Topic Editor: Robert Giles, MBBS, BPharm

Review Date: 8/28/2012

Definition

Hyperimmunoglobulinemia D with periodic fever syndrome (Hyper-IgD or HIDS) is also known as periodic fever with mevalonate kinase deficiency. It is a rare autosomal recessive disease in which recurrent episodes of fever, lymphadenopathy, diarrhea, abdominal pain, headache, arthralgia and rash occur.

Description

• Recurrent fever without infection is the hallmark of a group of disorders known as periodic fever syndromes. HIDS is one of six periodic fever syndromes which have been described
• Two forms of HIDS are known to exist. Classic and variant HIDS
• Classic HIDS is caused by specific mutations in the gene encoding for the enzyme mevalonate kinase (MVK), resulting in depressed activity in an important enzyme for cholesterol biosynthesis. Mutations in the MVK gene result in either HIDS or mevalonic aciduria. In HIDS, activity of MVK is reduced to 5–15% of normal; however, mevalonic aciduria is an autosomal recessive disorder with complete absence of MVK activity and usually presents with a more severe clinical picture
• MVK catalyses ATP-dependent phosphorylation of mevalonate to produce 5-phosphomevalonate, which is a key component of isoprenoid and cholesterol metabolism. The mechanism by which partial MVK deficiency causes inflammatory attacks remains unclear
• Elevated serum IgD was believed to be linked to the pathophysiology of the disease however it now appears that these elevated levels are secondary to a systemic inflammatory response
• Variant HIDS presents in older patients with no known gene mutations. Patients with variant HIDS have similar symptoms
• Patients with HIDS characteristically experience recurrent episodes of fever and inflammation that begin in infancy. Additional symptoms can include lymphadenopathy, gastrointestinal complaints, aphthous ulcers, arthralgias, and skin reactions
• Diagnosis is based on clinical signs associated with increased serum concentrations of IgD, low activity of the MVK enzyme, and MVK gene mutation analysis

Epidemiology

Incidence/Prevalence

• HIDS is extremely rare although it is difficult to know exactly how many people are affected
• A 2006 study suggested 180 patients with HIDS have been reported worldwide
• A recent Dutch study which screened newborn infants found a carrier frequency of 1:65 for the most common MVK deficiency. Given that the prevalence of HIDS in the Netherlands is far smaller than these screening results would suggest, it is likely that both under-diagnosis and incomplete gene penetrance exists

Age

• HIDS has a very early age at onset (median, 0.5 years) with life-long persistence of periodic fever. Although febrile attacks continue throughout life, the frequency of attacks is usuallyhighest in childhood and adolescence

Gender

• Male-to-female ratio may be 3:2 according to one study

Race

• Most patients with HIDS are of European descent, particularly the Netherlands, France, and Italy (~60% are either Dutch or French)
• More recently, HIDS has been identified in patients from England, Germany, Turkey, the Czech Republic, the United States and Japan

Genetics

• Approximately one in two patients with HIDS has an affected sibling
• The susceptibility gene frequency is low, with a ratio of 1:350 of persons with the gene versus those without it. Hence HIDS is not usually observed in the parents or offspring of affected patients
• Most patients with HIDS are compound heterozygotes for missense mutations in the MVK gene
• The V377I mutation is present in >80% of patients with HIDS. V377I mutation results in a slight reduction in the stability of recombinant human MVK protein and in the catalytic activity of the enzyme
• Less than 1% of cases have a complete deficiency. When there is complete deficiency, the patient has mevalonic aciduria

Risk factors

• 50% of patients have a positive family history
• Febrile attacks can be precipitated by vaccination, minor trauma, surgery, or stress

Etiology

• Caused by mutations in the gene encoding the enzyme MVK. This gene is located at chromosome 12q24 and is subjected to autosomal recessive inheritance

