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Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. REFERENCES

AA amyloidosis is the most serious potential complication of the inherited autoinflammatory syndromes and frequently results in end-stage renal failure. Although this complication is well recognized in familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and Muckle-Wells syndrome, there is only 1 previous published report of its occurrence in hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). We report 2 further cases of patients with AA amyloidosis in HIDS, both of whom developed dialysis-dependent renal failure, and we describe the outcome of the first renal transplant in this setting.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is a recessively inherited autoinflammatory condition predominantly found in patients originating from northwestern Europe. It was first described in 1984 (1) in a group of children of Dutch ancestry. The disease manifests in infancy and is characterized clinically by recurrent attacks of fever typically lasting 3–7 days and usually occurring 6–12 times a year. These episodes are often accompanied by headache, cervical lymphadenopathy, arthritis, diarrhea and vomiting, and rash (2). Attacks may be precipitated by immunizations or minor infection, and the disease usually ameliorates with age. Clinical features are accompanied by an acute-phase response and polyclonal elevations of serum immunoglobulin D and often IgA concentrations.

In 1999, HIDS was reported to be associated with mutations in the mevalonate kinase gene (MVK), encoding the enzyme mevalonate kinase (3), which is involved in cholesterol, farnesyl, and isoprenoid biosynthesis. Mutations in this gene can also cause mevalonate aciduria, which is a recessively inherited inborn error of metabolism that results in failure to thrive, developmental delay, hepatosplenomegaly, multisystem inflammation, and episodes of fever. HIDS, the milder disease, is associated with less impaired mevalonate kinase enzyme activity. To date, 39 HIDS-associated mutations have been described and are registered with the INFEVERS registry (http://fmf.igh.cnrs.fr/infevers/), of which the most common encode MVK V377I and I268T. In contrast to the other periodic fever syndromes, the risk of AA amyloidosis in HIDS seems to be extremely low. Only 1 case has been previously reported, that of a 27-year-old Italian man who presented with nephrotic syndrome (4), and the extensive Nijmegen registry (http://hids.net/index_bestanden/HIDSregistry.htm) of >200 patients contains no cases of AA amyloidosis. Herein we describe 2 further patients with HIDS complicated by AA amyloidosis.

CASE REPORTS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. REFERENCES

Patient 1.

The patient, a 19-year-old British Caucasian man, presented with end-stage renal failure, and kidney biopsy demonstrated AA amyloidosis (Figure 1). Whole-body 123I- labeled serum amyloid P scintigraphy showed additional amyloid deposits in the liver and spleen (Figure 2). A history of periodic fevers, which had begun in the patient's first year of life and had occurred every 6–8 weeks, lasting 7–14 days, was subsequently obtained. Febrile episodes were accompanied by cervical and axillary lymphadenopathy, nausea, vomiting and diarrhea, aphthous ulcers, anorexia, and transient arthralgia. Routine childhood immunizations had precipitated florid attacks. The patient's older brother had a very similar illness, which on limited grounds had been diagnosed as Crohn's disease. Both siblings thought that their disease had become milder by late adolescence.

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Figure 1. Renal biopsy specimen from patient 1, demonstrating A, amorphous amyloid deposits in the glomeruli with Congo red staining, and B, positive immunohistochemistry with anti–serum amyloid A protein monoclonal antibodies.

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Figure 2. Anterior whole-body123I-labeled serum amyloid P (SAP) scan in patient 1, showing amyloid deposits in the liver and spleen (the kidneys are not visible due to poor renal perfusion in end-stage renal failure). Encouragingly, there was no evidence of progressive amyloid deposition on repeat SAP scintigraphy 2 years later.

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Investigations demonstrated an elevated serum IgD concentration at 337 mg/liter and a variably intense acute-phase response (Figure 3). DNA sequencing demonstrated that both siblings were compound heterozygotes for the MVK V377I and I268T variants. Sequencing of MEFV and TNFRSF1A revealed no mutations. The patient's autoinflammatory disease remained very active while he was undergoing dialysis (median C-reactive protein [CRP] level 42 mg/liter, median serum amyloid A protein [SAA] concentration 39 mg/liter). A 6-week therapeutic trial of interleukin-1 receptor antagonist (IL-1Ra; anakinra) in April–May 2004 had no clear benefit, although he had a pronounced febrile attack when this treatment was discontinued. He had no adverse reactions to a peptide vaccine against hepatitis B, but in early 2005 he had a prolonged burst of inflammatory activity following vaccination against influenza, which culminated in pericarditis complicated by cardiac tamponade. In August 2005, he received a live related renal transplant from his mother, a confirmed carrier of MVK V377I, which is functioning well at 6-month followup. He has not had a symptomatic attack of HIDS in the 5 months since.

