Aspergillosis and Felty's syndromePediatric / S. Morelli et al. review CASE REPORT Mevalonate deficiency and Dutch type periodic fever

J. Frenkel1, S.M. Houten2, H.R. Waterham2, R.J.A. Wanders2, G.T. Rijkers3, J.L.L.Kimpen1, R. Duran4, B.T. Poll-The4, W. Kuis3

Departments of General Pediatrics1, ABSTRACT an abnormally high serum IgD concen- Pediatric Immunology3, and Metabolic Dutch type periodic fever (DPF) is an tration were published in 1984 (1). The Disorders4, Wilhelmina Children’s autosomal recessive hereditary fever first detailed description of this disorder, Hospital, University Medical Center, syndrome. Cases have been reported was published by van der Meer et al. (2), Utrecht; Department of Clinical Chemistry worldwide, the majority from France and who introduced the term hyperimmuno- and Pediatrics2, Emma Children’s Hospi- The Netherlands. From infancy the pa- globulinemia D and periodic fever syn- tal, Academic Medical Center, Amsterdam, The Netherlands. tients suffer fever attacks that recur every drome (HIDS). Most patients have been 2-8 weeks, often precipitated by immu- of Dutch extraction, although cases have Joost Frenkel, MD; Sander M. Houten, MSc; Hans R. Waterham, PhD; Ronald nizations, infections or emotional stress. been reported worldwide (3). Hence, the J.A. Wanders, PhD; Ger T. Rijkers, PhD; Fever lasts 2-7 days and can be accom- disease is also known as Dutch type pe- Jan L.L. Kimpen; Ries Duran, PhD; panied by malaise, headache, diarrhea, riodic fever (DPF, MIM#260920). BweeTien Poll-The, MD, PhD; and Wietse , vomiting, skin rashes, Inheritance is autosomal recessive. The Kuis, MD, PhD. , arthritis, tender lymphadeno- first febrile crises usually occur in in- Please address correspondence and reprint pathy, hepatosplenomegaly, and oral and fancy and recur at varying intervals. The requests to: Joost Frenkel, MD, Depart- genital ulcers. Labarotory evaluation crises are typically triggered by infec- ment of General Pediatrics, Wilhelmina during fever shows granulocytosis and tions and childhood immunizations. In Children’s Hospital - University Medical elevated acute phase reactants. addition to fever the patients often ex- Center Utrecht, Home mailbox DPF is caused by a deficiency of the en- perience malaise, chills, headache, arth- KE.04.133.1, P.O. Box 85090, zyme mevalonate kinase (MK). Besides ralgias, nausea, abdominal pain, and di- 3508AB Utrecht, The Netherlands. DPF, the spectrum of MK deficiency in- arrhea, and show cutaneous rashes, hepa- Email [email protected] cludes a severe phenotype, mevalonic tosplenomegaly, tender cervical lymph- Clin Exp Rheumatol 2000: 18: 525-532. aciduria (MA). MA patients have less adenopathy, and frank arthritis (3). Gran- © Copyright CLINICAL AND residual MK activity, leading to substan- ulocytosis and elevated acute phase re- EXPERIMENTAL RHEUMATOLOGY 2000. tially higher urinary actants during attacks are indicative of excretion than in DPF. Mevalonic aci- an acute inflammatory reaction, but a Key words: Fever, IgD, duria is characterized by mental retarda- satisfactory explanation for these find- hypergammaglobulinemia, mevalonate tion and dysmorphic features in addition ings is lacking. Linkage analysis exclu- kinase, mevalonic acid, familial to the clinical features of DPF. At the ge- ded the affected in FMF as a can- Mediterranean fever, periodicity. nomic level, several mutations of vary- didate involved in the etiology of HIDS ing severity have been identified. The (4). DPF phenotype is caused by one parti- The cause of HIDS remained obscure cular mild missense mutation. Most pa- until 1999. Then, HIDS patients were tients are compound heterozygotes for shown to have mutations in the gene this mutation and a more severe muta- MVK, which codes for the meva- tion. lonate kinase (MK, EC. 2.7.1.36) (5, 6). The mechanism by which MK deficiency MK is an early enzyme in isoprenoid bio- leads to fever is not understood. The vast synthesis (Fig. 1). This biochemical path- majority of DPF patients have persist- way produces several compounds, in- ently elevated serum IgD and can be cluding . Deficient MK en- classified as having hyperimmunoglo- zyme activity had been described previ- bulinemia D and periodic fever syndrome ously in a rare autosomal recessive dis- (HIDS). Conversely, most HIDS patients ease, mevalonic aciduria (MA, MIM# have MK deficiency and hence DPF, but 251170) (7). MA is characterized by mild the two disorders do not overlap entirely. to severe mental retardation, cerebellar atrophy, manifested by progressive atax- Introduction ia and dysarthria, myopathy, leading to The first reports of of children with re- hypotonia, and cataracts. Most of these current febrile attacks in the presence of children have dysmorphic facial features.

