The hyperimmunoglobulinemia D with periodic fever syndrome (HIDS; MIM no. 260920) is an autosomal recessively inherited autoinflammatory disease. It is characterized by febrile episodes of 3–7 days' duration recurring every 4–8 weeks and by a persistently high serum level of IgD (>100 IU/ml). Symptoms accompanying a typical attack comprise cervical lymphadenopathy, chills, headache, abdominal pain, vomiting, diarrhea, arthralgia, arthritis, skin rash, splenomegaly, hepatomegaly, and/or oral ulcers. Another concomitant finding is a strong acute-phase reaction with leukocytosis, elevated C-reactive protein levels, and a high erythrocyte sedimentation rate. The prognosis is good, since there is no development of amyloidosis (1–3).
HIDS is caused by mutations in the mevalonate kinase (MVK) gene on chromosome 12q24 which lead to a depressed enzymatic activity of mevalonate kinase (MK) (4, 5). MK is a key enzyme of cholesterol and isoprenoid biosynthesis and is present in the cytosol and peroxisomes of every mammalian cell. At an early step of cholesterol synthesis, it phosphorylates 3,R-mevalonic acid to 5-phosphomevalonate. In HIDS patients, MK activity in cultured skin fibroblasts and lymphocytes is reduced to 1–12% compared with that in controls (4–6). This leads to a slightly increased urinary excretion of mevalonic acid (<20 mmoles/mole of creatinine) during a febrile episode. In contrast, in the case of a very profound MK deficiency, usually with <0.5% of the enzymatic activity found in controls, patients present with the clinical phenotype of mevalonic aciduria (MA; MIM no. 251170), and renal excretion of mevalonic acid is much higher (from ∼3,000 mmoles/mole of creatinine up to >56,000 mmoles/mole of creatinine). In addition to the typical clinical picture of HIDS, MA patients present with psychomotor retardation, facial dysmorphia, cataract, failure to thrive, and ataxia (6–8). Thus, MK deficiency comprises a continuous spectrum of loss of enzymatic activity, with the severe phenotype of MA at the most pathologic extreme, occurring in <1% of MK-deficient patients, and with HIDS as the milder variant.
More than 30 mutations have been reported in all protein-coding exons of the MVK gene except exon 4, and the vast majority are missense mutations. The most common genetic defect is the substitution of valine by isoleucine at amino acid position 377 (V377I), which is found in >90% of HIDS patients. The second mutation is often one that has also been associated with MA, which suggests that it results in a nonfunctional enzyme. This indicates that the V377I substitution is responsible for the HIDS phenotype.
In addition, patients have been described with a clinical presentation typical of HIDS, but without MVK mutations. This HIDS subgroup, termed variant-type HIDS, is characterized by normal or only slightly decreased MK activities (9, 10). Given the phenotypic similarities, variant-type HIDS raises two important questions: 1) are there HIDS-related mutations in genes other than MVK? and 2) what are the pathophysiologic mechanisms involved (e.g., defective isoprenylation of key proteins )?
Tumor necrosis factor receptor–associated periodic syndrome (TRAPS; MIM no. 142680), on the other hand, is the most frequent autosomal dominantly inherited periodic fever syndrome. This condition is caused by mutations in exons 2–4 and 6 of the TNFRSF1A gene, which codes for the extracellular, soluble part of TNF receptor superfamily 1A (TNFRSF1A). Most common are the low-penetrance mutations P46L and R92Q, which were also present on ∼1% of healthy control chromosomes in one study (12). One HIDS patient with 2 MVK mutations has been reported to carry in addition the TNFRSF1A P46L variant on 1 allele (13).
Here, we report on the spectrum of MVK mutations in a group of HIDS patients with variable MK activities. We present the case of a proband with 1 MVK mutation and 1 low-penetrance TNFRSF1A mutation who exhibited symptoms of HIDS and TRAPS.
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- PATIENTS AND METHODS
Our study expands the spectrum of MVK mutations and polymorphisms, which are currently listed in the World Wide Web–accessible database INFEVERS (online at http://fmf.igh.cnrs.fr/infevers/). We also identified 2 previously undescribed, naturally occurring splice variants with combined deletions of exons 2, 4, and 5 as well as of exons 4–7.
The nonsense mutation W188X in patient B leads to premature termination of protein translation and to the synthesis of a truncated, and most likely inactive, enzyme. Together with heterozygosity for the common V377I mutation, this results in the classic HIDS phenotype with depressed MK enzyme activity. While we were in the process of preparing the manuscript for this report, this nonsense mutation was submitted to the INFEVERS database by F. T. Saulsbury in the form of a personal communication.