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Figure 3. Serial measurements of the acute-phase proteins serum amyloid A (SAA) and C-reactive protein (CRP) in patient 1. During this period, the patient had a median SAA concentration of 39 mg/liter. A 6-week trial of anakinra in April–May 2004 showed no clear benefit, but the patient had an attack of hyperimmunoglobulinemia D with periodic fever syndrome when this treatment was discontinued.

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Patient 2.

The patient, a German Caucasian man, presented at age 22 years with nephrotic syndrome and was found to have AA amyloidosis on renal biopsy. His renal function gradually declined, and dialysis was initiated within 3 years. He also reported a history of periodic febrile attacks from infancy, occurring every 6–8 weeks, more marked in winter. Accompanying symptoms characteristically included headache, cervical and inguinal lymphadenopathy, and diarrhea and vomiting. He was found to have IgG2/4 subclass deficiencies at age 9 years, and his attacks had been thought to represent recurrent infections, although he had received intravenous immunoglobulin supplementation without benefit. His serum IgD concentration was elevated at 104 mg/liter. DNA sequencing demonstrated not only MVK V377I and a previously unreported MVK mutation encoding L234P, but also a variant, R92Q, in TNFRSF1A, the gene responsible for tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS). The combination of TNFRSF1A R92Q and MVK V377I has been described in an unrelated patient with HIDS (5).

The patient was started on etanercept therapy, with good clinical and biochemical response (Figure 4). A live related renal transplant is planned.

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Figure 4. Serial measurements of the acute-phase response proteins SAA and CRP in patient 2. The patient's median CRP level was 7 mg/liter and his median SAA concentration was 8 mg/liter. He has received etanercept since September 2004. See Figure 3 for definitions.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. REFERENCES

These 2 young men are only the second and third patients reported to have developed AA amyloidosis as a complication of HIDS. Reactive systemic AA amyloidosis is a potential complication of any disorder associated with a sustained acute-phase response, and the list of underlying chronic inflammatory, infectious, or neoplastic disorders is almost without limit. This type of amyloid usually presents with kidney dysfunction, and the amyloid fibrils are derived from cleavage fragments of the circulating acute-phase reactant, SAA. SAA is an apolipoprotein of high-density lipoprotein, which is synthesized by hepatocytes under the transcriptional regulation of IL-1, IL-6, and TNFα (6). In healthy subjects, the circulating concentration of SAA is ∼1 mg/liter, but this can rise by >1,000-fold in the presence of inflammation. Sustained or frequent high plasma levels of SAA are a prerequisite for the development of AA amyloidosis, but this is clearly not sufficient, since this form of amyloid occurs in <10% of the overall population at risk (7, 8).

AA amyloidosis is a well-recognized complication of the inherited autoinflammatory conditions generally. Familial Mediterranean fever (FMF) carries a high risk, and prior to the discovery in 1972 that colchicine prophylaxis suppresses inflammation in this disease, up to 60% of patients with FMF died of amyloidosis (9); even recently, it has been reported in 12.9% of patients in a large Turkish series (10). The incidence of AA amyloidosis is 25% in our series of patients with TRAPS, and 26% among those with Muckle-Wells syndrome (MWS). It is thought that the high incidence of AA amyloidosis in these diseases is related to the intense inflammatory response which often continues to be present even when patients are asymptomatic. Patients with HIDS also seem to have marked acute-phase reactivity (11), suggesting that milder disease may not be the explanation for their apparent low susceptibility to AA amyloidosis.

Among patients attending our center, the median duration of symptomatic disease preceding the development of AA amyloidosis has been 21.5 years in 30 patients with FMF, TRAPS, or MWS, and in our entire cohort of 375 patients, the median latency to AA amyloidosis was 17 years. It is therefore possible that the frequent amelioration of HIDS after adolescence contributes to the low incidence of AA amyloidosis. Nevertheless, AA amyloidosis evidently can occur, and the mainstay of management needs to be the control of disease activity. Patients with HIDS do not respond to colchicine or thalidomide (12). There have been encouraging preliminary reports of response to etanercept in 2 patients (13), and the effect of IL-1Ra (anakinra) is also being studied (14), although it did not seem particularly effective in our patient 1. The mechanism by which childhood immunization produces attacks remains obscure; it has been postulated that vaccination-associated fever may lead to a reduction in residual mevalonate kinase activity as the body temperature rises (15). It is certainly encouraging that the much greater antigenic stimulus of a renal transplant has not exacerbated HIDS in patient 1 to date, but the long-term course of our patients' disease following renal transplantation remains to be determined.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. REFERENCES
  • 1
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  • 2
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  • 3
    Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, et al, International Hyper-IgD Study Group. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet 1999; 22: 17881.
  • 4
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  • 5
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    Bodar EJ, van der Hilst JC, Drenth JP, van der Meer JW, Simon A. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med 2005; 63: 2604.
  • 15
    Houten SM, Frenkel J, Rijkers GT, Wanders RJ, Kuis W, Waterham HR. Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome. Hum Mol Genet 2002; 11: 311524.