525 PEDIATRIC REVIEW Periodic fever and mevalonate kinase deficiency / J. Frenkel et al.

Fig. 1. Isoprenoid biosynthesis. Mevalonate kinase catalyzes the reaction immediately after HMG-CoA reductase. End products of this route include isopentenyl tRNAs, dolichol, Heme A, ubiquinone, farnesyl and geranylgeranyl groups for protein isoprenylation, and cholesterol, with all its derivatives. In mevalonate kinase deficiency there is accumulation of mevalonic acid.

Interestingly, MA patients suffer frequent Epidemiology Symptoms inflammatory attacks, with fever, vom- At least 144 patients have been diag- Disease onset in HIDS is, characteristi- iting, diarrhea, , cervical lym- nosed with HIDS worldwide (9). Most cally, in infancy. Subsequently, patients phadenopathy and hepatosplenomegaly, of these are from Europe, the majority suffer repeated attacks, which can be during which white blood cell counts and being Dutch (55%) and French (25%), precipitated by infections, minor trauma, acute phase reactants are elevated (8). with far smaller numbers being reported physical or emotional stress, menses, and Hence, despite the differences between from Sweden, Germany, the Czech Re- by childhood immunizations. Most at- MA and HIDS, the inflammatory crises public, the United Kingdom, Belgium, tacks, however, occur without any clear are similar. The attacks are caused in Italy, and Spain. Patients have also been precipitating event (3). The duration of some way by the MK deficiency, but it reported from Turkey (10), Japan (11) the fever attacks can vary between pa- is not yet understood how. Not all pa- and the United States (12). Heightened tients and even from attack to attack in tients with periodic fever and elevated awareness of the disorder in France and the same patient. In general, fever lasts IgD have MK deficiency. Most of what The Netherlands may partially account for 2 to 7 days, more commonly 3 to 4 we know about DPF dates from before for the higher numbers of patients re- days. However, after the normalization the identification of the molecular defect. ported from these countries as compared of body temperature, it may take several Here we will use the term DPF for those to neighboring states like Belgium and days to weeks before general wellbeing patients who suffer recurrent febrile at- Germany. is restored. Some patients with frequent tacks and have reduced MK activity. The Though the exact incidence of HIDS is febrile attacks do not recover entirely in- term HIDS then includes all patients with unknown, its prevalence in the Nether- between. The episodes typically recur periodic fever and hyper IgD not explain- lands is estimated to be 5 or 6 cases per without strict periodicity, once every 3 ed by infectious or immunological dis- million total population. In reality, this to 6 weeks. However, patients may ex- eases, irrespective of MK activity. figure is probably higher. perience attacks from once every two

526 Periodic fever and mevalonate kinase deficiency / J. Frenkel et al. PEDIATRIC REVIEW

Table I. Cumulative incidence of symptoms and signs during febrile attacks in HIDS (modified identification of MK deficiency, it has from reference 3). become possible to recognize DPF in pa- tients with persistently normal IgD lev- Fever 100% Lymphadenopathy 94% els. Only one such patient has been de- Chills 76% Skin rash 82% scribed, but this shows that increased Abdominal pain 72% Splenomegaly 48% IgD levels are not a prerequisite for the Diarrhea 82% 6% diagnosis of DPF (5). Vomiting 56% Arthritis 68% The high serum IgD level is more likely Headache 52% to be an epiphenomenon than a cause of Arthralgias 80% the inflammatory state in HIDS, despite indications that IgD may stimulate cyto- weeks to once every 2 years. As patients served (15). Serositis is not a regular fea- kine secretion in vitro (22). Furthermore, grow older, attacks tend to become less ture of HIDS. However, acute intestinal elevated IgD is not unique for HIDS severe and less frequent and there may obstruction due to adhesions has been since it has been described in patients even be prolonged disease-free intervals. described in 3 patients, 2 of whom had with other inflammatory conditions, no- Fever is the dominant feature of the at- had no prior surgery (3). tably the periodic fever aphtous stoma- tacks. Body temperature