Hyperimmunoglobulinemia D Syndrome Research Articles

Biological disease-modifying antirheumatic drugs in the main monogenic autoinflammatory diseases treatment. Experience of application in rheumatological practice

Objective: to assess the frequency of prescription, efficacy and tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) therapy in patients with major monogenic autoinflammatory diseases (mAID) according to the Federal Rheumatology Center clinical practice. Patients and methods. From 2008 to 2020 years, 158 patients with mAID were included in the study, 53 of whom were prescribed bDMARDs: 12 patients had Familial Mediterranean Fever (FMF); 26 – Cryopyrin-Associated Periodic Syndromes (CAPS), including 21 patients with MuckleWells Syndrome (MWS) and 5 – with Chronic Infantile Onset Neurologic Cutaneous Articular / Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID), 12 patients had Tumor necrosis factor (TNF) receptor-Associated Periodic Fever Syndrome (TRAPS) and 3 – Hyper-Immunoglobulinemia D-syndrome (HIDS/MKD). Among all these patients 25 were male and 28 female, aged 1.5 to 44 years, 45 were children (under 18) and 8 adults. Interleukin 1 inhibitors (iIL1) were prescribed in accordance with the following scheme: canakinumab – subcutaneously 2–5 mg/kg or 150 mg per injection, every 4–8 weeks; anakinra – subcutaneously 1–5 mg/kg or 100 mg/day, daily. Etanercept (ETC) was injected subcutaneously 0.4–0.8 mg/kg 1–2 times a week, and adalimumab (ADA) was injected subcutaneously 20–40 mg once every 2 weeks. Tocilizumab (TCZ) was administered intravenously, 8–12 mg/kg once every 2–4 weeks. The duration of the disease at the time of treatment initiation ranged from 1 to 44 years. The duration of bDMARDs therapy in patients with mAID ranged from 1 month to 12 years.Results and discussion. From 158 patients with mAID, in 53 (33.5%) bDMARDs were administered. They were used more often in patients with CAPS (56.6%), and less often – in TRAPS (26.4%), FMF (28.3%) and HIDS/MKD (5.7%). iIL1 were the most frequently prescribed bDMARDs (90.6%): canakinumab (in 38 patients) and anakinra (in 10), they were mainly used in patients with CAPS, in 2/3 of patients with TRAPS, HIDS/MKD and colchicine-resistant FMF. During the first days of iIL1 treatment, all patients with mAID showed a statistically significant clinical improvement: normalization of general condition, emotional recovery, relief of fever, disappearance of rash, decrease in the severity of lymphadenopathy and hepatosplenomegaly, relief or significant positive dynamics of eye symptoms, subjective improvement in hearing and audiogram (with dynamic control in patients with CAPS), decrease in the level of acute phase markers (in all cases). In 7 patients with CAPS, who received anakinra, after a positive response was achieved, switching to canakinumab was performed, which maintained the full effectiveness of therapy. TCZ (in 7 patients) and inhibitors of tumor necrosis factor α (iTNFα) – ADA (in 3) and ETC (in 4), – were used less frequently. iTNFα were more often prescribed to FMF patients with a complete response to treatment. Tolerability of bDMARD therapy was satisfactory in all patients.Conclusion. Currently, iIL1 are the first line of therapy among biological agents for mAID, especially in patients with CAPS. If they are ineffective or intolerant in certain situations, alternative bDMARDs (iTNFα and IL6 inhibitors) can also be used, but this issue needs further study.

СИНДРОМ ДЕФИЦИТА МЕВАЛОНАТКИНАЗЫ У РЕБЕНКА РАННЕГО ВОЗРАСТА: КЛЮЧЕВЫЕ АСПЕКТЫ ДИАГНОСТИКИ И ЛЕЧЕНИЯ

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease with an autosomal recessive inheritance. The severity of the disease is correlated with the residual enzyme activity. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria. A little more than 300 cases with MDK have been described worldwide. The rarity of this disease, and polymorphism of clinical manifestations lead to late diagnosis and late onset of specific treatment. We described the 7-month-old infant with pathogenic variants c.118C> T (p.R40W) and c.206_207del (p.S69fs) in the MVK gene in a compound heterozygous state with the successful use of an interleukin-1 blocker.

