SYSTEMIC AA-TYPE amyloidosis is a common

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1 CASE REPORT Hereditary Periodic Fever With Systemic Amyloidosis: Is Hyper-IgD Syndrome Really a Benign Disease? Rainer Siewert, MD, Jörg Ferber, MD, PhD, Rolf Dieter Horstmann, MD, PhD, Christof Specker, MD, PhD, Peter Julius Heering, MD, PhD, and Christian Timmann, MD We report a case of amyloidosis in association with hyperimmunoglobulinemia D syndrome (HIDS). The patient showed typical clinical features of HIDS. He had crescentic glomerulonephritis progressing to end-stage renal disease at age 13 years. Eight years later, he developed an AA-type amyloidosis with extensive involvement of the intestine, respiratory tract, and thyroid gland. These unusual complications of HIDS seriously challenge the assumption that the disease is associated with a good prognosis. Am J Kidney Dis 48:E41-E by the National Kidney Foundation, Inc. INDEX WORDS: Amyloidosis; hereditary periodic fever; hyperimmunoglobulinemia syndrome; pauci-immune crescentic glomerulonephritis; mevalonic aciduria; autoinflammatory syndromes; periodic fever. SYSTEMIC AA-TYPE amyloidosis is a common and serious complication affecting patients with such chronic inflammatory diseases as rheumatoid arthritis, Crohn disease, and periodic fever syndromes. Apart from the activity of the actual underlying disease, genetic dispositions also have a major role. 1-3 The periodic fever syndromes are a heterogeneous group of genetically determined diseases. They all share the common feature of cytokinemediated autoinflammation associated with a selflimiting febrile attack. Duration and frequency of the febrile attacks, as well as typical organ involvements, vary greatly, so that clinical criteria can be used primarily for classifying these syndromes. The possibilities opened up by molecular genetics permit a more reliable assignment to the respective disease entities. Apart from the elucidation of clinical overlap syndromes, evaluation of the different phenotypes and clinical courses also has become possible. The first onset of hyperimmunoglobulinemia D syndrome (HIDS) with febrile attacks of 3 to 7 days duration typically is reported before the age of 1 year. The clinical picture, with arthralgia, lymphadenopathy, abdominal pain, vomiting, diarrhea, and skin rashes, strongly reminds the clinician of a severe form of systemic juvenile arthritis. Through the detection of the typical increase in immunoglobulin D (IgD) levels ( 100 IU/mL) and the usually present increase in IgA levels, the diagnosis suggests itself clinically ( Molecular genetic analysis usually shows a compound heterozygotic missense mutation of the gene encoding mevalonate kinase (MVK) on chromosome 12. These missense mutations lead to reduced catalytic activity of MVK, 4 an enzyme that follows hydroxy-methylglutaryl coenzyme A reductase in the isoprenoid/cholesterol metabolism and catalyzes the phosphorylation of mevalonate (Fig 1). Previous pathophysiological assumptions involved the induction of cytokine expression by an imbalance of the metabolic products mevalonate and mevalonate phosphate; the precise mechanism remains unclear. In more than 200 cases of HIDS reported worldwide, the disease did not usually result in death; at the beginning of adolescence, HIDS often shows reduced activity and follows a benign course. 5,6 In contrast to the other febrile syndromes, systemic amyloidosis 7 or rapidly progressive glomerulonephritis each were described only as case reports. 8 Our patient experienced an From the Department of Nephrology, Solingen General Hospital, University of Cologne; Dialysis Center Leverkusen; Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg; and Department of Rheumatology and Clinical Immunology, Center of Internal Medicine, Essen-Sued, Germany. Received January 9, 2006; accepted in revised form May 23, Originally published online as doi: /j.ajkd on August 2, Support: None. Potential conflicts of interest: None. Address reprint requests to Rainer Siewert, MD, Solingen General Hospital, University of Cologne, Department of Nephrology, Gotenstr 1, D Solingen, Germany. siewert@klinikumsolingen.de 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 48, No 3 (September), 2006: E41-E45 e41

