One patient presented with the severe classic MA phenotype due to the homozygous p.Ile-268-Thr MVK genotype, with a poor response to conventional treatments. [ncbi.nlm.nih.gov]

In the present work five common patterns of clinical presentation of the disease that can lead to a late or wrong diagnosis are identified. [moh-it.pure.elsevier.com]

• Splenomegaly

  (Table) Gastrointestinal and joint symptoms were present in 54 and 62% of cases, respectively, 7 patients (54%) had cervical lymphadenopathy and 5 (38%) splenomegaly. [acrabstracts.org]

  French Autosomal recessive heritage Increased acute phase reactants in blood samples Increased IgA and IgD in blood Quickly onset fever of more than 38,5 degrees C Lymphadenopathy (90%) at the neck at fever episodes Abdominal pain as by Acute abdomen Splenomegaly [bindevevssykdommer.no]

  Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). [ncbi.nlm.nih.gov]

  Increased creatine phosphokinase Increased serum CK Increased serum creatine kinase Increased serum creatine phosphokinase [ more ] 0003236 Failure to thrive Faltering weight Weight faltering [ more ] 0001508 Fluctuating hepatomegaly 0006564 Fluctuating splenomegaly [rarediseases.info.nih.gov]

• Cervical Lymphadenopathy

  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly. Attacks can be provoked by vaccinations, stress, and viral infections. [immunodeficiencysearch.com]

  (Table) Gastrointestinal and joint symptoms were present in 54 and 62% of cases, respectively, 7 patients (54%) had cervical lymphadenopathy and 5 (38%) splenomegaly. [acrabstracts.org]

  Lymphadenopathy is present in 90% of cases, most frequently affecting the cervical region. There may be signs of an acute abdomen. [dermatologyadvisor.com]

• Generalized Lymphadenopathy

  Most patients (n = 102) had lymphadenopathy, which was usually, but not exclusively, cervical (n = 96) and tender (n = 59). Generalized lymphadenopathy occurred in a sizeable minority (n = 39). Table 1. [onlinelibrary.wiley.com]

• Fever

  Hyperimmunoglobulinemia D and periodic fever syndrome; Periodic fever, Dutch type (HIDS, OMIM 260920). [ojrd.biomedcentral.com]

  Abstract Dutch type periodic fever (DPF) is an autosomal recessive hereditary fever syndrome. Cases have been reported worldwide, the majority from France and The Netherlands. [ncbi.nlm.nih.gov]

• Pain

  […] lymph nodes: 13 Diarea (sometimes): 20 Diary persistent: 37 Absence of chest pain: 11 TOTAL score / score at least: 42 Sensitivity: 53%, Specificity: 89% Abdominal pain Appendicitis (appendicitis) Pancreatitis Perforated stomach / intestine Fever Other [bindevevssykdommer.no]

  […] joint pain with swelling. [rheumatology.org]

  The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. [ncbi.nlm.nih.gov]

  During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. [medlineplus.gov]

• Amyloidosis

  However, the prevalence of AA amyloidosis is far higher than expected. © 2016, American College of Rheumatology. [ncbi.nlm.nih.gov]

  AA amyloidosis AA amyloidosis was diagnosed in 5 patients. The median delay to the diagnosis of MKD in these 5 patients was 23 years (range 15–41 years). [onlinelibrary.wiley.com]

  HIDS/MKD. [1] Amyloidosis is a condition in which proteins build up in the kidneys leading to kidney damage. [periodicfevers.com]

  We learned that macrophage activation triggered by MKD may mimic primary HLH in neonatal period and that amyloidosis may complicate untreated MKD very early. [acrabstracts.org]

• Developmental Delay

  Weakness, unsteadiness, recurrent fevers, floppy muscles, anemia and developmental delays are important features. The lymph nodes, liver, and spleen are enlarged and there is an increased susceptibility to infections. [wohproject.org]

  Additional ongoing issues include developmental delay, progressive ataxia, progressive problems with vision, an unusually small, elongated head, and failure to thrive. [1] [2] Mevalonic aciduria is caused by deficiency of mevalonate kinase, the first [rarediseases.info.nih.gov]

  Affected children have developmental delay, progressive ataxia, progressive vision problems and growth retardation. [ivami.com]

  Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). [medlineplus.gov]