Canakinumab for the treatment of hyperimmunoglobulin D syndrome

ABSTRACTIntroduction: Mevalonate Kinase Deficiency (MKD) is a rare monogenic autoinflammatory disorder (AID) with autosomal recessive inheritance caused by mutations in the MVK gene. It includes hyperimmunoglobulinemia D syndrome (HIDS) and mevalonic aciduria (a severe form). Patients have recurrent inflammatory attacks with high fever, gastrointestinal symptoms, lymphadenopathy, splenomegaly, arthralgia, rash, pharyngitis, aphtosis and constitutional complaints. Heightened understanding of molecular mechanisms in monogenic autoinflammatory disorders has provided tools for targeted treatment. HIDS is an extrinsic inflammasomopathy and is responsive to anti-IL-1 therapies, such as the recombinant IL-1-receptor antagonist anakinra, the monoclonal antibody against IL-1b canakinumab (CAN), and the recombinant IL-1R fusion protein rilonacept.Areas covered: CAN is a human monoclonal anti-IL-1β antibody that binds with high affinity and neutralizes the activity of IL-1 β. Both observational registries and some case reports have seemed promising in the efficacy of CAN in the HIDS treatment. Two clinical trials have corroborated CAN as an effective and safe drug.Expert commentary: CAN is effective and safe for the treatment of HIDS patients. Some data suggest these patients may need higher dosage or shorter dosing interval than other AIDs, to achieve and maintain complete clinical and laboratory response. Reported adverse events were mild, most often non-complicated infections.

Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.

Mutations of pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases, familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutated or in response to bacterial modification of the GTPase RhoA. Here we show that RhoA activates the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin binds 14-3-3 proteins, which block the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin is substantially decreased, and the constitutive IL-1β release from FMF or HIDS patients’ peripheral blood mononuclear cells is attenuated by activating PKN1 and PKN2. Defects in prenylation, seen in HIDS, lead to RhoA inactivation and consequent pyrin inflammasome activation. These data indicate a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders.

Natural history of mevalonate kinase deficiency: a literature review.

Mevalonate kinase deficiency (MKD), a very rare autosomal recessive autoinflammatory disease with multiple organ involvement, presents clinically as hyperimmunoglobulinemia D syndrome (HIDS), a less severe phenotype and more common form, and mevalonic aciduria (MVA), a more severe phenotype and rare form. MKD is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. Patients with MVA also have intrauterine growth retardation, congenital defects (cataracts, shortened limbs, and dysmorphic craniofacial features), neurological disease, and failure to thrive. Mean age at onset of symptoms is within the first year of life. There is a delay by several years between symptom onset and diagnosis, which is in part attributable to the initial misdiagnosis due to the rarity and nonspecific clinical manifestations of disease. The frequency of recurrent febrile attacks is highest in childhood and gradually decreases after adolescence. MKD is associated with rare long-term complications such as type AA amyloidosis, joint contractures, abdominal adhesions, renal angiomyolipoma, and severe pneumococcal infections. Frequent febrile attacks significantly impair several aspects of patients’ and caregivers’ quality of life, with an adverse impact on patients’ daily activities, education, and employment. Lifespan is generally normal for HIDS whereas MVA can be fatal in early childhood.

Activation of the pyrin inflammasome through the RhoA signaling pathway in FMF and HIDS

Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause the autoinflammatory diseases familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS), respectively. The inflammation of both diseases is mediated by interleukin-1β (IL-1β). Recently it has been reported that pyrin forms an inflammasome, a multiprotein complex that mediates the maturation of IL-1β by activating caspase-1, in response to bacterial modifications of RhoA. However, the precise molecular mechanism by which the pyrin inflammasome is activated is unknown.