rises abruptly, titis adenitis syndrome (20), often with chills or rigors, remains high, Laboratory findings familial Mediterranean fever (18), Beh- often over 40°C, and then gradually re- Blood abnormalities during attacks are çet’s disease (23), bronchiectasis, and turns to normal. Immediately preceding indicative of an acute phase response. immunodeficiency disorders (19), but it the attacks many patients experience Leukocytosis and granulocytosis are is not a consistent finding in any of these malaise, headache, a sore throat or nasal consistent findings; furthermore, the ery- disorders. congestion; in children irritability and throcyte sedimentation rate and C reac- The high serum IgD concentration in hyperactivity are often noted. tive protein concentration are strongly HIDS is due to increased production, as During the febrile attacks the patients elevated. In between attacks these val- evidenced by the high numbers of IgD- may have various other symptoms (Ta- ues return to normal (16). Complement containing plasma cells (2) in bone mar- ble I). Abdominal pain, diarrhea and levels (C3, C4, CH50) are normal or row aspirates (21). The mechanism that vomiting are common. The pain is some- raised with no indication of an increas- leads to this increased synthesis of IgD times sufficiently severe to be confused ed consumption of complement, whereas in HIDS is unknown. with that of acute appendicitis. Non- circulating immune complexes are pre- bloody diarrhea is prominent in young sent at low levels in 20% of patients (3). Other immunoglobulins children. Arthralgias accompany fever in About 16% of patients have microscopic Other immunoglobulins are freqently most cases. Frank arthritis, mostly affect- hematuria during attacks, but impairment elevated as well. IgA is raised in up to ing the large joints of the lower extremi- of renal function is very rare (17). 82% of HIDS patients. Serum IgM can ties, is also common and may persist be- be high as well, but may be normal or tween crises. Patients frequently com- Immunological findings even low. Similarily, serum IgG is usu- plain of severe headaches (3). IgD ally normal but may be raised, predomi- IgD is a heavily glycosylated immuno- nantly due to elevated IgG3 levels. Signs globulin. It comes in two forms, mem- Tender cervical lymphadenopathy is a brane bound and secreted. Its physiologi- Cytokines constant finding during febrile attacks (3) cal role is largely unknown, as is its role Cytokine production in HIDS has been and the axillary, inguinal and intra-ab- in the pathogenesis of HIDS. Normally studied both in vivo and in vitro, with dominal lymph nodes may also be swol- serum IgD concentrations are below 100 attention focused on cytokines, known len. IU/ml, but they can rise during infectious to induce fever and on mediators with Splenomegaly is present in nearly half and non-infectious inflammatory dis- antiinflammatory properties. These mea- of the patients, though it is a rare find- eases (18-20). Polyclonal elevation of surements have been performed in plas- ing in adult patients, whereas hepatome- serum IgD is a prerequisite for the diag- ma and in supernatants of cultured leu- galy is almost exclusively seen in pedia- nosis of HIDS. Hence, all patients re- kocytes from HIDS patients. During fe- tric patients. ported have had raised serum IgD at brile attacks the serum levels of inter- Rashes have been observed in most some point in their disease course. There feron-g, and interleukin (IL)-6 rise sharp- HIDS cases. These may be macular, ma- is, however, no relationship between dis- ly (24, 25), and tumor necrosis factor culopapular, urticarial, nodular or, rare- ease activity and the IgD concentration (TNF)-a rises to high normal values, ly, purpuric (13). One Japanese patient (2). IgD can even be entirely normal at whereas IL-1a and IL-1b are not ele- has been reported with erythema eleva- times, despite patients having active dis- vated (25). The effect of the increased tum diutinum (11). Oral and genital ul- ease. In young children symptoms can stimulation of mononuclear phagocytes cers occur frequently in HIDS (14) and exist for as long as 3 years before there by interferon-g is reflected in a rise in in one patient rectal ulcers have been ob- is any rise in serum IgD (21). With the urinary neopterin excretion simultane-