2 e42 SIEWERT ET AL West European origin. Since the age of 2 months, short febrile attacks (39 C to 40 C) had occurred, initially interpreted as viral infections of the upper respiratory tract. These febrile attacks lasting 4 to 6 days were accompanied by painful arthralgia; diffuse abdominal pain also occurred, associated with emesis and diarrhea. Attacks recurred every 4 to 6 weeks. Long phases of repetitive activity were followed by terms of 3 to 4 months in which the disease paused. Acute renal failure occurred between the ages of 13 and 14 years; the biopsy showed pauci-immune crescentic glomerulonephritis. In the course, the patient developed endstage renal disease. At this point, there was no evidence for renal amyloidosis. Physical Examination On physical examination during a febrile attack, we noted a maculopapular rash (Fig 2); aphthous stomatitis; swelling of the lips, tongue, and pharynx; and computed tomographic defined extensive edema of the entire gastrointestinal tract. Intermittently, enlargement of mainly cervical lymph nodes was documented. Fig 1. Metabolic cascade of cholesterol metabolism. MVK is a key enzyme in cholesterol synthesis. aggressive course of the disease associated for the first time with both complications. CASE REPORT Patient History Our male patient, aged 22 years, with HIDS was born in 1981 as the second child of healthy unrelated parents of Pathology Our laboratory findings showed a marked increase in IgA (800 to 1,080 mg/dl [8.0 to 10.8 g/l]; normal level, 380 mg/dl) and IgD levels (515 to 690 mg/dl [5,150 to 6,900 g/l]; normal level, 140 mg/dl), as well as a serum increase in amyloid A protein level (24 mg/l [0.024 g/l]; normal level, 10 mg/l). Febrile attacks were accompanied by an increase in C-reactive protein (22 mg/dl [220 g/l]; normal level, 0.5 mg/dl) and interleukin 6 levels (105 pg/ml [105 g/l]; normal level, 5 pg/ml), as well as mild leukocytosis. Biopsy specimens showed extensive amyloid- Fig 2. Typical maculopapular rash occurring during fever episodes in our patient.

3 HYPER-IGD SYNDROME AND AMYLOIDOSIS e43 attacks, diarrhea, and cachexia (body weight, 44 kg), as well as end-stage renal disease, our patient was administered subcutaneous etanercept, 25 mg/wk. No more fever episodes occurred with this treatment, and the patient s exercise capacity improved markedly. About 3 months after initiation of anti tumor necrosis factor therapy, the patient developed severe left ventricular failure, possibly caused by cardiac amyloidosis, leading to death in outpatient care. Conclusion The case presented fulfills all clinical and laboratory criteria for HIDS. A typical compound heterozygotic missense mutation was confirmed genetically. There was no clinical or laboratory evidence of a competing disease, such as rheumatoid arthritis, Crohn disease, or tuberculosis. A second disease from the group of periodic fever syndromes was excluded by using molecular genetic analysis. Fig 3. Genotyping of relatives showed healthy parents and brother and a compound heterozygotic patient. osis of the thyroid gland, entire intestines, and lower respiratory tract. Immunohistochemical staining of amyloid fibrils of the respiratory tract confirmed the diagnosis of AA amyloidosis. Based on the suspected diagnosis of hereditary periodic fever, the presence of HIDS was shown by molecular genetic testing of the MVK (H20P [exon 2] and V250I [exon 8]; case 216, HIDS Register Nijmwegen, The Netherlands). The latter mutation has not been described yet. A compound heterozygosity of the patient s MVK genotype was confirmed by genotyping of his parents (Fig 3). In addition, genotyping of the Mediterranean fever gene and tumor necrosis factor receptor superfamily, member 1A gene showed no evidence of familial Mediterranean fever and tumor necrosis factor receptor associated periodic fever syndrome, respectively. Molecular analysis of the serum amyloid A 1 (SAA1) gene showed the SAA1 / genotype (homozygous for val 52, ala 57). Clinical Course Trials with glucocorticoids, nonsteroidal anti-inflammatory drugs, various antibiotics, or prophylactic immunoglobulin failed. As an ultimate rescue therapy for persisting febrile DISCUSSION In childhood, our patient showed a typical course of HIDS, with a first unusual complication (rapid progressive glomerulonephritis) in early adolescence. First seen in our center at age 21 years, he had already developed severe systemic amyloidosis. Irrespective of the discussed causes, this case argues against the clinical view of HIDS as a benign disease. Assumptions that earlier initiation of causal therapy had modified the course of the disease remain speculative. The severe course of disease in our patient was extraordinary. The mutations in MVK, an enzyme in the isoprenoid pathway (Fig 1), define 2 disease entities: HIDS and mevalonic aciduria. Both share recurrent fever episodes, whereas patients with mevalonic aciduria additionally develop growth disturbance, cerebellar ataxia, cataracts, severe cognitive disorders, and retinal dystrophies. Measurement of different enzyme activities (mevalonic aciduria, 0.5%; HIDS, 1% to 15%) supports the hypothesis that both entities represent different forms of one and the same disease. 9 The patient described here was compound heterozygous for H20P and V250I. H20P has been described for patients with HIDS and patients with mevalonic aciduria. All other cases of mevalonic aciduria resulted from mutations causing amino acid exchanges located between positions 243 and 334 of the MVK polypeptide chain (Fig 4). 4 V250I found in our patient with generalized amyloidosis, as well as L265R identified in a patient defined as HIDS with systemic amyloid-