Overlap of familial Mediterranean fever and hyper-IgD syndrome in an Arabic kindred.

Hyperimmunoglobulinemia D Syndrome (HIDS) has rarely been reported in Arabs. Moreover, the simultaneous presence of mutations in MEFV and MVK segregating in the same family is exceptional. We report an Arabic girl presenting since the age of 8-years with two patterns of recurrent episodes of fever, and associated with a spectrum of clinical features suggestive of overlap between familial Mediterranean fever (FMF) and HIDS. Her 19-year old brother presented since the age of 1 year with prolonged episodes of fever and was diagnosed with HIDS at the age of 7 years based on clinical features and homozygosity for p.V377I mutation in MVK. Shorter episodes of fever and abdominal pain more consistent with FMF ensued since the age of 17 years. Genetic testing done for both patients and all other family members revealed simultaneous presence of mutations in MEFV and MVK but with a variable clinical spectrum ranging from asymptomatic to severe manifestations. Both of our patients are homozygous for p.V377I MVK mutation; the girl is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.E167D/p.F479L MEFV mutations whereas the brother is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.M680I MEFV mutations. The clinical implications of having more than one mutation in different genes of monogenic autoinflammatory diseases in the same individual are not clear but may explain atypical clinical manifestations such as the overlap features of both FMF and HIDS in this family.

AB0918 Efficacy and Safety of Treatment of Children with Traps and Hids with IL1 Blocker (CANAKINUMAB)

BackgroundThe hyperimmunoglobulinemia D syndrome (HIDS),so-called mevalonate kinase deficiency, is caused by recessive mutations in the gene MVK encoding mevalonate kinase enzyme.HIDS is characterized by recurrent fever attacks of 3-7 days...

AUTOINFLAMMATORY DISEASES IN CHILDREN(The Lecture from 18th of September 2013, Conference «Topical Problems of Diagnostics and Treatment of Juvenile Rheumatoid Arthritis» (18–20 of September, 2013, St. Petersburg))

Data about clinical signs, diagnostics and treatment of hereditary autoinflammatory syndromes, e.g. cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), TNF-receptor associated periodic syndrome (TRAPS-syndrome), hyperimmunoglobulinemia D syndrome (HIDS), Pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome, juvenile sarcoidosis (Blau-syndrome) are shown in the article. These diseases are typically genetic disease with autosomal dominant and autosomal recessive type of inheritance. All diseases have common pathogenic features, such as spontaneous activation of innate immunity, maintaining of uncontrolled inflammation, absence of auto-antibodies and antigen-specific T-lymphocytes, over-secretion of interleukin-1 and good response to anti-interleukin-1 treatment. In this article you can see the basis of pathogenesis of the diseases, which determine the choice of treatment modalities and diagnostic algorhythms. Differences between clinical phenotypes of cryopyrin-associated periodic syndrome, such as familial cold urticaria (FCAS), Muckle-Wells syndrome and CINCA / NOMID syndrome are described thoroughly. You can find information about the whole group of periodic fevers and their differentiation. Data about international project «EuroFever» which can facilitate international collaboration in the fields of periodic fever are available.

A81: Spectrum of Mevalonate Kinase Deficiency: Is Colitis More Common Than We Think?

