An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment

2021 ◽  
pp. 1-6
Author(s):  
Merve Koç Yekedüz ◽  
Neslihan Doğulu ◽  
Ümmühan Öncül ◽  
Engin Köse ◽  
Serdar Ceylaner ◽  
...  
Keyword(s):  
Periodic Fever ◽  
Mevalonic Acid ◽  
Colchicine Treatment ◽  
Recurrent Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Atypical Presentation ◽  
Genetic Investigation ◽  
Duration Of Treatment ◽  
Inflammatory Drugs

Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G&#x3e;C (p.Gly309Arg) variant and a heterozygous c.1129G&#x3e;A (p.Val377Ile) mutation in the <i>MVK</i> gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.

P084 Recurrent fever in children: why not a mevalonate kinase deficiency?

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_5) ◽  
Author(s):  
K Ouahbi ◽  
O Gacem ◽  
F Boukandoura ◽  
H Benmekhmouf ◽  
N Hamadouche ◽  
...  
Keyword(s):  
Mevalonic Acid ◽  
Abdominal Ultrasound ◽  
Febrile Episode ◽  
Clinical Spectrum ◽  
Recurrent Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Large Joint ◽  
Chest X Ray ◽  
Long Term Prognosis

Abstract Background Mevalonate kinase deficiency (MKD) is a rare autosomal recessive auto inflammatory disease. The clinical spectrum of this disease is a continuum ranging from the moderate form of Hyper-IgD syndrome (HIDS) to lethal forms of mevalonic aciduria (MA). An autoinflammatory disease should be considered in children with recurrent fever of unexplained origin. Case report M, 28 months old boy from a non-consanguineous marriage of Algerian parents, presented since the age of two months’ episodes of unexplained fever resistant to antibiotics and requiring several hospitalizations. Family history found that the mother and a maternal uncle experienced an unexplained recurrent fever. Personal history found episodes of fever lasting in average 6 days, with no obvious cause and recurring every 15–20 days; associated with bilateral cervical adenopathy, mouth ulcers, arthralgia, abdominal pain with vomiting and diarrhea. Clinical examination confirmed the fever with temperature of 38.7°, Chills and irritability, Multiple cervical adenopathy oral aphthae, tongue of geographical aspect, cervical pain and large joint arthralgia, tender abdomen with no organomegaly. Biologic workups found major inflammatory syndrome with hyper leucocytosis at 14X103/mm3 predominantly polynuclear, high CRP level, high ESR at 110 mm. Blood cultures and viral serologies were negative. Immunoelectrophoresis found elevated IgA, IgG and IgM with a normal IgD level. Chest X-ray and abdominal ultrasound were normal. The diagnosis of MKD in its moderate form was supported by elevated urinary mevalonic acid excretion to 5.1 mmol/mol during the febrile episode and subsequently confirmed by a 2nd contributory urine assay during another febrile episode. Conclusion MKD is a rare disease. The clinical spectrum of this condition is variable and could benefit of an effective treatment. Our patient developed a moderate form with a better long-term prognosis.

Validation of the new classification criteria for hereditary recurrent fever in an independent cohort: experience from the JIR Cohort Database

Rheumatology ◽  
2020 ◽  
Vol 59 (10) ◽  
pp. 2947-2952
Author(s):  
Glory Dingulu ◽  
Sophie Georgin-Lavialle ◽  
Isabelle Koné-Paut ◽  
Pascal Pillet ◽  
Anne Pagnier ◽  
...  
Keyword(s):  
Periodic Fever ◽  
Classification Criteria ◽  
Recurrent Fever ◽  
Mevalonate Kinase Deficiency ◽  
Periodic Syndrome ◽  
Mevalonate Kinase ◽  
New Classification ◽  
Clinical Criteria ◽  
Clinical Variables ◽  
Independent Cohort

Abstract Objective The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases. Methods We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician’s diagnosis served as the gold standard for the determination of specificity. Results We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets. Conclusion This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly.

O007. Register of hereditary auto-inflammatory diseases in a pediatric rheumatology unit

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_5) ◽  
Author(s):  
M Souali ◽  
F Semlali ◽  
G Benbrahim ◽  
A Sakhi ◽  
N Mikou ◽  
...  
Keyword(s):  
Clinical Features ◽  
Periodic Fever ◽  
Diagnostic Delay ◽  
Chronic Recurrent Multifocal Osteomyelitis ◽  
Recurrent Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Genetic Syndromes ◽  
Mediterranean Fever ◽  
Wells Syndrome