527 PEDIATRIC REVIEW Periodic fever and mevalonate kinase deficiency / J. Frenkel et al. ously with the onset of fever. The neop- (0 to 4% of the control mean) (8, 30). In order to block mevalonate production, terin excretion remains high for several DPF, however, a residual MK activity however, was unsuccessful and had to days after normalization of the body tem- varying between 1 and 7% can be meas- be abandoned because of the develop- perature (24). Serum levels of the anti- ured both in fibroblasts and leukocytes ment of severe clinical crises. inflammatory mediators IL-1 receptor from patients (5). As a result of the MK Currently, five metabolic diseases have antagonist, soluble TNF receptor p55 and deficiency, excretion of mevalonic acid been described which are caused by de- soluble TNF receptor p75 are raised dur- in urine occurs, although the levels of fects in the . Three ing attacks, whereas IL-10 remains nor- excreted mevalonic acid vary signifi- disorders, Smith-Lemli-Opitz syndrome mal (25). cantly between both syndromes. MA is (32-34), desmosterolosis (35), and X- The production of many of these media- characterized by a massive and consti- linked dominant chondrodysplasia punc- tors has been studied in vitro. In super- tutive excretion (1000-56000 mmol/mol tata (36, 37) only affect the sterol bio- natants of unstimulated cultures of whole creatinine) (8), while in DPF the meval- synthesis. MA and DPF affect the bio- blood samples, obtained during attacks, onic acid excretion is moderate (4-28 synthesis of all isoprenoids. Periodic fe- IL-1b is not increased (25). Culture su- mmol/mol creatinine) and may be nor- vers and dysregulation of the immune pernatants of peripheral blood mononu- mal between febrile crises (5). In healthy system are only present in DPF and MA, clear cells (MNC) obtained between at- controls, the excretion of mevalonic acid which indicate that a shortage of choles- tacks, however, contained high concen- in urine is usually less than 1 mmol/mol terol is not the pathogenetic basis of the trations of IL-1b which increased even creatinine. periodic fevers. This is also supported further upon stimulation with LPS (26). MK is the first enzyme to follow 3-hy- by the observation that cholesterol lev- Although plasma levels of TNF-a stay droxy-3-methyl-glutaryl-CoA reductase els are usually (near) normal in patients within normal limits, its concentration (HMG-CoA reductase) in the mevalo- with MA (8). Furthermore, the incorpo- is increased in the supernatants of unsti- nate pathway and converts mevalonate ration of radiolabeled acetyl-CoA into mulated cultures of whole blood samples into 5-phosphomevalonate (Fig. 1). The cholesterol by cultured skin fibroblasts drawn between attacks. When stimulated mevalonate pathway provides cells with of DPF and MA patients appears to be with LPS the supernatants of such cul- isoprenoids that are essential for diverse comparable with that in controls (38). tures showed an elevated TNF-a level, cellular processes. The main end prod- The differences in mevalonate excretion which was even higher when the blood ucts include ubiquinone-10 and haem A, between DPF and MA could be caused cells had been obtained during an attack both of which are necessary for electron by a difference in the regulation of (25). Similar results were obtained in cul- transport, isopentenyl tRNA (involved in HMG-CoA reductase activity. In MA ture supernatants of isolated MNC ob- protein translation), dolichol (essential there may be a constitutive derepression tained between attacks (26). for N-linked protein glycosylation), and of HMG-CoA reductase, as suggested by Taken together these data are compat- the farnesyl and geranylgeranyl groups the elevated reductase activity in fibro- ible with macrophage activation during used for isoprenylation of the proteins blasts from MA patients (38) and the lev- the febrile attacks. Between the febrile involved in cell proliferation and differ- els of excreted mevalonate (> 800 mmol/ attacks the in vitro findings are still com- entiation. In addition to these non-sterol day) which greatly exceed the level of patible with an increased activity of the isoprenoids the mevalonate pathway pro- normal whole body cholestrol biosynthe- mononuclear phagocytic compartment. duces cholesterol, a structural compo- sis (4 mmol/day, equivalent to 24 mmol The cause of this macrophage activation nent of cellular membranes and precur- of mevalonate/day) (8), while in DPF the is unknown. While activated Thelper-1 sor for bile acids and hormones reductase activity may only be derepress- cells are known to induce macrophage (31). ed during fever episodes. Studies to in- activation, the high IgD and IgA levels HMG-CoA reductase, which converts vestigate this in further detail are under- are more compatible with an increased HMG-CoA into mevalonate, catalyzes way. activity of Thelper-2 cells (27). However, the main rate-limiting step in isoprenoid direct evidence of T-cell activation dur- biosynthesis and is among the most tight- Molecular biology ing attacks is lacking. ly regulated in nature (31). In- The cause of DPF was independently deed the statins, which are drugs widely identified in 1999 by a Dutch research Biochemistry used to treat atherosclerosis and famil- group and Dutch/French consortium us- The identification of MK deficiency as ial hypercholesterolaemia, are potent ing two different approaches. Both groups the cause of DPF links this syndrome to competitive inhibitors of the reductase; ended up with the same gene, MVK, cod- mevalonic aciduria. This latter inborn they block the synthesis of mevalonate ing for the enzyme MK. Houten et al. error was first described by Berger et al. and as a consequence lower the endog- (5) performed organic acid analysis of in 1985 (28) and subsequently recog- enous synthesis of cholesterol. The use urine from one periodic fever patient dur- nized to be caused by a deficiency of MK of statins can trigger adaptive reactions ing an episode of fever and found el- enzyme activity (29). In MA the MK yielding up to 200-fold increased HMG- evated levels of mevalonic acid. This pa- enzyme activity is usually virtually ab- CoA reductase activity. A therapeutic tient had all the characteristics of HIDS sent when measured in cultured skin trial in which two MA patients were except for an elevated IgD. Subsequent fibroblasts or lymphoblasts of patients treated with low doses of lovastatin in organic acid analysis in 2 HIDS patients,

