hives 0001025 Vasculitis Inflammation of blood vessel 0002633 5%-29% of people have these symptoms Acrocyanosis [rarediseases.info.nih.gov]

  Headache, abdominal pain, nausea, and vomiting were also present in some of the attacks. The initial attacks were occurring as frequently as every 3 weeks, but the interval became larger as the child grew. [cags.org.ae]

• Seizure

  Other features may include problems with movement and balance (ataxia), eye problems, seizures, and a high number of immune system proteins that help fight infections (immunoglobulins) in the blood. [diseaseinfosearch.org]

  Case report: We report on a 2 year-old Austrian boy with recurrent episodes of fever, febrile seizures, arthralgias, and splenomegaly. Rash and abdominal pain were also seen occasionally. During attacks an acute-phase response was detected. [egms.de]

  Babies born with hydrops fetalis may also have underdeveloped lungs and be at a higher risk of: heart failure brain damage hypoglycemia seizures [healthline.com]

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.

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