History

• HIDS has a very early age ( 1 year) of onset. Patients present with a history of episodic attacks of fever which may occur every 4-8 weeks, with duration of 4-7 days. Intervals between attacks can vary substantially in an individual and from one individual to another. Some patients have a lack of attacks for months or years. Attacks may be precipitated by vaccination, minor trauma, surgery, or stress
• High fever is preceded by chills in 76% of patients. Other common manifestations are lymphadenopathy (94% of patients), abdominal pain (72%), vomiting (56%), diarrhea (82%), headache (52%), and skin lesions (82%). Joint manifestations such as polyarthralgia (80% of patients), and nondestructive arthritis mainly involve large joints such as knees and ankles (reported in 68% of patients). Some patients develop painful aphthous ulcers orally and/or vaginally. Serositis is rare
• Amyloidosis is common in other periodic fever syndromes. It has only recently been described in a few patients with HIDS
• During an attack, symptoms may mimic acute abdomen, with some patients undergoing unnecessary laparotomy and/or appendectomy.
• Patients usually have symptom-free periods after an attack; however, skin and joint symptoms resolve slowly
• Arthritis may lead to joint destruction in some cases
• Cutaneous manifestations can occur, with erythematous macules being the most common manifestation during an attack. Other skin lesions may present, including erythematous papules, urticarial lesions, erythematous nodules, and more rarely petechiae and/or purpura. When biopsy is performed, mild vasculitis is the typical finding

Physical findings on examination

• High spiking fever
• Lymphadenopathy (present in 94% of cases)
• Other clinical findings:
• Splenomegaly
• Arthritis mainly of the large joints (eg, knee and ankle)
• Skin lesions (erythematous macules and papules, urticaria, erythematous nodules, and occasionally petechiae and purpura), and aphthous ulcers in the mouth or vagina

Blood test findings

• Serum IgD and IgA levels: Persistently elevated (>100 IU/mL or >14 mg/dL). 82% of cases also have elevated serum IgA levels (2.6 g/L or 260 mg/dL). Measure IgD on 2 occasions at least 1 month apart. Normal results do not exclude this disease (especially in younger patients). If serum IgD/ IgA is elevated then the diagnosis is likely. If levels are normal the diagnosis should be sought on genetic and clinical grounds
• Complete blood count and C-reactive protein (CRP): During an attack, a brisk acute phase response occurs with leukocytosis and high levels of CRP
• Serum amyloid A: May be increased; however, the risk of amyloidosis in HIDS seems to be extremely low
• Inflammatory mediators: During symptomatic episodes there are increased concentrations of
• Inflammatory mediators including:
• Interferon [IFN]-gamma
• Interleukin [IL]-6
• Tumor necrosis factor [TNF]-alpha
• Anti-inflammatory compounds including:
• IL-1 receptor antagonist
• Soluble TNF receptors p55 [sTNFr p55] and sTNFr p75]

Other laboratory test findings

• Urine screening:
• Increased urine mevalonic acid/ creatinine ratio is found during severe episodes of fever but not between crises
• Elevated urinary excretion of neopterin reflects disease activity
• Urine should be screened for protein (may be due to renal amyloid)

Other diagnostic test findings

• Molecular genetic test of the MVK gene: 76% of patients clinically affected with HIDS are reported to have mutations in the MVK gene, with most patients being compound heterozygotes. About 80% of mutations are missense. In HIDS, mutations are along the area that encodes for the protein; whereas in mevalonic aciduria, the MVK mutations are mainly clustered to the same region of the protein. The most common mutations are V377I and I268T
• Histological examination of skin lesions: May reveal vasculitis

• Any typical or atypical viral/bacterial or other infectious process
• Mevalonic aciduria (MVA)
• Other periodic fever syndromes
• Chronic infantile neurologic cutaneous articular disease
• Familial cold autoinflammatory syndrome
• Familial Mediterranean fever
• Muckle-wells syndrome
• Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAFA syndrome)
• Tumor necrosis factor receptor associated periodic syndrome
• Causes of elevated IgD
• Aspergillosis
• Ataxia-telangiectasia
• HIV/AIDS
• Hodgkin Disease
• Sarcoidosis
• Tuberculosis
• Surgical causes of recurrent severe abdominal pain
• Non surgical causes of recurrent severe abdominal pain
• Acute intermittent porphyria
• Hereditary or acquired angioedema