Background/Purpose:Mevalonate kinase deficiency (MKD) is an autosomal recessive inflammatory disorder caused by a mutation in the mevalonate kinase (MVK) gene. This leads to decreased enzymatic activity, resulting in impaired cholesterol biosynthesis and increased production of inflammatory mediators such as interleukin 1‐β. There are two known forms of MKD, with Hyperimmunoglobulinemia D Syndrome (HIDS) carrying a milder phenotype and Mevalonic Aciduria (MA) representing a severe form. HIDS is characterized by recurrent febrile episodes accompanied by varying clinical features that include lymphadenopathy, gastrointestinal symptoms, oral ulcers, and arthralgia. A recent report identified early onset colitis as a feature of MKD in two patients (Levy M et al, 2013). Here we report the clinical and laboratory phenotypes of patients cared for at Boston Children's Hospital who were diagnosed with HIDS/MKD.Methods:We conducted a retrospective chart review of children with HIDS/MKD treated from 2002–2012 at the Rheumatology Clinic at Boston Children's Hospital. Charts were first identified by searching for key words or billing codes related to autoinflammatory syndromes. A manual chart review was then performed to confirm appropriate case identification.Results:Four patients were diagnosed with HIDS/MKD over the 10‐year period. Age of symptom onset varied from 2 months to 1 year. Fever duration ranged from 1–5 days, with duration between fevers ranging from 9 days to 12 weeks. Symptoms included sore throat, oral lesions, vomiting, diarrhea, abdominal pain, rash, and arthralgia. Prodromal symptoms were identified in all patients, and included irritability, anorexia, fatigue, geographic tongue, rash, and neck pain. Three of the four patients had a history of bloody stools beginning in infancy/early childhood, and were followed by gastroenterology. All patients had lymphadenopathy on exam, and splenomegaly was detected in two patients by ultrasound. Labs obtained during febrile episodes showed elevated inflammatory markers, however, in two out of three patients evaluated in between fevers, the ESR was persistently elevated. All four patients had elevated IgA when compared to age matched normal values, and two patients had elevated IgD levels. Genetic testing was performed in all patients, with all four having two heterozygous mutations within the MVK gene. In addition, one patient also had single variant mutations of unclear significance in two other genes associated with autoinflammatory syndromes. Two patients were treated with steroids and in each case this aborted febrile episodes, however, in one patient steroid use was also associated with increased fever frequency. One patient had decreased severity of symptoms when treated with colchicine as well as with montelukast, and had rapid resolution of fever and associated symptoms when treated with anakinra.Conclusion:The persistence of ESR elevation outside of febrile episodes seen in patients with HIDS/MKD may indicate the presence of chronic subclinical inflammation. Hematochezia was commonly seen, and could indicate the presence of colitis. Of the immunomodulatory medications used in this small patient population, anakinra appeared to be effective.

Establishment of a transgenic mouse model with liver-specific expression of secretory immunoglobulin D

Mutation of mevalonate kinase (MVK) is thought to account for most cases of hyperimmunoglobulinemia D syndrome (HIDS) with recurrent fever. However, its mechanism and the relationship between elevated serum immunoglobulin D (IgD) and the clinical features of HIDS are unclear. In this study, we generated by fusion PCR a vector to express high levels of chimeric secretory IgD (csIgD) specifically in the liver. We then generated seven founder lines of transgenic mice by co-microinjection, and verified them using genomic PCR and Southern blotting. We detected the expression of csIgD by reverse transcription PCR, quantitative PCR, western blotting, and enzyme-linked immunosorbent assays. We demonstrated that csIgD could be specifically and stably expressed in the liver. We used flow cytometry to show that overexpression of csIgD in the bone marrow and spleen cells had no effect on B cell development. Morphologic and anatomical observation of the transgenic mice revealed skin damage, hepatosplenomegaly, and nephromegaly in some transgenic mice; in these mice, pathological sections showed high levels of cell necrosis and protein-like sediments in the liver, spleen, and kidney. We demonstrated that the genomic insertion sites of the transgenes did not disrupt the MVK gene on mouse chromosome 5. This transgenic mouse will be useful to explore the pathogenesis of HIDS.

Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report

Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3-7 days and recurring every 4-6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C-reactive protein are elevated during the episode, and in addition, high levels of interleukine-1 (IL-1), IL-6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF-alpha inhibitor, and three children with anakinra, IL-1 receptor antagonist. This review summarizes currently available data on the use biological medicines for HIDS in children. A Finnish 1.5-year-old patient with disease onset at 6 months of age, treated successfully with anakinra, is presented.

