Hyperimmunoglobulinemia D With Periodic Fever Syndrome Research Articles

OP0119 Patient Journey and Treatment Route to Use of First Biologic in Rare Autoinflammatory Diseases: an International Retrospective Chart Review

BackgroundDue to low incidence rates, treatment data and guidelines in hereditary periodic fevers are limited. To complement published data from the autoinflammatory diseases PRINTO/Eurofever registry, an international noninterventional study of...

Novel mutations of MVK gene in Japanese family members affected with hyperimmunoglobulinemia D and periodic fever syndrome

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is a recessively inherited recurrent fever syndrome. We describe a family of eldest son and monozygotic twin younger sisters with characteristic syndrome of HIDS, but normal level of IgD. Mevalonate kinase (MK) activity was deficient in all of them, and analysis of the MVK gene revealed compound heterozygosity for 2 new mutations, one of which was the disease-causing splicing mutation and the other was a novel missense mutation. All the patients had the same compound heterozygous mutations c.227-1 G > A and c.833 T > C, which resulted in exon 4 skipping and p.Val278Ala. This is the first case in which exon skipping mutation of the MVK gene has been certainly identified at the genomic DNA level. In each case, in which HIDS is clinically suspected, despite normal IgD level, analysis of MK activity and the MVK gene should be performed.

Autoinflammatorische Erkrankungen als Ursache von Wundheilungsstörungen

Ulcerations of the skin and mucosal membranes are a common feature of autoinflammatory diseases. They can give raise to chronic wound healing defects and should be considered in the differential diagnosis of chronic skin ulcers. The increased activation of the innate immune system in the absence of an apparent provocation for inflammation is a hallmark of autoinflammatory diseases. Mutations and alterations of signaling pathways regulating the innate immune response to physical trauma/tissue damage result into an unrestrained activation of the inflammasome, which leads to increased activation of Interleukin-1. Uncontrolled recruitment and activation of myeloid effector cells within the wound site lead to the release of potent proteases that cause the degradation of structural components of the skin. The majority of these diseases respond well to immunosuppressive and immunomodulatory treatment regimes. Therapeutic resistance converts the acute inflammatory response into a chronic and non-resolving inflammatory process that leads to tissue degeneration. In this article we will focus on the review of those autoinflammatory diseases that often display ulcerative cutaneous and aphthous lesions including pyoderma gangrenosum, Behçet disease, PAPA syndrome and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). Furthermore, the article will be complemented by an overview of those inflammatory diseases that are associated with non-ulcerative cutaneous manifestations.

Macrophage activation syndrome revealing familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome, is caused by recessively inherited mutations in the MEFV gene, and is observed predominantly in Sephardim Jewish and Mediterranean populations. FMF is characterized by short and self-limited recurrent episodes of fever and systemic inflammation involving serous membranes, skin, and joints. Macrophage activation syndrome (MAS) is a macrophage-related histiocytic disorder caused by excessive activation and proliferation of macrophages and T lymphocytes leading to uncontrolled production of inflammatory cytokines. Acute infection (especially Epstein-Barr virus [EBV]) and systemic inflammatory disorders (especially systemic-onset juvenile idiopathic arthritis [JIA]) are the most common causes of this life-threatening disorder. MAS has been reported twice in patients with hereditary autoinflammatory diseases: first, a patient with chronic infantile neurologic, cutaneous, articular syndrome (CINCA), and second, a patient with hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). To our knowledge, this is the first case of MAS reported in a patient with FMF.

The 423Q polymorphism of the X‐linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever

Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1beta or tumor necrosis factor alpha (TNFalpha). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-kappaB signaling, both of which are processes that influence the development of inflammatory cells. The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFalpha. These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.

AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: A report of two cases

AA amyloidosis is the most serious potential complication of the inherited autoinflammatory syndromes and frequently results in end-stage renal failure. Although this complication is well recognized in familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and Muckle-Wells syndrome, there is only 1 previous published report of its occurrence in hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). We report 2 further cases of patients with AA amyloidosis in HIDS, both of whom developed dialysis-dependent renal failure, and we describe the outcome of the first renal transplant in this setting.

Pseudodominant inheritance of the hyperimmunoglobulinemia D with periodic fever syndrome in a mother and her two monozygotic twins

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is a recessively inherited recurrent fever syndrome. We describe a family of 2 monozygotic twins and their mother with characteristic symptoms of HIDS, but normal levels of IgD and IgA, and with a dominant inheritance pattern. Mevalonate kinase (MK) activity was deficient in both children, and analysis of the MVK gene revealed compound heterozygosity for 2 new mutations, G25G and R277H. Being positioned adjacent to a donor splice site, the G25G mutation was shown by reverse transcription-polymerase chain reaction analyses to cause aberrant splicing of the MVK messenger RNA, thus being disease-relevant. The mother, who was also symptomatic during her childhood and adolescence, was a compound heterozygote for I268T and R277H. Our findings expand the genetic and ethnic spectrum of HIDS and show that the possible presence of this disease cannot be excluded based solely on inheritance patterns. In each case in which HIDS is clinically suspected, analysis of MK activity and/or the MVK gene (especially exons 9 and 11) should be performed.

Molecular and Genetic Characteristics of Hereditary Autoinflammatory Diseases

Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

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.

To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A low-penetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured. Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal. The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.