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Rheumatology 2001; 40: 579-584
© 2001 British Society for Rheumatology
Paediatric Rheumatology |
Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D
Paediatric Rheumatology/Series Editor: P. Woo
Departments of General Paediatrics,
2 Paediatric Immunology and
3 Metabolic Disorders, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, Departments of
1 Clinical Chemistry and Paediatrics and
4 Paediatric Immunology, Emma Children's Hospital, Academic Medical Centre, Amsterdam and
5 Department of Paediatric Rheumatology, Beatrix Children's Clinic, Academic Hospital Groningen, The Netherlands
Abstract
Objectives. The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency.
Methods. The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced.
Results. Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations.
Conclusions. Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.
KEY WORDS: Familial Mediterranean Fever, Fever, Hypergammaglobulinaemia, IgD, Mevalonate kinase, Mevalonic acid, Periodicity.
The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), also known as Dutch-type periodic fever (MIM no. 260920), is an autosomal recessive disorder characterized by febrile attacks recurring at more or less regular intervals and a high serum immunoglobulin D (IgD) concentration (>100 IU/ml) [1]. The clinical features of the febrile attacks include cervical lymphadenopathy, splenomegaly, hepatomegaly, skin rash, vomiting, diarrhoea, arthralgias and arthritis. Patients often complain of malaise, chills, headache and nausea or abdominal pain [2]. The diagnosis of HIDS has always been based on the occurrence of both recurrent unexplained fever and elevated serum IgD levels. Recently, we and others identified the underlying genetic defect of the syndrome, namely mutations in the gene MVK that lead to a deficiency of the enzyme mevalonate kinase (MV) [3, 4]. MK catalyses the phosphorylation of mevalonic acid into 5-phosphomevalonate. It is the enzyme immediately following 3-hydroxy-3-methylglutaryl-CoA reductase in the isoprenoid biosynthesis pathway. This pathway produces cholesterol and numerous non-sterol isoprenoids that are involved in a large variety of cellular processes [5]. In HIDS, the deficiency of MK becomes evident during febrile attacks, when its substrate, mevalonic acid, accumulates in plasma and is excreted in the urine. Although it is known that febrile episodes in HIDS can be triggered by injuries, infections or vaccinations, it is unclear how these exogenous factors interact with the endogenous biochemical defect to give rise to the inflammatory episodes. So far, nine cases of HIDS have been published in whom MK activity had been determined [3, 4]. All were found to have markedly reduced MK enzyme activity. Here, we describe our findings in a group of 15 children with HIDS, including four who have been described previously [2, 3]. Surprisingly, in four children, normal MK activity was found. These cases will be described in more detail.
Patients and methods
We included in this study all children with HIDS who visited the three participating children's hospitals between January 1997 and October 1999. The diagnosis of HIDS was based on the following criteria: (i) recurrent fever over 38.5°C not explained by infections or otherwise, and (ii) a serum IgD concentration >100 IU/ml established at least once, preferably on two occasions at least 1 month apart. Throughout the text, patients are identified by their entry number in the international Hyper-IgD Study Group registry [2]. Four patients (patients 26, 50, 132 and 139) have been described previously [2, 3].
After the study had been approved by the Wilhelmina Children's Hospital medical ethics committee and we had obtained informed consent from the parents, patient charts were reviewed for clinical characteristics, disease history and serum immunoglobulin levels.
MK activity was determined in peripheral blood mononuclear cells (MNC) using 14C-labelled mevalonate as the substrate [6], and was expressed as the percentage of the average MK activity determined simultaneously in MNC from healthy control subjects. The normal value is 166.3±69.1 nmol/min/mg.
Urine samples were collected during febrile crises that were not due to intercurrent infection. Mevalonic acid was measured in urine by stable isotope dilution gas chromatography mass spectroscopy of the trimethylsilyl ether/esters using [2H7]mevalonolactone as an internal standard [7].