528 Periodic fever and mevalonate kinase deficiency / J. Frenkel et al. PEDIATRIC REVIEW however, also revealed elevated levels the isoleucine at position 268 into a fied missense mutations on MK activi- of mevalonic acid during episodes of threonine (I268T), respectively. Since ty, most of the mutant proteins have been fever. The elevated levels of mevalonic the latter two mutations were also iden- characterized by immunoblotting and acid in urine suggested a defect in the tified in MA patients (30, 40), this strong- heterologous expression. The first iden- of mevalonate, and enzyme ly suggested that the V377I mutation is tified mutation in MA, N301T, was ex- measurements revealed a profound de- responsible for the DPF phenotype of pressed in COS-7 cells and showed a ficiency of MK enzyme activity. MK deficiency. Indeed, thus far only one markedly decreased enzyme activity Subsequent mutation analysis revealed patient has been described without this varying between 5 and 20% of the ac- several disease-causing mutations in the mutation (6). This patient was compound tivity of wild type MK 41). More recent- MVK gene. Drenth et al. performed link- heterozygous for a C > T transition at ly, a mutation in MA was characterized, age analysis and obtained linkage at nucleotide 500, changing the proline at which changed the affinity of the enzyme 12 position q24 (6). After position 165 into a leucine (P165L). The for its substrate mevalonate when ex- narrowing the region to 9 cM, they con- other allele carried the I268T mutation, pressed as a recombinant fusion protein cluded that MVK was a good candidate which was also found in MA patients, in Escherichia coli (A334T) (43). The gene and subsequently identified muta- suggesting that the P165L mutation is V377I mutation had considerable resi- tions in this gene in several HIDS pa- responsible for the DPF phenotype in this dual activity when expressed in E. coli tients. Since the human MVK cDNA patient. (35% compared to the control), but MK sequence had already been cloned, both The MVK gene was previously reported protein in fibroblast lysates of HIDS pa- groups performed mutation analysis at to be a single copy gene located on chro- tients was hardly detectable, as shown the cDNA level. This revealed a com- mosome 12 postion q24 (41, 42), which by immunoblotting with an MK-specific mon missense mutation, a G > A transi- is in accordance with the linkage analy- antibody. This indicates that, although tion at nucleotide 1129 changing the sis performed by Drenth et al. (6). We this mutation has some effect on enzyme valine at position 377 into a isoleucine have recently resolved the genomic or- activity, it predominantly affects the sta- (V377I) (5, 6), in 20 out of 21 HIDS ganization of the mevalonate kinase gene, bility of the MK protein in vivo (5). All patients (39). Most patients were com- showing it to consist of 11 exons (un- of the other characterized mutations re- pound heterozygotes for this mutation. published data). Figure 2 is a schematic sult in MK proteins with markedly de- Two additional missense mutation were representation of the MVK gene and in- creased enzyme activity when expressed identified, an A > C transversion at nu- cludes all the mutations currently iden- in E. coli and/or decreased protein cleotide 59 and a T > C transition at nu- tified in both MA and Dutch type peri- levels in fibroblast lysates (H20P, T243I, cleotide 803, which change the histidine odic fever. L264F, L265P, I268T and V310M) (30, at position 20 into a proline (H20P) and In order to study the effect of the identi- 40).