  The disorder was first described in 1985. [8] Classified as an inborn error of metabolism, mevalonate kinase deficiency usually results in developmental delay, hypotonia, anemia, hepatosplenomegaly, various dysmorphic features, mental retardation, an [en.wikipedia.org]

• Anemia

  Patient N.M. manifested minor anomalies, hepatosplenomegaly, anemia, thrombocytopenia, recurrent febrile crises, and facial rashes. [ncbi.nlm.nih.gov]

  Abstract We experienced a 6-year-old girl diagnosed with mevalonate kinase deficiency (MKD) who had cholestasis, anemia, and elevated inflammatory markers in neonatal period. [jstage.jst.go.jp]

  Weakness, unsteadiness, recurrent fevers, floppy muscles, anemia and developmental delays are important features. The lymph nodes, liver, and spleen are enlarged and there is an increased susceptibility to infections. [wohproject.org]

• Pharyngitis

  A wide variety of diseases had been suspected: systemic juvenile idiopathic arthritis, periodic fever aphtous stomatitis pharyngitis adenitis syndrome, other hereditary recurrent fever, vasculitis, connective tissue disease, inflammatory bowel disease [ncbi.nlm.nih.gov]

  In children, the clinical picture of HIDS can be indistinguishable from periodic fever aphtosis pharyngitis adenitis (PFAPA) syndrome. Antenatal diagnosis Antenatal diagnosis is theoretically possible, but not usually done. [orpha.net]

  Tasher D, Stein M, Dalal I et al (2008) Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr 97:1090–1092 PubMed CrossRef Google Scholar 31. [link.springer.com]

• Cough

  […] symptoms of TB during treatment with ILARIS check you for symptoms of any type of infection before, during, and after treatment with ILARIS Tell your healthcare provider right away if you have any symptoms of an infection such as fever, sweats or chills, cough [ilaris.com]

  Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). [ncbi.nlm.nih.gov]

  Some individuals have a cough and inflammation of the back of the throat (pharyngitis). The specific symptoms present during an episode and their severity vary from person to person. [rarediseases.org]

• Abdominal Pain

  The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. [ncbi.nlm.nih.gov]

  […] lymph nodes: 13 Diarea (sometimes): 20 Diary persistent: 37 Absence of chest pain: 11 TOTAL score / score at least: 42 Sensitivity: 53%, Specificity: 89% Abdominal pain Appendicitis (appendicitis) Pancreatitis Perforated stomach / intestine Fever Other [bindevevssykdommer.no]

• Diarrhea

  Hyperimmunoglobulinemia D is characterized by febrile attacks, often associated with transient digestive manifestations, such as abdominal pain, diarrhea, and vomiting. [ncbi.nlm.nih.gov]

• Failure to Thrive

  MA is an early-onset disorder characterized by a marked failure to thrive, diverse neurologic symptoms, dysmorphic features, and recurrent febrile episodes. [ncbi.nlm.nih.gov]

• Vomiting

  Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. [ncbi.nlm.nih.gov]

  Most patients experience nausea, vomiting or diarrhea. Skin rashes on all parts of the body—Including the hands and feet and painful sores in the mouth – may occur. [rheumatology.org]

  Cardinal manifestations from late infancy include mild to severe psychomotor retardation, recurrent crises (fever, vomiting and diarrhea), failure to thrive, hypotonia and myopathy. [ojrd.biomedcentral.com]

  These are often accompanied by headache, enlarged lymph nodes (glands) in the neck, joint pains, diarrhoea, vomiting and rash. Attacks often occur within hours of immunizations or minor infections, trauma, surgery or stress. [amyloidosis.org.uk]

• Aphthous Stomatitis

  Classification criteria Eurofever / PRINO 2019 (Gattorno M, 2019) Gene test shows MVK genotype and at least one of the following: Gastrointestinal symptoms (Gastrointestinal) Swollen lymph nodes on the neck / neck After in the mouth (Aphthous stomatitis [bindevevssykdommer.no]

  Mucocutaneous involvement Ninety‐nine patients had mucocutaneous symptoms, such as aphthous stomatitis (n = 67) and pharyngitis (n = 31). Fifteen percent of the patients had aphthous stomatitis independent of fever. [onlinelibrary.wiley.com]