In all patients, mutation analysis of the MVK cDNA was performed as described previously [8]. Briefly, cDNA was prepared from total RNA isolated from MNC. Two sets of MVK-specific primers with –21M13 or M13rev extensions were used to amplify MVK cDNA in two overlapping fragments by the polymerase chain reaction (PCR). Both PCR fragments were sequenced in both directions using fluorescent primers on an ABI 377A DNA sequencer (Perkin-Elmer, Wellesley, MA, USA), according to the manufacturer's instructions.
Results
Clinical heterogeneity
The demographic data and disease courses of the 15 patients are summarized in Table 1
. Of the 15 patients, five were girls and 10 were boys. Age ranged from 2 to 20 yr with a mean of 9.4 yr. One patient (patient 138) was of Turkish descent, whereas the remaining 14 patients were of Dutch origin. There was no consanguinity in any of the families and there were no additional family members affected. The febrile attacks started between 2 months and 14 yr of age, with a median of 6 months. On average, fever lasted for 4.2 days and recurred every 3–7 weeks. In individual patients, however, the duration of the febrile episodes varied considerably. Similarly, the interval between attacks varied during the disease course from less than 2 weeks to many months. In fact, two children (patients 50 and 138) had been free of symptoms for over 12 months.
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Table 1
summarizes the clinical features accompanying the febrile crises. All children had fever up to 40°C, accompanied by malaise and fatigue. In many instances, fever was elicited by mental stress, strenuous exercise or infections. Pharyngitis was documented in eight patients, pneumonia in seven and otitis in five, but there were no recurrent severe infections in any patient. Childhood vaccinations were followed by fever in the majority of patients. However, most attacks were apparently unprovoked. Usually there was a prodrome, such as fatigue, anorexia or a behavioural change. Onset of fever was brisk, 40% of patients experiencing chills. One patient (patient 139) suffered repeated febrile seizures. Temperature normalized after 3–7 days of high fever. Subsequently, most patients remained listless and tired for another 3–7 days.
The rashes that were reported in 11 of the 15 patients varied from faint erythema to maculopapular and urticarial exanthemata. One patient had recurrent swelling of the hands and feet during attacks; another had such an attack only once. Of the 15 patients, 11 reported headaches during attacks. Abdominal pain was very common and was often accompanied by diarrhoea and/or vomiting. Arthralgias were present in 80% of patients, whereas arthritis, defined as painful swelling of joints, was rare. Lymphadenopathy, hepatomegaly and splenomegaly were present in the majority of patients. Notably, there was no recurrent pharyngitis or aphthous stomatitis in any patient.
Growth was normal in all children, but two patients had very mild developmental delay and one patient (patient 136) was severely mentally retarded. He died at the age of 17 yr.
Biochemical and molecular heterogeneity
Serum IgD levels were raised above the upper limit of normal (100 IU/ml) at least once in all 15 children and on more than one occasion in 14. Serum levels of IgG, IgA and IgM were raised repeatedly in most patients (Table 2).
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Eleven of the 15 patients were found to have deficient MK activity in peripheral blood MNC (1–7%, normally 100±42%), In nine of these 11 patients urine was obtained during fever. Urinary mevalonic acid concentration, normally below 1 mmol/ mol creatinine, was elevated in all nine samples (4.8–41.5 mmol/mol creatinine, average 17.5), whereas it was not elevated in the three living patients with normal MK activity.
In all 11 patients with reduced MK activity, mutations could be identified in the MVK cDNA. The mutations observed and their consequent amino acid changes are represented in Table 3. All MK-deficient patients were carriers of the substitution of adenine for guanine at position 1129 (1129 G
A), leading to an amino acid change from valine to isoleucine at position 377 (V377I). Two patients were homozygous for this mutation at the cDNA level; this was confirmed by sequencing the parental cDNAs. All other patients were compound heterozygotes for two mutations (Table 3).
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Clinical features appear unrelated to molecular variability
We found no clear relationship between the different genotypes and residual MK activity. Neither the genotype nor the degree of enzyme deficiency correlated with the clinical severity of the disease. In four male patients, normal MK activity was found (patients 50, 138, 141 and 143). These boys are described in more detail below.