Fig. 2. Schematic representation of the organization of the MVK gene. The locations of all the mutations identified at present in Dutch type periodic fever and mevalonic aciduria are indicated.

529 PEDIATRIC REVIEW Periodic fever and mevalonate kinase deficiency / J. Frenkel et al. Differential diagnosis after which febrile attacks recur at irregu- childhood has too many side effects, DPF should be distinguished from a lar intervals, typically 2 to 4 times every however, to justify their use as mainte- number of hereditary and non-hereditary year (49). The duration of fever varies nance treatment to prevent attacks. disorders with which it has features in from some days to many weeks. The fe- common. First, infectious diseases and ver may be accompanied by conjuncti- Prognosis cyclic neutropenia should be ruled out. vitis, myalgias, painful erythema of the The frequency and the severity of attacks Systemic onset juvenile chronic arthri- arms and legs, arthralgias, and scrotal appear to decrease with age. In our ex- tis, like DPF, is characterized by fevers, and abdominal pain. As in FMF, these perience, however, all children with DPF transient rashes, lymphadenopathy, he- patients may have serositis, and some have remained symptomatic. In contrast, patosplenomegaly, and arthritis. How- have developed . In contrast children with recurrent fever and eleva- ever, the onset is rarely in the first year to DPF, lymphadenopathy is absent. In- ted serum IgD but normal MK activity of life, the fever has a spiking pattern, heritance is autosomal dominant and mo- were likely to enter long-term remission. the disease flares usually last many lecular diagnosis has become possible There are some indications that preg- weeks instead of days, and the arthritis with the identification of the affected nancy may further decrease disease ac- is destructive. Contrary to DPF, serosi- gene, TNFR1. This gene encodes the 55 tivity (52). Some patients have long-term tis is common and diarrhea is usually ab- kDa TNF receptor protein (50) and mu- sequelae, however. Three patients devel- sent. Furthermore, there is no ethnic pre- tations affect the extracellular domain of oped peritoneal adhesions, possibly as a disposition and the disease is not famil- this receptor, interfering with receptor consequence of serositis. Amyloidosis ial in occurrence. shedding. was described in one patient (3) and one Familial Mediterranean fever typically The periodic fever known as aphtous child developed end stage renal failure occurs in patients of Turkish, Armenian, stomatitis, pharyngitis and adenopathy due to crescentic glomerulonephritis Iraqi or Sephardic Jewish ancestry. It is (PFAPA) syndrome is characterized by (17). Joint damage has not been reported characterized by recurrent bouts of high febrile attacks that last 2-8 days and re- in HIDS. fever, accompanied by arthritis and by cur every 2-8 weeks. The fever is accom- Among the patients in the HIDS regis- severe abdominal pain due to serositis. panied by aphtous stomatitis, cervical try two deaths have been reported, one Patients may have pleuritis, pericarditis lymphadenopathy and pharyngitis, but by suicide and one from a stroke (3). It or an erysipeloid rash of the lower part some patients also experience headache, is doubtful whether these complications of the legs. The onset of attacks is usu- abdominal pain, diarrhea or rashes. IgD are related to HIDS. ally at a later age (2-10 years) than in may be mildly elevated. Hence, differ- Though HIDS may cause little excess HIDS and the attacks typically last only entiation from HIDS can be particularly mortality or permanent organ damage, 12-72 hours (44). Diarrhea, headache, difficult. The PFAPA syndrome is, how- the impact of a disease that causes pa- generalized rashes, lymphadenopathy ever, not familial in occurrence (20, 51). tients to miss school frequently from kin- and hepatosplenomegaly do not feature Although the majority of patients ini- dergarden through high school cannot be in FMF. Amyloidosis is a common seri- tially classified as HIDS were MK defi- underestimated. Data on the psychoso- ous late complication of FMF, which cient when tested, some patients were cial effects are lacking, however. may lead to nephrotic syndrome and re- found to have normal MK activity. These nal failure. In contrast to DPF, the attacks children tend to have a later age of dis- Future directions of FMF can be prevented by colchicine. ease onset, but could not otherwise be The identification of the molecular de- This treatment reduces the future devel- distinguished from DPF cases. fect in DPF will have implications for opment of amyloidosis. Inheritance is Ultimately, the correct diagnosis of DPF our understanding of the disease, its autosomal recessive and the responsible can only be made by the demonstration pathogenesis, its natural history and its gene, MEFV, on chromosome 16p13.3 of a reduced MK activity in cultured skin treatment. Efforts are underway to elu- codes for a protein of unknown function fibroblasts or mononuclear cells cidate the pathophysiological mecha- called pyrin or marenostrin (45, 46). Mo- A simplified flow diagram of the diag- nisms by which mevalonate kinase defi- lecular diagnosis is feasible in most FMF nostic approach in children with recur- ciency leads to periodic fever. Other de- patients, but in at least 20% of patients rent fever is shown in Figure 3. fects in the isoprenoid pathway with one or both alleles appear normal (44, similar clinical effects might be expect- 47, 48). Treatment ed, but these have not yet been identi- The TNF-receptor associated periodic No systematic study of therapeutic in- fied. syndrome (TRAPS) is a rare disorder terventions in HIDS has been reported. With a definitive diagnostic criterion at that has been encountered primarily in Non-steroidal anti-inflammatory drugs, hand, the patient population is better Irish and British families and was there- colchicine, intravenous immunoglobu- defined, which will enable us to reap- fore called familial hibernian fever, but lins, and cyclosporin A have been tried praise the clinical presentation and the it has also been encountered in families in some patients and were, in most cases, natural course of the disease. from other countries, including France found to be ineffective. Some patients Finally, we are now in a position to as- and The Netherlands. The onset of this responded favorably to . sess prospectively the effect of interven- disease is between 2 and 20 years of age, The long-term use of corticosteroids in tions in a circumscript patient group. The