In the 2 sisters C1 and C2, we found the second most common I268T mutation in combination with the replacement of valine by alanine at amino acid position 203. The side chains of these 2 nonpolar amino acids are different, suggesting functional differences. In addition, the valine residue is conserved among mammalian species and is located in close proximity to Asp204, which is part of the catalytic site of the enzyme and functions as the catalytic base (18–20). In comparison with their mother, who was heterozygous for the V203A mutation and completely healthy, both sisters had nearly absent MK activities and strong febrile, HIDS-typical attacks. Therefore, the V203A substitution, in combination with the I268T mutation, appears to cause a severe form of HIDS.
As in other studies (5, 21, 22), V377I was the most frequent MVK mutation causing HIDS. Furthermore, also in accordance with earlier observations, the majority of patients were compound heterozygous for this genetic defect and another mutation. Interestingly, we also identified 2 patients who were solely heterozygous for this particular amino acid substitution. Proband E had also inherited the R92Q mutation, encoded by exon 4 of the TNFRSF1A gene, on the maternal allele. Accordingly, the patient exhibited a mixed phenotype, with symptoms of both disorders. She presented with mild clinical features typical of HIDS (cervical lymphadenopathy, mild abdominal pain, arthralgia, splenomegaly), had a low-normal MK activity with normal mevalonic acid excretion values, and responded very well to steroid therapy. This suggests that another MVK mutation was probably absent, which is supported by the results of the DNA sequence analyses. The patient's father was a healthy V377I heterozygote and showed a slightly depressed MK enzyme activity, while her mother was an asymptomatic carrier of the TNFRSF1A R92Q substitution.
Generally, R92Q is regarded as a low-penetrance mutation associated with a broader range of symptoms than most TRAPS mutations and found especially in sporadic cases of TRAPS (12), although segregation with disease has been observed in 4 families (23). The R92Q allele frequency ranges from 1.8% (23) to 3.3% (12) in patients with clinical symptoms suggestive of TRAPS and amounts to ∼1% in Irish and North American control populations (12). Although an in vitro shedding defect is absent, soluble TNFRSF1A levels did not increase during an inflammatory episode in an R92Q carrier, suggesting that this amino acid substitution leads to an in vivo dysfunctional receptor (12). Thus, one could also speculate that our patient had TRAPS with the V377I mutation probably contributing to the symptoms.
Arkwright et al (13) already described a patient who was a compound heterozygote for 2 MVK mutations (G211A and V377I) and who also carried the P46L TNFRSF1A variant on 1 allele. Subsequently, they tested 15 confirmed HIDS patients for the 3 low-penetrance mutations P46L, R92Q, and R92P. Since no additional TNFRSF1A mutations were detected, those investigators suggested that probands with HIDS have no increased frequency of TNFRSF1A mutations. However, based on our findings, we suggest that patients with periodic fever should be tested for TNFRSF1A mutations, irrespective of whether they carry 2, 1, or no MVK mutations. This could answer the question of whether HIDS patients have an increased frequency of TNFRSF1A mutations, which could contribute to the severity of the disease.
Patient D, carrying the V377I variant on only 1 allele, showed the typical clinical and laboratory features of HIDS, with high IgD and IgA levels and sharply decreased MK activity. However, we were unable to detect a second mutation in the MVK and TNFRSF1A genes of this patient. Unfortunately, the parents did not agree to a second withdrawal of blood from their daughter in order to confirm the low MK activity as well as to perform cDNA analyses. Blood was always drawn during the asymptomatic interval, since temperature is known to affect MK activity (24); thus, a false-positive result can be excluded in this case. The disease may therefore be the result of another alteration in the promoter region (of which only 35 bp directly upstream of the cap site were sequenced), in the 3′-untranslated region, or in intronic sequences of the MVK gene locus which were also not covered by our analyses.
In probands F, G, and H, with the clinical phenotype of HIDS, no MVK or TNFRSF1A mutation could be detected. Interestingly, these patients showed milder or no laboratory abnormalities, with normal MK activities (all 3 patients) and urinary mevalonic acid concentrations (tested for patients G and H only), only slightly elevated IgD levels (except for patient F), and normal IgA levels. Since other hereditary periodic fever syndromes have been excluded from a clinical and molecular genetic point of view, and since all patients displayed the typical HIDS phenotype, we consider these probands to be variant-type HIDS patients.
In summary, our study illustrates the clinical and genetic heterogeneity of HIDS. A possible association with low-penetrance TNFRSF1A mutations in heterozygous or variant-type HIDS patients needs to be investigated, since this is likely to influence the phenotype.