4 e44 SIEWERT ET AL Fig 4. Summary of mutations identified in HIDS and mevalonic aciduria. Regions of interest in our case are highlighted in red; HIDS mutations, bold type. Mevalonic aciduria mutations (#) are summarized in the large square. Data from Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S, van der Meer JW, Grateau G, Delpech M, for the International Hyper-IgD Study Group: Molecular analysis of MVK mutations and enzymatic activity in hyper-igd and periodic fever syndrome. Eur J Hum Genet 9: , (With permission of the Eur J Hum Genetics). osis, 7 are located in the same region. Possibly, mutations affecting this particular part of the molecule may be associated with more severe courses of MVK-associated disease. Pathophysiological processes involved in the development of AA amyloidosis are largely known. Allelic variants of the SAA1 were reported to modify the risk for amyloidosis in patients with inflammatory diseases. The homozygous genotype and allele of SAA1 showed association with amyloidosis in patients with familial Mediterranean fever and rheumatoid arthritis, respectively. The homozygous genotype of SAA1 found in our patient may indicate a risk factor for amyloidosis as described for familial Mediterranean fever, but additional studies with more patients are needed to evaluate this association In conclusion, additional investigations are needed to explain why HIDS, as shown in this patient, may no longer be regarded as a benign disease because it can cause systemic amyloidosis and pauci-immune crescentic glomerulonephritis. In this context, elucidation of the key enzymes MVK and hydroxy-methylglutaryl coenzyme A reductase in the biosynthesis of cholesterol should be given a more prominent role. Solving these problems by using, for example, a suitable animal model thus could act as a bridge between autoinflammation, cholesterol, and arteriosclerosis. REFERENCES 1. Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349: , Buxbaum JN: Systemic amyloidoses. Curr Opin Rheumatol 16:67-75, Drenth JP, van der Meer JW: Hereditary periodic fever. N Engl J Med 345: , 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 9: , van der Meer JW, Vossen JM, Radl J, et al: Hyperimmunoglobulinaemia D and periodic fever: A new syndrome. Lancet 1: , Drenth JP, Haagsma CJ, van der Meer JW: Hyperimmunoglobulinemia D and periodic fever syndrome: The clinical spectrum in a series of 50 patients. Medicine 73: , 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 50: , Tsimaratos M, Kone-Paut I, Daniel L, Gubler MC, Dussol B, Picon G: Crescentic glomerulonephritis in hyper IgD syndrome. Pediatr Nephrol 13: , Houten SM, Koster J, Romeijn GJ, et al: Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Hum Genet 9: , Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN: Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358:24-29, Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 48: , 2003

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