530 Periodic fever and mevalonate kinase deficiency / J. Frenkel et al. PEDIATRIC REVIEW

175-7. 6. DRENTH JP, CUISSET L, GRATEAU G et al .: Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syn- drome. International Hyper-IgD Study Group. Nat Genet 1999; 22: 178-81. 7. HOFFMANN G, GIBSON KM, NYHAN WL, SWEETMAN L: Mevalonic aciduria: Pathobio- chemical effects of mevalonate kinase defi- ciency on cholesterol metabolism in intact fi- broblasts. J Inherit Metab Dis 1988; 11 (Suppl. 2): 229-32. 8. HOFFMANN GF, CHARPENTIER C, MAYA- TEPEK E et al.: Clinical and biochemical phe- notype in 11 patients with mevalonic aciduria. Pediatrics 1993; 91: 915-21. 9. SIMON A, DRENTH JP: associated with periodic fevers highlighted at Dutch workshop. Lancet 1999; 354: 2139. 10. TOPALOGLU R, SAATCI U: Hyperimmunoglo- bulinaemia D and periodic fever mimicking familial Mediterranean fever in the Mediter- ranean. Postgrad Med J 1991; 67: 490-1. 11. MIYAGAWA S, KITAMURA W, MORITA K, SAISHIN M, SHIRAI T: Association of hyper- immunoglobulinaemia D syndrome with ery- thema elevatum diutinum. Br J Dermatol 1993; 128: 572-4. 12. GROSE C, SCHNETZER JR, FERRANTE A, VLADUTIU AO: Children with hyperimmuno- globulinemia D and periodic fever syndrome. Pediatr Infect Dis J 1996; 15:72-7. 13. DRENTH JP, BOOM BW, TOONSTRA J, VAN DER MEER JW: Cutaneous manifestations and his- tologic findings in the hyperimmunoglobulin- emia D syndrome. International Hyper IgD Study Group. Arch Dermatol 1994; 130: 59- 65. 14. GROUTEAU E, CHAIX Y, GRABER D et al: Pseudomaladie periodique avec hyperim- munoglobulinemie D: Une histoire sans fin de debut antenatal probable. Arch Pediatr 1998; 5: 280-4. 15. OZIOL E, RIVIERE S, LE QUELLEC A, CIUR- ANA AJ: La fievre qui venait du nord. Rev Med Interne 1999; 20 (Suppl. 2): 236s-8s. 16. HAVENAAR EC, DRENTH JP, VAN OMMEN EC, VAN DER MEER JW, VAN DIJK W: Elevated Fig. 3. Diagnostic approach to recurrent fever in childhood. serum level and altered glycosylation of alpha 1-acid glycoprotein in hyperimmunoglobulin- emia D and periodic fever syndrome: Evidence involvement of the isoprenoid pathway Hyperimmunoglobulinaemia D and periodic for persistent . Clin Immunol Im- in the pathogenesis suggests that treat- fever: A new syndrome. Lancet 1984; 1: 1087- munopathol 1995; 76: 279-84. ment with statins, which interfere in the 90. 17. TSIMARATOS M, KONE-PAUT I, DANIEL L, 3. DRENTH JP, HAAGSMA CJ, VAN DER MEER GUBLER MC, DUSSOL B, PICON G: Crescentic earliest step of this route, might be ben- JW: Hyperimmunoglobulinemia D and peri- glomerulonephritis in hyper IgD syndrome. eficial. A clinical trial with such a com- odic fever syndrome. The clinical spectrum in Pediatr Nephrol 1999; 13: 132-4. pound is to start soon (9). a series of 50 patients. International Hyper-IgD 18. LIVNEH A, DRENTH JP, KLASEN IS et al.: Results of both mechanistic studies and Study Group. Medicine (Baltimore) 1994; 73: Familial Mediterranean fever and hyperim- 133-44. munoglobulinemia D syndrome: Two diseases intervention trials should ultimately shed 4. DRENTH JP, MARIMAN EC, VAN DER VELDE- with distinct clinical, serologic, and genetic light on the physiological role of isopre- VISSER SD, ROPERS HH, VAN DER MEER JW: features. J Rheumatol 1997; 24: 1558-63. noid metabolism in inflammation. Location of the gene causing hyperimmuno- 19. HIEMSTRA I, VOSSEN JM, VAN DER MEER JW, globulinemia D and periodic fever syndrome WEEMAES CM, OUT TA, ZEGERS BJ: Clinical differs from that for familial Mediterranean fe- and immunological studies in patients with an References ver. International Hyper-IgD Study Group. increased serum IgD level. J Clin Immunol 1. PRIEUR AM, GRISCELLI C: Aspect nosolo- Hum Genet 1994; 94: 616-20. 1989; 9: 393-400. gique des formes systemiques d’arthrite juve- 5. HOUTEN SM, KUIS W, DURAN M et al.: Muta- 20. PADEH S, BREZNIAK N, ZEMER D et al.: Per- nile a debut tres precoce. A propos de dix-sept tions in MVK, encoding mevalonate kinase, iodic fever, , pharyngitis, observations. Semin Hôp 1984; 60: 163-7. cause hyperimmunoglobulinaemia D and pe- and adenopathy syndrome: Clinical character- 2. VAN DER MEER JW, VOSSEN JM, RADL J et al.: riodic fever syndrome. Nat Genet 1999; 22: istics and outcome. J Pediatr 1999; 135: 98-101.