  Tasher D, Stein M, Dalal I et al (2008) Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr 97:1090–1092 PubMed CrossRef Google Scholar 31. [link.springer.com]

  In light of these results, thorough clinical examination was performed, but no symptoms compatible with HIDS were found (no abdominal pain, no vomiting, no aphthous stomatitis, no maculopapular rash, no recurrent headache, no myalgia and no lymph node [rmdopen.bmj.com]

• Exudative Pharyngitis

  Mucocutaneous involvement Ninety‐nine patients had mucocutaneous symptoms, such as aphthous stomatitis (n = 67) and pharyngitis (n = 31). Fifteen percent of the patients had aphthous stomatitis independent of fever. [onlinelibrary.wiley.com]

• Visual Impairment

  refractory epilepsy, hearing deficit, and visual impairment; human cis-prenyltransferase complex complements yeast null mutant (375 aa) 0.983 [string-db.org]

  MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. [ojrd.biomedcentral.com]

  Symptoms may include a combination of: Dysmorphic facies with dolichocephaly, frontal prominence and large anterior fontanelle Hypotonia Seizures Dysplastic brain abnormalities, cortical atrophy and/or white matter disease Spasticity Visual impairment [rarediseasesnetwork.org]

• Arthralgia

  The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. [ncbi.nlm.nih.gov]

  Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. [genecards.org]

• Arthritis

  Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. [ncbi.nlm.nih.gov]

  arthritis Orencia abatacept Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis Otezla apremilast Plaque psoriasis Psoriatic arthritis Remicade infliximab Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis [aetna.com]

  Arthritis Rheum 2010;62 Suppl 10:2105. [12] Mulders-Manders, C et al. Semin Immunopathol (2015) 37:371. doi:10.1007/s00281-015-0492-6. [periodicfevers.com]

  A patient who previously suffered from neonatal colitis and recurrent fever with rash, without etiological diagnosis, was diagnosed with HIDS at the age of 28, following a record for recurrent arthritis. [pubag.nal.usda.gov]

  Arthritis & Rheumatology (Hoboken, N.J.) 68 (11): 2795–2805. Touitou I (2016) Infevers: An Online Database for Autoinflammatory Mutations (04 Aug 2016). [els.net]

• Myalgia

  MKD is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. [ncbi.nlm.nih.gov]

  Patients with MKD present with fever, gastrointestinal (GI) symptoms, lymphadenopathy, arthralgia, myalgia, skin rash, and mucosal ulcers. [onlinelibrary.wiley.com]

  The attacks can involve isolated and recurring fever, meningitis, myalgia or orchitis sometimes leading to testicular necrosis. Splenomegaly is only observed exceptionally. [therapeutique-dermatologique.org]

  The most important finding is recurring fever, which may be accompanied by headache, myalgia, arthralgia, abdominal pain, vomiting, diarrhea, cervical lymphadenopathy, aphthous ulcers, and skin rash.( 1 ) It develops as a result of mutations of the gene [archivesofrheumatology.org]

• Skin Lesion

  Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). [ncbi.nlm.nih.gov]

  Joint involvement (arthralgias/arthritis), swollen lymph nodes, skin lesions, and headaches are also observed. Attacks usually last 3-7 days and recur every 2-8 weeks but can vary between patients. [orpha.net]

  Other common features include nausea, vomiting, skin lesions and headaches (Figure 1). Less frequently patients may have hepatosplenomegaly. Emotional and physical stress are reported as precipitating factors for an attack. [dermatologyadvisor.com]

• Urticaria

  […] fever of more than 38,5 degrees C Lymphadenopathy (90%) at the neck at fever episodes Abdominal pain as by Acute abdomen Splenomegaly (large spleen at 50%) Polyartralgi (joint pain) (80%) during fever episodes Eczema: macular with transition to papules, urticaria [bindevevssykdommer.no]

  HIDS patients may (but not always) have a diffuse erythematous maculpapular rash, urticaria, headaches, joint pain, large joint arthritis, enlarged cervical lymph nodes, vomiting and diarrhea during the flares. [nomidalliance.org]

  Chronic urticaria: Standard management and patient education. UpToDate Inc., Waltham, MA. Last reviewed Julyy 2018. Kocaturk E, Zuberbier T. New biologics in the treatment of urticaria. [aetna.com]