Normal MK activity in four patients
Case 50
This 8-yr-old Dutch boy had suffered repeated bouts of fever from the age of 5 weeks. Fever started abruptly, remained high for 2–5 days and recurred every 2–3 weeks. Episodes were often triggered by minor infections. General malaise and painful cervical lymphadenopathy accompanied the attacks. On occasions he suffered from a sore throat. He had no rash, oral ulcers, arthralgias, headache, abdominal pain, diarrhoea or vomiting during attacks. Once, mild hepatomegaly without splenomegaly was noted.
During attacks there was leucocytosis (14.1–16.7x 109/l) with granulocytosis and band forms. Paracetamol reduced the temperature, but non-steroidal anti-inflammatory agents were ineffective in preventing attacks.
Case 136
This 17-yr-old Dutch boy was born small for date (2250 g) after a full-term pregnancy. He was noted to have hypotelorism, downward slanting, short palpebral fissures, low-set ears, a high arched palate, dental crowding, and clinodactyly of the fifth fingers. His psychomotor development was severely delayed. No syndromal diagnosis had been made, despite a full metabolic and cytogenetic workup. From the age of 4 yr he had suffered repeated attacks of diarrhoea.
Recurrent bouts of fever started at the age of 14 yr. The fever was sudden in onset, remained around 40°C for 3–7 days and then recurred monthly without strict periodicity. There were no evident triggers for the attacks. The episodes were accompanied by fatigue, anorexia, abdominal pain, diarrhoea and vomiting. He experienced arthralgias, and later in the disease course he had painful swellings of the metacarpophalangeal and proximal interphalangeal joints. Rash, lymphadenopathy and hepatosplenomegaly were absent. Serositis was suspected, as he suffered intestinal obstruction due to adhesions, without prior abdominal surgery. During attacks, he had leucocytosis with granulocytosis and band forms and an elevated sedimentation rate and C-reactive protein. IgG, IgA, IgM and IgD were elevated (Table 2). Antibiotic treatment was ineffective and only long-term treatment with tolmetine and prednisolone was able to reduce (but not abort) the symptoms.
At the age of 17 yr he died from the complications of a perforated gastric ulcer. The gastric perforation and peritonitis were confirmed at autopsy. An unexpected finding was a sterile pericarditis, further supporting the presence of polyserositis.
Case 138
This 8-yr-old Turkish boy had developed febrile reactions after childhood vaccinations but had otherwise been well during the first years of life. He suffered repeated bouts of fever from the age of 3.5 yr until the age of 7 yr. His fever recurred every 4 weeks. Onset was abrupt but without chills. His fever was spiking and lasted 4–7 days before resolving spontaneously. Accompanying symptoms were headache, anorexia, general malaise, abdominal pain and diarrhoea. Examination during attacks revealed cervical lymphadenopathy and hepatosplenomegaly, but no recurrent pharyngitis, uveitis or oral or genital ulcers. He had recurrent otitis media and streptococcal pharyngitis once, but most febrile episodes were without any recognizable infectious focus. There were no other affected family members.
Immunoglobulins were repeatedly elevated. Notably, IgD was persistently raised (231–415 IU/ml) despite clinical remission. The sequence of the MEFV gene was normal, rendering familial Mediterranean fever (FMF) unlikely, and Behçet's syndrome was excluded on clinical grounds.
