Hyperimmunoglobulin D syndrome: Pathophysiology
- Yoram C Padeh, MD
Yoram C Padeh, MD
- Instructor in Clinical Medicine
- Mount Sinai Medical Center
- Arye Rubinstein, MD
Arye Rubinstein, MD
- Professor of Pediatrics Microbiology and Immunology
- Albert Einstein College of Medicine and Montefiore Hospital Medical Center
Hyperimmunoglobulin D syndrome (HIDS) is a rare genetic disorder characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level (MIM #260920). The syndrome can be further categorized into classic and variant forms. The genetic defect is known in the classic form, which makes up 75 percent of cases. The variant form has similar clinical manifestations, although its genetic basis is unknown .
This topic reviews the genetics and pathophysiology of HIDS. The clinical manifestations, diagnosis, and management of this disorder are discussed in detail separately. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)
Classic HIDS is caused by mevalonate kinase (MVK) deficiency and is inherited as an autosomal-recessive trait [2-6]. Most patients are compound heterozygous for two different mutations in the MVK gene. However, some patients may be homozygous for the same defect on both alleles. Patients with similar clinical features but lacking mutant MVK genes are referred to as having variant HIDS. (See 'Variant HIDS' below.)
Mevalonate kinase — The MVK gene (MIM *251170) is located on the long arm of chromosome 12 (12q24) . The gene product, MVK, is a cytosolic protein that is localized to the peroxisome [8,9]. It is an enzyme in the cholesterol synthesis pathway. This pathway is responsible for the synthesis of sterol products, such as cholesterol and its derivatives, as well as nonsterol isoprenoids, including prenylated proteins, heme A, dolichol, and ubiquinone-10 [10,11]. MVK is one enzyme downstream of the highly regulated hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase enzyme (figure 1).
Compound heterozygous MVK mutations in HIDS patients usually consist of one allele with a mutation that causes mevalonic aciduria when present in a homozygous state (eg, H20P, I268T, or A334T mutation)  (see "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Mevalonic aciduria (MEVA)'). The other allele has a mutation that is not typical for mevalonic aciduria. The V377I mutation is the second most common mutation in patients with HIDS (52 to >90 percent) [7,13-15]. In the remaining HIDS patients without the V377I mutation, the second mutation probably causes a similar enzymatic defect, leading to residual MVK activity .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Simon A, Cuisset L, Vincent MF, et al. Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med 2001; 135:338.
- Hospach T, Lohse P, Heilbronner H, et al. Pseudodominant inheritance of the hyperimmunoglobulinemia D with periodic fever syndrome in a mother and her two monozygotic twins. Arthritis Rheum 2005; 52:3606.
- Frenkel J, Kuis W. Overt and occult rheumatic diseases: the child with chronic fever. Best Pract Res Clin Rheumatol 2002; 16:443.
- Simon A, Mariman EC, van der Meer JW, Drenth JP. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am J Med 2003; 114:148.
- Drenth JP, Cuisset L, Grateau G, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 1999; 22:178.
- Houten SM, Kuis W, Duran M, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet 1999; 22:175.
- 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 2001; 9:253.
- Biardi L, Sreedhar A, Zokaei A, et al. Mevalonate kinase is predominantly localized in peroxisomes and is defective in patients with peroxisome deficiency disorders. J Biol Chem 1994; 269:1197.
- Wanders RJ, Romeijn GJ. Differential deficiency of mevalonate kinase and phosphomevalonate kinase in patients with distinct defects in peroxisome biogenesis: evidence for a major role of peroxisomes in cholesterol biosynthesis. Biochem Biophys Res Commun 1998; 247:663.
- Houten SM, Frenkel J, Waterham HR. Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation. Cell Mol Life Sci 2003; 60:1118.
- Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343:425.
- Houten SM, van Woerden CS, Wijburg FA, et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet 2003; 11:196.
- Houten SM, Frenkel J, Kuis W, et al. Molecular basis of classical mevalonic aciduria and the hyperimmunoglobulinaemia D and periodic fever syndrome: high frequency of 3 mutations in the mevalonate kinase gene. J Inherit Metab Dis 2000; 23:367.
- 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 2001; 9:260.
- Houten SM, Frenkel J, Rijkers GT, et al. Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome. Hum Mol Genet 2002; 11:3115.
- Hager EJ, Tse HM, Piganelli JD, et al. Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome. J Inherit Metab Dis 2007; 30:888.
- Grose C. Periodic fever in children with hyperimmunoglobulinemia D and mevalonate kinase mutations. Pediatr Infect Dis J 2005; 24:573.
- Messer L, Alsaleh G, Georgel P, et al. Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS). RMD Open 2016; 2:e000196.
