Hyperimmunoglobulinemia D with recurrent fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Synonyms and keywords:: Mevalonate kinase deficiency (MKD), HIDS

Hyperimmunoglobulinemia D with recurrent fever (commonly abbreviated as HIDS) is a periodic fever syndrome originally described in 1984 by the internist Prof. Jos van der Meer, then at Leiden University Medical Center. No more than 300 cases have been described worldwide.

• Hyperimmunoglobulinemia D with recurrent fever was first discovered by Prof. Jos van der Meer, a Dutch internist, in 1984 during the workup of 6 patients with recurrent attacks of fever of unknown origin.^[1]
• In 1999, MVK gene mutations were first implicated in the pathogenesis of hyperimmunoglobulinemia D with recurrent fever.^[2][3]

• There is no established system for the classification of hyperimmunoglobulinemia D with recurrent fever.

• Hyperimmunoglobulinemia D with recurrent fever is a autosomal recessive disorder that occurs due to mutation in MVK gene, encoding for mevalonate kinase enzyme.^[2][3]

acetyl-CoA + acetoacetyl-CoA

3-hydroxy-3-methylglutaryl-CoA

Mevalonic acid

Absent enzyme

Mevalonate kinase deficiency

5-phosphomevalonate

Multiple enzymaic pathway

Cholesterol

The above algorithm is adopted from Orphanet Journal of Rare Diseases[4]

• Mutation in this gene is associated with reduced activity of mevalonate kinase enzyme engaged in cholesterol and isoprene biosynthesis.^[5]
• Isoprenes are used in a variety of cellular functions, and the pathogenic mechanism leading to recurrent inflammatory attacks remains poorly understood.^[6]
• Previously it was thought that elevated levels of mevalonate is the cause of presenting symptoms. However, attempts to reduce its level via statin usage led to the exacerbation of attacks.
• Currently, it is hypothesized that lack of other metabolites produced by the absent enzyme mediates inflammation and leads to a caspase-mediated increase in IL‑1β production.

• Hyperimmunoglobulinemia D with recurrent fever may be caused by mutation in MVK gene.^[2][3]
• Mutation in this gene result in reduced activities of mevalonate kinase (MK), a key enzyme of isoprenoid biosynthesis.

• Hyperimmunoglobulinemia D with recurrent fever must be differentiated from other diseases that cause fever, abdominal pain, and arthritis, such as infections, other autoinflammatory diseases, and autoimmune disorders.
• For more information on the differential diagnosis of hyperimmunoglobulinemia D with recurrent fever please click here.

• The exact prevalence of hyperimmunoglobulinemia D with recurrent fever is not known. However, no more than 300 cases have been described worldwide.^[5]
• Hyperimmunoglobulinemia D with recurrent fever commonly affects individuals younger than 1 year of age. All the cases will develop this disorder before 5 years of age.^[7]
• The majority of hyperimmunoglobulinemia D with recurrent fever cases are reported in western European countries.^[8]
• Approximately, 60% of the reported cases are Dutch or French.^[9]
• This disorder affects men and women equally.
• White ethnicity is affected at a greater extent.

There are no established risk factors for hyperimmunoglobulinemia D with recurrent fever. However, attacks may be provoked by factors such as:^[10]

• Emotional stress
• Trauma
• Infection
• Vaccinations

• HIDS manifests usually in the first year of life with episodes of fever lasting 4 to 7 days accompanied with headache, abdominal pain, prominent cervical lymphadenopathy, polyarthralgia or polyarticular arthritis, diffuse maculopapular rash, and aphthous ulcerations.^[11]
• Prognosis differs according to the degree of enzyme deficiency.^[12]
• The majority of patients develop fewer attacks as they age and some may even attain spontaneous remission. However, the complete absence of enzymatic activity is associated with death in early infancy in 40% of the cases.
• Approximately, 3% of patients may develop amyloidosis as they age.
• Infections is another complication of this disorder which may be the cause of morbidity and mortality.

• The diagnosis of hyperimmunoglobulinemia D with recurrent fever is based on clinical features. In 2014, the international registry of autoinflammatory diseases (Eurofever) developed validated, evidence-based criteria for the diagnosis of this disorder. The following table is the suggested criteria:^[13]

Presence	Score
Age at onset <2 years	10
Aphthous stomatitis	11
Generalised enlargement of lymph nodes or splenomegaly	8
Painful lymph nodes	13
Diarrhoea (sometimes/often)	20
Diarrhoea (always)	37
Absence	Score
Chest pain	11

• The cut-off value for the diagnosis of hyperimmunoglobulinemia D with recurrent fever is score equal or higher than 42 scores.
• The overall sensitivity and specificity of this set of criteria for the diagnosis of hyperimmunoglobulinemia D with recurrent fever is 53% and 89%, respectively.
• The gold standard diagnostic study for this disorder is the genetic analysis of MVK gene.^[14]

• The hallmark of hyperimmunoglobulinemia D with recurrent fever is a high fever. A positive history of diarrhea, lymph node enlargement, and arthralgia is suggestive of hyperimmunoglobulinemia D with recurrent fever.^[15]
• Episodes of fever may take 3 to 7 days and is accompanied by shaking chills.
• The episodes may recur at irregular intervals of 2 to 8 weeks.

• Patients with hyperimmunoglobulinemia D with recurrent fever usually appear normal. Physical examination of patients with hyperimmunoglobulinemia D with recurrent fever is usually remarkable for high fever (regularly exceeds 40 °C), .^[15]
• Other possible findings are maculopapular rash, urticaria, and arthritis.

• Laboratory features include:^[11]
  • acute phase response (elevated CRP and ESR).
  • Markedly elevated IgD (and often IgA), although cases with normal IgD have been described.^[16]
• Systemic amyloidosis is a rare finding in HIDS, however it has been reported.^[11]
  • A possible characteristic finding for the diagnosis of HIDS is elevated urinary levels of mevalonic acid during episodes.^[17]

• There are no ECG findings associated with hyperimmunoglobulinemia D with recurrent fever.

• There are no x-ray findings associated with hyperimmunoglobulinemia D with recurrent fever.

• There are no echocardiography/ultrasound findings associated with hyperimmunoglobulinemia D with recurrent fever.

• There are no CT scan findings associated with hyperimmunoglobulinemia D with recurrent fever.

• There are no MRI findings associated with hyperimmunoglobulinemia D with recurrent fever.

• There are no other imaging findings associated with hyperimmunoglobulinemia D with recurrent fever.

• There are no other diagnostic studies associated with hyperimmunoglobulinemia D with recurrent fever.

• There is no treatment for hyperimmunoglobulinemia D with recurrent fever; the mainstay of therapy is supportive care.
• Dietary supplementation of cholesterol may change the frequency of attacks in those with mild disorder.^[18]
• Although statins may not be beneficial in the classic mevalonic aciduria disorder and result in clinical decompensation, it may reduce the febrile episodes in HIDs.^[19]
• Interleukin-1 inhibitors (Anakinra) have also been observed to be beneficial.^[20]

• Surgical intervention is not recommended for the management of hyperimmunoglobulinemia D with recurrent fever.

• There are no established measures for the primary prevention of hyperimmunoglobulinemia D with recurrent fever.
• Genetic studies may be recommended to the families with one affected child for the subsequent pregnancies.

• There are no established measures for the secondary prevention of hyperimmunoglobulinemia D with recurrent fever.

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