Fièvre périodique avec élévation des immunoglobulines D

Periodic fever or hereditary inflammatory fevers are characterized by intermittent inflammatory attacks. Many entities are well recognized today such as familial mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). We report on the case of a 6-year-old boy referred for evaluation of a recurrent fever associated with chest pain, pneumonitis, or pleuritis since the age of 5 years. Laboratory data showed leukocytosis, a high erythrocyte sedimentation rate, and C-reactive protein; however, a permanent high serum level IgD was noted. Stereotypical episodes of fever appeared every 4-6 weeks, while infectious, malignant, and auto-immune causes were eliminated. A search for the most common mutations of the FMF gene in Tunisian patients (M694V, M680I, V726A, E148Q, M694I, and A744S) were negative. Likewise, urinary leukotriene E(4), which may be increased in HIDS, was normal in this patient. Mevalonate kinase activity in lymphocytes was not assayed. Ethnic origin and clinical presentation suggest FMF with an increased IgD rather than authentic HIDS, in spite of the lack of improvement under colchicine treatment and the negativity of the main mutations involved in FMF.

Nummular keratopathy in a patient with Hyper-IgD Syndrome

PurposeTo report a case of recurrent nummular keratitis in a pediatric patient with Hyperimmunoglobulinemia D syndrome.MethodsA retrospective chart review.ResultsA 14-year-old boy with Hyperimmunoglobulinemia D syndrome (HIDS) presented with photophobia and ocular irritation concomitant with disease exacerbation. He was found on exam to have significant nummular keratitis, which responded to a short course of topical steroids. Despite acute response to local immunosuppression, the patient had several recurrent attacks and eventually developed a large corneal scar and decreased vision. After initiation of infliximab therapy his ocular sequelae improved dramatically and his vision returned to 20/20.ConclusionOne possible form of end-organ damage associated with HIDS is vision threatening nummular keratopathy.

Auto inflammatory syndromes: Diagnosis and treatment

Hereditary recurrent fevers are rare genetic diseases characterized by apparently spontaneous attacks of inflammation. They include familial Mediterranean fever (FMF); tumor necrosis factor (TNF) receptor periodic syndrome (TRAPS); hyperimmunoglobulinemia D syndrome (HIDS); and hereditary periodic fevers related to mutations in the CIAS1 (cold induced autoinflammatory syndrome 1) gene, such as Muckle–Wells syndrome, familial cold urticaria, and CINCA/NOMID (chronic infantile neurological cutaneous and articular/neonatal-onset multisystemic inflammatory disease). Musculoskeletal manifestations are common. They may occur as features of the acute inflammatory attacks or persist for longer periods. Among them, the most common include arthritis of the large and medium-sized joints in FMF and CINCA, arthralgia in HIDS, and myalgia or pseudo-fasciitis in TRAPS. The outcome is usually favorable, although joint destruction may develop in CINCA or at the hip in FMF. The recurrent bouts of fever and accompanying clinical manifestations suggest the diagnosis, which can be confirmed by genetic testing. Among differential diagnoses, infection should be considered routinely. The treatment of the inflammatory attacks is nonspecific. New pathophysiological insights have led to the development of promising maintenance treatments designed to reduce the number and severity of the inflammatory attacks and to diminish the risk of secondary amyloidosis.

GHMP Kinases - Structures, Mechanisms and Potential for Therapeutically Relevant Inhibition