- Hammoudeh M. Hyperimmunoglobulinemia D syndrome in an Arab child. Clin Rheumatol 2005; 24:92.
- Frenkel J, Houten SM, Waterham HR, et al. Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D. Rheumatology (Oxford) 2001; 40:579.
- Stojanov S, Lohse P, Lohse P, et al. Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa. Arthritis Rheum 2004; 50:1951.
- Hoffmann F, Lohse P, Stojanov S, et al. Identification of a novel mevalonate kinase gene mutation in combination with the common MVK V377I substitution and the low-penetrance TNFRSF1A R92Q mutation. Eur J Hum Genet 2005; 13:510.
- 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 2004; 50:2966.
- van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 2005; 5:87.
- Siewert R, Ferber J, Horstmann RD, et al. Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease? Am J Kidney Dis 2006; 48:e41.
- Arkwright PD, McDermott MF, Houten SM, et al. Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept. Clin Exp Immunol 2002; 130:484.
- Drenth JP, Göertz J, Daha MR, van der Meer JW. Immunoglobulin D enhances the release of tumor necrosis factor-alpha, and interleukin-1 beta as well as interleukin-1 receptor antagonist from human mononuclear cells. Immunology 1996; 88:355.
- de Wolff JF, Dickinson SJ, Smith AC, et al. Abnormal IgD and IgA1 O-glycosylation in hyperimmunoglobulinaemia D and periodic fever syndrome. Clin Exp Med 2009; 9:291.
- Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore) 1994; 73:133.
- Houten SM, Schneiders MS, Wanders RJ, Waterham HR. Regulation of isoprenoid/cholesterol biosynthesis in cells from mevalonate kinase-deficient patients. J Biol Chem 2003; 278:5736.
- Hoffmann GF, Charpentier C, Mayatepek E, et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics 1993; 91:915.
- Frenkel J, Rijkers GT, Mandey SH, et al. Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum 2002; 46:2794.
- Simon A, Bijzet J, Voorbij HA, et al. Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response. J Intern Med 2004; 256:247.
- Pontillo A, Paoluzzi E, Crovella S. The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency. Eur J Hum Genet 2010; 18:844.
- De Leo L, Marcuzzi A, Decorti G, et al. Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches. Pharmacol Res 2010; 61:506.
- Marcuzzi A, Decorti G, Pontillo A, et al. Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency. Inflamm Res 2010; 59:335.
- Marcuzzi A, Tommasini A, Crovella S, Pontillo A. Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes. Int Immunopharmacol 2010; 10:639.
- Marcuzzi A, Crovella S, Pontillo A. Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency. In Vivo 2011; 25:87.
- Marcuzzi A, De Leo L, Decorti G, et al. The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency. Pediatr Res 2011; 70:78.
- Marcuzzi A, Pontillo A, De Leo L, et al. Natural isoprenoids are able to reduce inflammation in a mouse model of mevalonate kinase deficiency. Pediatr Res 2008; 64:177.
- Kuijk LM, Beekman JM, Koster J, et al. HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 2008; 112:3563.
- Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat 2006; 27:796.
- Stoffels M, Simon A. Hyper-IgD syndrome or mevalonate kinase deficiency. Curr Opin Rheumatol 2011; 23:419.
- Levy BD, Petasis NA, Serhan CN. Polyisoprenyl phosphates in intracellular signalling. Nature 1997; 389:985.
- Mandey SH, Kuijk LM, Frenkel J, Waterham HR. A role for geranylgeranylation in interleukin-1beta secretion. Arthritis Rheum 2006; 54:3690.
- Massonnet B, Normand S, Moschitz R, et al. Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes. Eur Cytokine Netw 2009; 20:112.
- Kuijk LM, Mandey SH, Schellens I, et al. Statin synergizes with LPS to induce IL-1beta release by THP-1 cells through activation of caspase-1. Mol Immunol 2008; 45:2158.
- Normand S, Massonnet B, Delwail A, et al. Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation. Eur Cytokine Netw 2009; 20:101.
- Drenth JP, van Deuren M, van der Ven-Jongekrijg J, et al. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood 1995; 85:3586.
- Havenaar EC, Drenth JP, van Ommen EC, et al. Elevated serum level and altered glycosylation of alpha 1-acid glycoprotein in hyperimmunoglobulinemia D and periodic fever syndrome: evidence for persistent inflammation. Clin Immunol Immunopathol 1995; 76:279.
- Drenth JP, Powell RJ, Brown NS, Van der Meer JW. Interferon-gamma and urine neopterin in attacks of the hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Clin Invest 1995; 25:683.