Case 140
This 6-yr-old Dutch boy had suffered repeated febrile attacks from the age of 3 months. Attacks were triggered by vaccinations and infections but usually came unexpectedly, starting with chill and peripheral cyanosis followed by a sudden rise in temperature up to 41.4°C. Fever remained high for 3–5 days and recurred every 3–5 weeks. Over the last 12 months his fever had not exceeded 38.5°C and attacks were 2–3 months apart. Fatigue and anorexia preceded the attacks. The crisis was accompanied by abdominal pain, headache, vomiting and cervical lymphadenopathy, but not by joint pains, rash, hepatosplenomegaly, oral ulcers or pharyngitis. Once the fever had abated, the boy remained tired and listless for about 3 more days. Serum IgG concentration had ranged between 9.7 and 12.6 g/l, IgM between 0.8 and 2.2 g/l and IgA between 0.8 and 1.25 g/l. Serum IgD was persistently elevated between 157 and 180 IU/ml. During attacks, leucocytes, granulocytes, sedimentation rate and C-reactive protein were raised.
Apart from oral antibiotics, which seemed ineffective, no other medications had been tried.
In all four boys, the family history was negative for recurrent fever, making the autosomal dominant tumour necrosis factor receptor-associated periodic syndrome (TRAPS) very unlikely. In three patients the ethnic background did not suggest FMF. Cyclic neutropenia was formally ruled out in all four patients, and the periodic fever–aphthous stomatitis–pharyngitis–adenitis (PFAPA) syndrome and systemic onset juvenile idiopathic arthritis were ruled out on clinical grounds. During most of the attacks, no infectious focus could be identified.
Discussion
Periodic fever in childhood is not uncommon. Currently, various clinical syndromes characterized by periodic fever can be distinguished. These include the autosomal recessive syndromes HIDS and FMF, the autosomal dominant TRAPS, and the non-hereditary disorders PFAPA [9, 10] and systemic-onset juvenile idiopathic arthritis.
In the past these syndromes could only be diagnosed on the basis of clinical criteria. Recently, however, the molecular defects in HIDS [3, 4], FMF [11, 12] and TRAPS [13] have been identified. This knowledge now helps us to differentiate these disorders from each other and will provide better insight into the pathogenetic mechanisms involved in the various periodic fever syndromes.
The clinical presentation of most periodic fever syndromes shows considerable inter-individual variation. With the identification of the molecular defects, the question of whether this clinical heterogeneity reflects an underlying genetic heterogeneity can be addressed. We investigated a group of patients who had originally been diagnosed with HIDS by the occurrence of episodic fever in combination with elevated serum IgD after the exclusion of other (infectious) causes for the fever. As we now know, HIDS is due to a deficiency of MK, an enzyme involved in one of the early steps of isoprenoid biosynthesis. This biochemical pathway yields many substances, including cholesterol, dolichol, haem A, ubiquinone and hydrophobic moieties used for post-translational protein modification (farnesyl- and geranyl-geranyl groups). It is not known how MK deficiency leads to recurrent febrile episodes. Our previous work has shown that MK deficiency can also give rise to periodic fever without raised IgD [3]. Hence, MK activity should be determined in patients with unexplained periodic fever irrespective of their serum IgD concentration.
To examine whether our clinically diagnosed HIDS patients indeed had MK deficiency, we measured MK enzyme activity in all 15 of them. MK was deficient in 11 patients. Urinary mevalonic acid excretion in HIDS is known to rise during fever, but it is not known whether MK activity can be affected adversely by influences such as fever and mental stress. Hence, enzyme activity measurements were performed only on blood that was drawn between fever episodes. In the 11 MK-deficient patients we found mutations in both alleles of MVK, the gene encoding MK. At the molecular level there was heterogeneity among the MK-deficient patients. All patients carried the V377I allele, which has been shown previously to lead to an unstable protein with reduced enzyme activity [3]. Two patients were homozygous for the V377I allele. The other patients were compound heterozygotes for this allele and one of four other mutant alleles. Two of these, 59 AC and 803 TC, are known not to produce an enzymatically functional protein [3]. Patients homozygous for mutations that completely abolish MK activity are known to present with a distinct clinical syndrome, called mevalonic aciduria (MA). MA is characterized by mental retardation, facial dysmorphy and failure to thrive, in addition to febrile crises [14]. Apparently the V377I allele is responsible for the milder phenotype of HIDS as compared with classical mevalonic aciduria. The mutations 1162 CT and 404 TC had not been described previously in HIDS or MA. The predicted effect of the mutation 1162 CT is truncation of the protein at position 388. The functional effect of the S135L substitution, resulting from the mutation 404 TC, is unknown. However, it is likely to lead to loss of function because the serine residue at position 135 is highly conserved among mammalian species and the measured MK activity in the patient was only 1% of normal. A genotype–phenotype relationship exists within the broad spectrum of MK deficiency, in that severe mutations leading to virtually abolished MK activity give rise to the MA phenotype, whereas mild changes lead to the HIDS phenotype. In contrast to findings in MA, none of the patients described here had less than 1% residual enzyme activity. Among these, we could not establish a relationship between the different mutations and residual MK activity. Neither could we relate the severity of clinical symptoms to the residual activity of MK. For example, four patients were compound heterozygous for I268T and V377I. Yet the residual MK activity varied from 2% in patient 132 to 7% in patient 135. These two patients were both severely affected. On the other hand, patient 137 was only mildly affected, although her residual MK activity was intermediate between that of patients 132 and 135.