531 PEDIATRIC REVIEW Periodic fever and mevalonate kinase deficiency / J. Frenkel et al.

21. HARALDSSON A, WEEMAES CM, DE BOER 31. GOLDSTEIN JL, BROWN MS: Regulation of the nase and identification of a missense mutation AW, BAKKEREN JA, STOELINGA GB: Immu- mevalonate pathway. Nature 1990; 343: 425- in the genetic disease mevalonic aciduria. J nological studies in the hyper-immunoglobu- 30. Biol Chem 1992; 267: 13229-38. lin D syndrome. J Clin Immunol 1992; 12: 424- 32. FITZKY BU, WITSCH-BAUMGARTNER M, 42. GIBSON KM, HOFFMANN GF, TANAKA RD, 8. ERDEL M et al.: Mutations in the Delta7-sterol BISHOP RW, CHAMBLISS KL: Mevalonate ki- 22. DRENTH JP, GOERTZ J, DAHA MR, VAN DER reductase gene in patients with the Smith- nase map position 12q24. Chromosome Res MEER JW: Immunoglobulin D enhances the Lemli-Opitz syndrome. Proc Natl Acad Sci 1997; 5: 150. release of tumor necrosis factor-alpha, and USA 1998; 95: 8181-6. 43. HINSON DD, CHAMBLISS KL, HOFFMANN interleukin-1 beta as well as interleukin-1 re- 33. WASSIF CA, MASLEN C, KACHILELE- GF, KRISANS S, KELLER RK, GIBSON KM: ceptor antagonist from human mononuclear LINJEWILE S et al.: Mutations in the human Identification of an alanine in me- cells. Immunology 1996; 88:355-62. sterol delta7-reductase gene at 11q12-13 cause valonate kinase through characterization of a 23. SAKANE T, TAKENO M, SUZUKI N, INABA G: Smith-Lemli-Opitz syndrome. Am J Hum novel mutation in mevalonate kinase defi- Behçet’s disease. N Engl J Med 1999; 341: Genet 1998; 63: 55-62. ciency. J Biol Chem 1997; 272: 26756-60. 1284-91. 34. WATERHAM HR, WIJBURG FA, HENNEKAM 44. ÖZEN S: New interest in an old disease: Fa- 24. DRENTH JP, POWELL RJ, BROWN NS, VAN DER RC et al.: Smith-Lemli-Opitz syndrome is milial Mediterranean fever. Clin Exp Rheum- MEER JW: Interferon-gamma and urine neop- caused by mutations in the 7- dehydrocholes- atol 1999; 17: 745-9. terin in attacks of the hyperimmunoglobulin- terol reductase gene. Am J Hum Genet 1998; 45. The International FMF Consortium: Ancient aemia D and periodic fever syndrome. Eur J 63: 329-38. missense mutations in a new member of the Clin Invest 1995; 25: 683-6. 35. FITZPATRICK DR, KEELING JW, EVANS MJ et RoRet gene family are likely to cause familial 25. DRENTH JP, VAN DEUREN M, VAN DER VEN- al.: Clinical phenotype of desmosterolosis. Am Mediterranean fever. Cell 1997; 90: 797-807. JONGEKRIJG J, SCHALKWIJK CG, VAN DER J Med Genet 1998; 75: 145-52. 46. The French FMF Consortium: A candidate MEER JW: Cytokine activation during attacks 36. DERRY JM, GORMALLY E, MEANS GD et al.: gene for familial Mediterranean fever. Nat of the hyperimmunoglobulinemia D and peri- Mutations in a delta 8-delta 7 sterol Genet 1997; 17:25-31. odic fever syndrome. Blood 1995; 85: 3586- in the tattered mouse and X-linked dominant 47. CAZENEUVE C, SARKISIAN T, PECHEUX C et 93. chondrodysplasia punctata. Nat Genet 1999; al.: MEFV-Gene analysis in armenian patients 26. DRENTH JP, VAN DER MEER JW, KUSHNER I: 22: 286-90. with Familial Mediterranean fever: Diagnos- Unstimulated peripheral blood mononuclear 37. BRAVERMAN N, LIN P, MOEBIUS FF et al.: tic value and unfavorable renal prognosis of cells from patients with the hyper-IgD syn- Mutations in the gene encoding 3 beta-hydrox- the M694V homozygous genotype-genetic and drome produce cytokines capable of potent in- ysteroid-delta 8, delta 7- isomerase cause X- therapeutic implications. Am J Hum Genet duction of C- reactive protein and serum amy- linked dominant Conradi-Hunermann syn- 1999; 65: 88-97. loid A in Hep3B cells. J Immunol 1996; 157: drome. Nat Genet 1999; 22: 291-4. 48. BOOTH DR, GILLMORE JD, BOOTH SE, PEPYS 400-4. 38. GIBSON KM, HOFFMANN G, SCHWALL A et al.: MB, HAWKINS PN: Pyrin/marenostrin muta- 27. LEVAN-PETIT I, LELIEVRE E, BARRA A et al.: 3-Hydroxy-3-methylglutaryl coenzyme A re- tions in familial Mediterranean fever. QJM T(h)2 cytokine dependence of IgD production ductase activity in cultured fibroblasts from pa- 1998; 91: 603-6. by normal human B cells. Int Immunol 1999; tients with mevalonate kinase deficiency: dif- 49. MCDERMOTT EM, SMILLIE DM, POWELL RJ: 11: 1819-28. ferential response to lipid supplied by fetal Clinical spectrum of familial Hibernian fever: 28. BERGER R, SMIT GP, SCHIERBEEK H, bovine serum in tissue culture medium. J Li- a 14-year follow-up study of the index case BIJSTERVELD K, LE COULTRE R: Mevalonic pid Res 1990; 31:515-21. and extended family. Mayo Clin Proc 1997; aciduria: An inborn error of cholesterol bio- 39. HOUTEN SM, FRENKEL J, KUIS W, WANDERS 72:806-17. synthesis ? Clin Chim Acta 1985; 152: 219- RJ, POLL-THE BT, WATERHAM HR: Molecular 50. MCDERMOTT MF, AKSENTIJEVICH I, GALON 22. basis of classical mevalonic aciduria and the J et al.: Germline mutations in the extracellu- 29. HOFFMANN G, GIBSON KM, BRANDT IK, hyperimmunoglobulinaemia D and periodic lar domains of the 55 kDa TNF receptor, BADER PI, WAPPNER RS, SWEETMAN L: Me- fever syndrome: High frequency of 3 muta- TNFR1, define a family of dominantly inher- valonic aciduria - an inborn error of choles- tions in the mevalonate kinase gene. J Inherit ited autoinflammatory syndromes. Cell 1999; terol and nonsterol isoprene biosynthesis. N Metab Dis (in press). 97: 133-44. Engl J Med 1986; 314: 1610-4. 40. HINSON DD, ROSS RM, KRISANS S et al.: 51. THOMAS KT, FEDER HM JR, LAWTON AR, 30. HOUTEN SM, ROMEIJN GJ, KOSTER J et al.: Identification of a mutation cluster in mevalo- EDWARDS KM: Periodic fever syndrome in Identification and characterization of three nate kinase deficiency, including a new muta- children. J Pediatr 1999; 135: 15-21. novel missense mutations in mevalonate ki- tion in a patient of Mennonite ancestry. Am J 52. DE HULLU JA, DRENTH JP, STRUYK AP, VAN nase cDNA causing mevalonic aciduria, a dis- Hum Genet 1999; 65:327-35. DER MEER JW: Hyper-IgD syndrome and preg- order of isoprene biosynthesis. Hum Mol Genet 41. SCHAFER BL, BISHOP RW, KRATUNIS VJ et al.: nancy. Eur J Obstet Gynecol Reprod Biol 1996; 1999; 8:1523-8. Molecular cloning of human mevalonate ki- 68: 223-5.

532