Abstract Background Autoinflammatory diseases (AID) are a group of genetic syndromes resulting from an excessive activation of the innate immune system, caused by mutations in genes regulating the inflammatory pathways and can involve several organs. The aim of this study is to evaluate the clinical, paraclinical, epidemiogical and genetic data of Moroccan patients with confirmed AID, in order to allow a first experience of AID registry in our unit. Material We have retrospectively analyzed 30 cases of patients in our unit over a period of 13 years (between 2006 and 2019), according to inclusion criterias (recurrent fever &gt; 3 episodes and a CRP &gt; 40mg/L) and having excluded immune deficiency, autoimmune disease, neoplasia and infectious diseases. Results The mean age of our patients at 1st consultation was 6.9 years (with extremes ranging from 8 months to 14 years). Consanguinity was reported in 16 cases, and unknown in one case of an adopted child. The patients were classified as follows: 66% of cases with Familial Mediterranean Fever (FMF) including 1 case with a characteristic phenotype of Marshall/Periodic Fever Aphtous Pharyngitis Adenitis (PFAPA) syndrome, 16% of cases with Mevalonate Kinase Deficiency (MKD), 10% of cases with Chronic Recurrent Multifocal Osteomyelitis (CRMO), 1 patient with Familial Pustular Psoriasis (FPP) and another symptomatic patient with Muckle Wells syndrome. An association with Henoch Schonlein purpura was reported in 30% of cases and with periarteritis nodosa in 1 case in FMF patients. The mean diagnostic delay was 3 years (with extremes ranging from 1 month to 12 years). The main clinical features found in our patients included fever (83%), abdominal pain (90%), arthralgia (83%), arthritis (46%), adenopathies (40%), aphtous (30%) and other specific signs. Genetic analysis revealed that M694V was the most frequent mutation (60%), followed by A744S (15%), E148Q (10%), K695R (10%) and P369S/ R408Q (5%) in all FMF patients, and V337I found in 1 patient with MKD while the 4 others were confirmed basing on a high rate of urinary mevalonic acid. CRMO patients were confirmed by radiological and histological analysis. The case of FPP was confirmed histologically by skin biopsy and the patients with Muckle Wells and PFAPA syndroms were diagnosed basing on characteristic clinical features. Therapeutically, all FMF patients were treated with colchicine in addition of corticosteroids in 1 case of PFAPA syndrome. Patients with MKD received targeted therapy (Anakinra, Etanercept) and Ibuprofen in 1 case. CRMO patients were treated with targeted therapy and NSAIDs. The case of FPP was treated with Methotrexate combined with Etanercept and the patient with Muckel Wells Syndrome received corticosteroid therapy combined with Azathioprine and then Anakinra. The clinical and biological evolution was considered favorable in 76% of cases, partial in 13% of cases and 3 death cases were reported. Conclusion AIDs remain rare genetic syndromes whose lack of knowledge explains the late diagnostic delay. Therefore, it is necessary for any pediatrician to know how to evoke an AID in front of recurrent fever with free intervals, clinical features and inflammatory syndrome, in order to choose the optimal treatment as well as to make the genetic counseling. Abbreviations AID: Auto-Inflammatory Disease CAPS: Cryopyrin Associated Periodic Syndromes CARD14: Caspase Recruitment Domain Family Member 14 CIAS1: Cold-Induced Autoinflammatory Syndrome 1 CRMO: Chronic Recurrent Multifocal Osteomyelitis CRP: C-Reactive Protein CT scan: Computerized Tomography scan DNA: DeoxyriboNucleic Acid ESR: Erythrocyte Sedimentation Rate FMF: Familial Mediterranean Fever FPP: Familial Pustular Psoriasis IL-1β: Interleukine-1beta IL-17A: Interleukine 17A MEFV: Mediterranean fever gene MKD: Mevalonate Kinase Deficiency MVK: Mevalonate Kinase MW: Muckle Wells NALP3: NAcht Leucine-rich repeat Protein 3 NLRP3: NOD-like receptor family, pyrin domain containing 3 NSAID: Non-Steroidal Anti Inflammatory Drugs PFAPA: Periodic Fever Aphtous Pharyngitis Adenitis PRINTO: Pediatric Rheumatology INternational Trials Organization SAA: Serum Amyloid A TRAPS: TNF Receptor Associated Periodic Syndroms TNF: Tumor Necrosis Factor

scholarly journals Classification criteria for autoinflammatory recurrent fevers

2019 ◽  
Vol 78 (8) ◽  
pp. 1025-1032 ◽  
Author(s):  
Marco Gattorno ◽  
Michael Hofer ◽  
Silvia Federici ◽  
Federica Vanoni ◽  
Francesca Bovis ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Periodic Fever ◽  
Classification Criteria ◽  
Nominal Group ◽  
Recurrent Fever ◽  
Tumour Necrosis Factor Receptor ◽  
Mevalonate Kinase Deficiency ◽  
Data Set ◽  
Clinical Variables ◽  
Selection Of

BackgroundDifferent diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.MethodsStep 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.ResultsThe panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).ConclusionEurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

Mevalonate kinase deficiency in a child with periodic fever and without hyperimmunoglobulinaemia D

2001 ◽  
Vol 24 (3) ◽  
pp. 411-412 ◽  
Author(s):  
M. Di Rocco ◽  
U. Caruso ◽  
H. R. Waterham ◽  
P. Picco ◽  
A. Loy ◽  
...  
Keyword(s):  
Periodic Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase

scholarly journals Diagnostic value of urinary mevalonic acid excretion in patietns with a clinical suspicion of mevalonate kinase deficiency (MKD)