Interestingly, of the 15 children originally diagnosed with HIDS, four showed normal MK activity, indicating that HIDS is a genetically heterogeneous disorder. These patients had been diagnosed as having HIDS because of elevated IgD and recurrent fever. In two of these four patients, however, the febrile episodes had been absent for more than 18 months. Although this is not uncommon in HIDS, it sets these cases apart from the MK-deficient patients in this report. Indeed, the symptoms of these four patients, all boys, differed slightly from those of our MK-deficient patients. The diagnosis of HIDS could not have been rejected on clinical grounds, however. The clinical phenotype reported in HIDS patients before MK testing became available [2] and in our MK-deficient patients is not uniform, and the clinical spectrum of HIDS accommodates all the characteristics of these four boys.
In two patients with normal MK activity the onset of disease was later than 3 yr of age. In contrast, all MK-deficient patients described here and 70% of reported HIDS cases [2] had their onset of disease in the first year of life. Another difference was the absence of vomiting, arthralgias and rash in three of four patients with normal MK activity, while these features were present in the majority of the MK-deficient patients as well as in most reported HIDS patients. Therefore, although not obligatory in MK deficiency, the absence of vomiting, arthralgias and rash in a child with fever and elevated IgD seems to make MK deficiency less likely. The same applies to the absence of diarrhoea. Diarrhoea was present in all MK-deficient patients and in only two of four patients with normal MK activity. One patient without MK deficiency was mentally retarded. However, the literature includes a report [2] of two mentally retarded brothers with HIDS who were later shown to be MK-deficient.
This study shows that HIDS is a heterogeneous disease. At the biochemical level, most of the patients showed MK deficiency. Here we report on four patients who were originally characterized as having HIDS but who had normal MK activity. Because the clinical differences were discrete, determination of MK activity is the only certain way to differentiate these patients from those who have MK deficiency. It remains to be determined whether measurement of urinary mevalonic acid excretion is equally reliable. The distinction between these groups is important because MK deficiency is an autosomal recessive disease, with the consequent implications for genetic counselling. The defect or defects in the patients with periodic fever, elevated IgD and normal MK activity are unknown at present. Despite the predominance of boys in this subgroup, an X-linked disorder is unlikely in view of the negative family history. Because of the small size of Dutch families, a negative family history does not rule out autosomal recessive disease, which is illustrated by the 11 MK-deficient children, none of whom had affected siblings. One of the possibilities is that disorders of isoprenoid biosynthesis other than MK deficiency could also cause periodic fever. Investigations to test this possibility are under way.
Acknowledgments
We thank the International Hyper-IgD Study Group, notably J. P. H. Drenth, and the referring paediatricians J. Doddema, K. Illy, H. T. Spit and C. V. Tjon Pian Gi.
Notes
Correspondence to: J. Frenkel, Department of General Paediatrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Home mailbox KE.04.133.1, P.O. Box 85090, 3508AB Utrecht, The Netherlands. 
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