General treatment items

• Treatment is generally based on expert opinion, as this is a rare condition, with most evidence presented in the form of case reports or very small trials
• Symptomatic control with NSAIDs may mitigate symptoms including fever. They may or may not be of benefit in the prodromal phase (before fever onset)
• Glucocorticoids may be effective and some authors recommend their use if NSAIDs fail to alleviate symptoms.
• Treatment with thalidomide resulted in a non-significant decrease of acute phase protein synthesis but did not reduce recurrence in a recent double-blind, randomized, crossover trial involving 6 patients.
• Simvastatin 80mg /day resulted in a drop in urinary mevalonic acid concentration and decreased the number of febrile days in a double blind crossover trial of six patients
• Trials of etanercept have shown mixed results. A rare subset of patients with HIDS may benefit from its use.
• IL-1 antagonist (anakinra) has recently been reported to be more effective than etanercept
• Unlike some other periodic fever syndromes, colchicines are not effective

Medications indicated with specific doses

• Ibuprofen
• Adult Dosing
• Pediatric Dosing
• Prednisone
• Adult Dosing
• Pediatric Dosing
• Prednisolone
• Adult Dosing
• Pediatric Dosing
• Simvastatin
• Adult Dosing

Prognosis

• Patients with HIDS have febrile attacks throughout their lives, though frequency is highest in childhood and adolescence. There may be attack-free period for months or years
• There are few reports of amyloidosis associated with HIDS
• Attacks of arthritis generally do not lead to joint destruction except in rare cases

Pregnancy/Pediatric effects on condition

• HIDS is not associated with complications in pregnancy and does not appear to adversely affect fetal outcome. Attack frequency tends to diminish during pregnancy
• HIDS is inherited via an autosomal recessive trait

Synonyms/Abbreviations

Abbreviations

• Hyper-IgD
• HIDS

ICD-9-CM

• 279.9 Unspecified disorder of immune mechanism

ICD-10-CM

• D89.9 Disorder involving the immune mechanism, unspecified

1. Oretti C, Barbi E, Marchetti F, et al. Diagnostic challenge of hyper-IgD syndrome in four children with inflammatory gastrointestinal complaints. Scand J Gastroenterol. 2006;41(4):430-6.
2. Scolozzi R, Boccafogli A, Vicentini L. Hyper-IgD syndrome and other hereditary periodic fever syndromes. Reumatismo. 56(3):147-55.
3. Kraus CL, Culican SM. Nummular keratopathy in a patient with Hyper-IgD Syndrome. Pediatr Rheumatol Online J. 2009;7:14.
4. Padeh S. Periodic fever syndromes. Pediatr Clin North Am. 2005;52(2):577-609, vii.
5. de Wolff JF, Dickinson SJ, Smith AC, et al. Abnormal IgD and IgA1 O-glycosylation in hyperimmunoglobulinaemia D and periodic fever syndrome. Clin Exp Med. 2009;9(4):291-6.
6. Genetic Home Reference. Mevalonate kinase deficiency. http://ghr.nlm.nih.gov/condition/mevalonate-kinase-deficiency. Updated April, 2011. Last accessed July 24, 2012.
7. Simon A, Cuisset L, Vincent MF, et al. Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med. 2001;135(5):338-43.
8. Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med. 2001;345(24):1748-57.
9. Steichen O, Van der hilst J, Simon A, et al. A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol. 2009;36(8):1677-81.
10. Klasen IS, Göertz JH, van de Wiel GA, et al. Hyper-immunoglobulin A in the hyperimmunoglobulinemia D syndrome. Clin Diagn Lab Immunol. 2001;8(1):58-61.
11. Drenth JP, van Deuren M, van der Ven-Jongekrijg J, et al. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood. 1995;85(12):3586-93.
12. Cuisset L, Drenth JP, Simon A, et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet. 2001;9(4):260-6.
13. Yao Q, Furst DE. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology (Oxford). 2008;47(7):946-51.
14. Grateau G. Clinical and genetic aspects of the hereditary periodic fever syndromes. Rheumatology (Oxford). 2004;43(4):410-5.
15. de Hullu JA, Drenth JP, Struyk AP, et al. Hyper-IgD syndrome and pregnancy. Eur J Obstet Gynecol Reprod Biol. 1996;68(1-2):223-5.
16. Lachmann HJ, Goodman HJ, Andrews PA, et al. AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases. Arthritis Rheum. 2006;54(6):2010-4.
17. Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.
18. Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis. 2006;1:13.
19. Houten SM, van Woerden CS, Wijburg FA, et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003;11(2):196-200.
20. Haraldsson A, Weemaes CM, De boer AW, et al. Immunological studies in the hyper-immunoglobulin D syndrome. J Clin Immunol. 1992;12(6):424-8.