The GHMP kinases are a structurally related family of small molecule kinases named after four of its members - galactokinase, homoserine kinase, mevalonate kinase and phosphomevalonate kinase. The group also includes the enzymes N-acetylgalactosamine kinase, arabinose kinase, mevalonate 5-diphosphate decarboxylase, archeal shikimate kinase and 4-(cytidine 5-diphospho)-2-c-methyl-D-erythritol kinase. In addition the group includes two members not known to be catalytically active, the Caenorhabditis elegans sex-fate determining protein XOL-1 and the Saccharomyces cerevisiae transcriptional activator Gal3p. Two catalytic mechanisms have been proposed for GHMP kinases. The structure of mevalonate kinase suggests that an aspartate residue acts as an active site base, removing a proton from the substrate to facilitate attack on the γ- phosphate of MgATP. In contrast, in homoserine kinase there is no potential catalytic base and it is proposed that catalysis is driven by transition state stabilisation. Potential chemotherapeutic interventions against GHMP kinases fall into three main categories: inhibition of galactokinase to assist suffers of galactosemia, inhibition of mevalonate kinase or mevalonate 5-diphosphate decarboxylase to reduce flux through the cholesterol biosynthesis pathway and inhibition of bacterial GHMP kinases for novel anti-microbial therapies. These are in the early stages of development, but the accumulation of structural and mechanistic data will assist future progress. Keywords: Galactokinase, homoserine kinase, mevalonate kinase, cholesterol metabolism, carbohydrate metabolism, galactosemia, mevalonic aciduria, hyperimmunoglobulinemia D syndrome (HIDS), anti-microbial chemotherapy, enzyme mechanism

Hereditary Periodic Fever With Systemic Amyloidosis: Is Hyper-IgD Syndrome Really a Benign Disease?

We report a case of amyloidosis in association with hyperimmunoglobulinemia D syndrome (HIDS). The patient showed typical clinical features of HIDS. He had crescentic glomerulonephritis progressing to end-stage renal disease at age 13 years. Eight years later, he developed an AA-type amyloidosis with extensive involvement of the intestine, respiratory tract, and thyroid gland. These unusual complications of HIDS seriously challenge the assumption that the disease is associated with a good prognosis.

Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.

La maladie périodique au sein des maladies auto-inflammatoires

During the first attacks of familial Mediterranean fever, each of the disease symptoms can suggest a series of disorders. When the disease is older, the recurrence of symptoms may simulate some systemic diseases, but mainly suggests familial Mediterranean fever, one of a group of hereditary autoinflammatory diseases. Before the gene for familial Mediterranean fever was identified, various sets of criteria were used for diagnosis. The presence of MEFV mutations confirms the diagnosis, but the clinical criteria still determine who should undergo this genetic testing. The genotype-phenotype correlations add a prognostic dimension to the mutations identified. Genotyping can also lead to the diagnosis of the other autoinflammatory diseases, which constitute the basis of the differential diagnosis of familial Mediterranean fever. The hyperimmunoglobulinemia D syndrome (HIDS) is very similar to familial Mediterranean fever in its recessive transmission and abdominal and articular symptoms. It can be distinguished by the European origin of the patients, the presence of cervical lymph nodes and the increased IgD levels. Of the diseases with dominant transmission, the TNF receptor-associated periodic syndromes (TRAPS) are suggested by periorbital edema and migrating inflammatory cellulitis. Muckle and Wells syndrome is revealed by episodes of fever with urticaria and arthralgia, complicated by deafness and amyloidosis. Mutations in the same gene are responsible for two disorders, both appearing in childhood: familial cold urticaria syndrome (FCUS) and chronic infantile neurocutaneous articular syndrome (CINC). The pathogenesis of familial Mediterranean fever is still unclear. Pyrin/marenostrin, the protein produced by the MEFV gene, appears to hae a physiological antiinflammatory effect that inhibits proinflammatory cytokines. Mutation of the gene may eliminate this feedback mechanism and expose the patient to flares from any inflammatory stimulus, even minimal. Amyloid is produced by the serum amyloid A protein (SAA), and its occurrence is influenced by the type of MEFV mutation, but also the genotype of the gene producing SAA.

Periodic Fever in Children With Hyperimmunoglobulinemia D and Mevalonate Kinase Mutations

Hyperimmunoglobulinemia D syndrome (HIDS) is one cause of periodic fevers in children. HIDS is associated with mutations in the mevalonate kinases gene on chromosome 12. Most cases of HIDS have been reported from the Netherlands and surrounding European countries. It is likely that HIDS is underdiagnosed in the United States.