2015 ◽  
Vol 13 (S1) ◽  
Author(s):  
J Jeyaratnam ◽  
N ter Haar ◽  
M de Sain-van der Velden ◽  
H Waterham ◽  
M van Gijn ◽  
...  
Keyword(s):  
Mevalonic Acid ◽  
Diagnostic Value ◽  
Clinical Suspicion ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Acid Excretion

Mevalonate Kinase Deficiency as Cause of Periodic Fever in Two Siblings

2020 ◽  
Vol 57 (2) ◽  
pp. 180-181 ◽  
Author(s):  
Alec Reginald Errol Correa ◽  
Neerja Gupta ◽  
Narendra Bagri ◽  
Pandiarajan Vignesh ◽  
Seema Alam ◽  
...  
Keyword(s):  
Periodic Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase

A Clinical Criterion to Exclude the Hyperimmunoglobulin D Syndrome (Mild Mevalonate Kinase Deficiency) in Patients with Recurrent Fever

2009 ◽  
Vol 36 (8) ◽  
pp. 1677-1681 ◽  
Author(s):  
OLIVIER STEICHEN ◽  
JEROEN van der HILST ◽  
ANNA SIMON ◽  
LAURENCE CUISSET ◽  
GILLES GRATEAU
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Recursive Partitioning ◽  
Clinical Criterion ◽  
Recurrent Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Single Patient ◽  
Kinase Gene ◽  
Mevalonate Kinase Gene

Objective.The hyperimmunoglobulin D syndrome (HIDS) is an autosomal recessive autoinflammatory disease caused by mutations in the mevalonate kinase gene. Our objective was to define a clinical criterion able to exclude HIDS without the need of genetic testing.Methods.A recursive partitioning algorithm was applied to derive the clinical criterion in 149 patients with genetic testing in a French laboratory, among whom 35 had HIDS. The criterion was validated in 93 patients with genetic testing in a Dutch laboratory, among whom 28 had HIDS.Results.The most discriminatory composite clinical criterion satisfied by all patients with HIDS in the derivation group was [onset age < 5 years old OR (joint pain during attacks AND length of attacks < 14 days)]. It had a sensitivity of 100% (95% confidence interval 88% to 100%) and a specificity of 28% (95% CI 17% to 40%) in the validation group. If genetic testing had been limited to patients fulfilling this criterion, 18 tests (19%) would have been avoided in this highly selected validation sample, without missing a single patient with HIDS.Conclusion.Even among patients already selected by expert physicians, this criterion could help prevent unnecessary genetic testing, which is resource- and time-consuming.

scholarly journals Long-Term Follow-Up and Optimization of Interleukin-1 Inhibitors in the Management of Monogenic Autoinflammatory Diseases: Real-Life Data from the JIR Cohort

2021 ◽  
Vol 11 ◽  
Author(s):  
Véronique Hentgen ◽  
Isabelle Koné-Paut ◽  
Alexandre Belot ◽  
Caroline Galeotti ◽  
Gilles Grateau ◽  
...  
Keyword(s):  
Standard Dose ◽  
Real Life ◽  
Underlying Disease ◽  
Recurrent Fever ◽  
Treat To Target ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Treatment Regimens ◽  
On Demand ◽  
Fever Syndromes

Objectives: The major role of interleukin (IL)-1 in the pathogenesis of hereditary recurrent fever syndromes favored the employment of targeted therapies modulating IL-1 signaling. However the best use of IL1 inhibitors in terms of dosage is difficult to define at present.Methods: In order to better understand the use of IL1 inhibitors in a real-life setting, our study assessed the dosage regimens of French patients with one of the four main hereditary recurrent fever syndromes (Familial Mediterranean Fever (FMF), TNF receptor associated periodic syndrome (TRAPS), cryopyrin associated periodic fever (CAPS) and mevalonate kinase deficiency). The patients were retrieved retrospectively from the JIR cohort, an international platform gathering data of patients with pediatric inflammatory diseases.Results: Forty five patients of the JIR cohort with a hereditary recurrent fever syndrome had received at least once an IL1 inhibitor (anakinra or canakinumab). Of these, 43% received a lower dosage than the one suggested in the product recommendations, regardless of the type of the IL1 inhibitor. Especially patients with FMF and TRAPS seemed to need lower treatment regimens; in our cohort none of the FMF or TRAPS patients received an intensified dose of IL-inhibitor. On-demand treatment with a short half-life IL-1 inhibitor has also been used successfully for some patients with one of these two conditions The standard dose was given to 42% of the patients; whereas an intensified dose of IL-1 inhibitors was given to 15% of the patients (44% of CAPS patients and 17% of mevalonate kinase deficiency patients). In our cohort each individual patient’s need for treatment seemed highly variable, ranging from on demand treatment regimens to intensified dosage maintenance therapies depending on the activity and the severity of the underlying disease.Conclusion: IL-1 inhibitors are a good treatment option for patients with a hereditary recurrent fever syndrome, but the individual need of the dosage of IL-1 inhibitors to control the disease effectively seems highly variable. Severity, activity but also the type of the underlying disease, belong to the parameters underpinning the treat-to-target strategy implemented in an everyday life practice.

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