  Muckle TJ, Wells M (1962) Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med 31:235–248 PubMed Google Scholar 14. [link.springer.com]

• Maculopapular Skin Rash

  The clinical features are: fever non-migratory maculopapular skin rash headache painful enlarged lymph nodes in the neck abdominal and joint pain. The attacks last for up to one week, longer than those of familial Mediterranean fever. [dermnetnz.org]

• Headache

  Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. [ncbi.nlm.nih.gov]

  These are often accompanied by headache, enlarged lymph nodes (glands) in the neck, joint pains, diarrhoea, vomiting and rash. Attacks often occur within hours of immunizations or minor infections, trauma, surgery or stress. [amyloidosis.org.uk]

  Introduction Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder characterised by recurring episodes of high fever associated with multiple non-specific inflammatory symptoms including headache, arthritis, abdominal [rmdopen.bmj.com]

• Encephalopathy

  "Mevalonic aciduria in 3 siblings: a new recognizable metabolic encephalopathy". Pediatr. Neurol. 9 (3): 243–246. doi : 10.1016/0887-8994(93)90095-T. [en.wikipedia.org]

  PubMed Central View Article PubMed Google Scholar Mancini J, Philip N, Chabrol B, Divry P, Rolland MO, Pinsard N: Mevalonic aciduria in 3 siblings: a new recognizable metabolic encephalopathy. [ojrd.biomedcentral.com]

Two patients with MA started continuous treatment with anakinra (1-2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5-7 days). [ncbi.nlm.nih.gov]

Conclusions: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases. [eurekaselect.com]

[…] spectrum of disease phenotypes, from those with prevailing autoinflammatory syndrome and variable response to anti-inflammatory therapies, to mevalonic aciduria, which is associated with dysmorphic features, severe neurologic involvement, and the worst prognosis [ncbi.nlm.nih.gov]

Prognosis HIDS has a good prognosis. Life expectancy is not shortened except for in rare cases where severe infections or renal amyloidosis occur. The documents contained in this web site are presented for information purposes only. [orpha.net]

Prognosis - Hyper-IgD syndrome atients with hyper IgD syndrome have a good prognosis because amyloidosis has not been reported in any patient with this syndrome. [checkorphan.org]

The overall prognosis for HIDS is quite good with relatively benign clinical course. Amyloidosis can be a serious complication, but it has been reported in only 3% of HIDS patients. [immunodeficiencysearch.com]

A patient who previously suffered from neonatal colitis and recurrent fever with rash, without etiological diagnosis, was diagnosed with HIDS at the age of 28, following a record for recurrent arthritis. [pubag.nal.usda.gov]

Code first - Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology. [icdlist.com]

Etiology HIDS is an autosomal recessively inherited syndrome caused by mutations in the mevalonate kinase ( MVK ) gene. Due to this mutation HIDS patients have MVK enzymes with reduced, but not abolished activity. [orpha.net]

Review 1 Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste 34128, Italy 2 Health Genetic Unit, Institute for Maternal and Child Health "Burlo Garofolo", via dell'Istria 65/1, Trieste 34137, Italy 3 Epidemiology [mdpi.com]

Summary Epidemiology The prevalence is unknown but the estimated incidence is at around 200 patients worldwide. [orpha.net]

Relevant External Links for MVK Genetic Association Database (GAD) MVK Human Genome Epidemiology (HuGE) Navigator MVK Atlas of Genetics and Cytogenetics in Oncology and Haematology: MVK No data available for Genatlas for MVK Gene Molecular cloning of [genecards.org]

But, liver transplantation did not influence febrile attacks in this patient. [6] Epidemiology [ edit ] In the world less than 1 in 1.00.000 have HIDS [5]. 200 individuals throughout the world do suffer from MVK. [5] Additional images [ edit ] See also [en.wikipedia.org]

In search of the pathophysiology of this disorder, another mevalonate kinase product, ubiquinone-10, was studied. [ncbi.nlm.nih.gov]

Summary Both pathophysiological studies and clinical observations in the last 2 years have supported the central role of IL-1 in HIDS. [insights.ovid.com]

Fortunately, this complication is extremely rare in the United states, and may be prevented by appropriate therapy. [rheumatology.org]

FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. [pesquisa.bvsalud.org]