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]

• 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]

• Inflammation

  Keywords: Cholesterol, Statin, Squalene synthase inhibitor, Lapaquistat acetate, Mevalonate kinase deficiency, Hypercholesterolemia, Inflammation. [eurekaselect.com]

  Abstract Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. [ncbi.nlm.nih.gov]

  In this context, we believe it is necessary to clarify statements in the Perspective that imply that a causal effect of the inflammation in patients with mevalonate kinase deficiency may relate to a type 2 helper T cell bias. .. Elizabeth J. [nejm.org]

• 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]

• 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]

• Fatigue

  Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. [ncbi.nlm.nih.gov]

  Seventy‐nine patients had constitutional symptoms, such as malaise (n = 70), fatigue (n = 69), and weight loss (n = 16). In 23% of these patients, malaise was reported independent of fever, while fatigue occurred independent of fever in 35% of them. [onlinelibrary.wiley.com]

  These episodes are accompanied by fatigue, chills, abdominal pain, swelling of affected lymph nodes (lymphadenopathy), a rash, joint inflammation (arthritis) and pain (arthralgia). [rarediseases.org]

  She had three or four polyarthritis attacks/year, each lasting 2–3 weeks, associated with fever (38–39°C), chills, fatigue, headaches, maculopapular rash, diarrhoea, vomiting with severe abdominal pain (macroscopically inflammatory peritonitis without [academic.oup.com]

• 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]

• Acute Abdomen

  abdomen AppendicitisRecurrent infections 4 Laboratory evaluations: - Increased acute phase reactants and leukocytosis during attacks - in severe cases, lowered cholesterol during attacks - increased mevalonic acid in blood and urine during attacks (HyperIgD [slideplayer.com]

  […] 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 [bindevevssykdommer.no]

  There may be signs of an acute abdomen. Arthralgia and arthritis have been seen in up to 83% of patients, mainly restricted to large peripheral joints, although both metacarpophalangeal and proximal interphalangeal may be involved. [dermatologyadvisor.com]

• 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]

• 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]

• 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]

• 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]

• 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]

• Pruritus

  Pruritus is a prominent feature that is not found in most other types of ichthyosis. Rarely, the ichthyosis may first appear in some patients after the first year of life. [rarediseasesnetwork.org]

• Neonatal Onset

  "— Presentation transcript: 1 Mevalonate Kinase Deficiency A metabolic and inflammatory disorder 2 Deficiency of Mevalonate Kinase enzyme = MKD Transmission autosomal recessive Undetectable MK activity = mevalonic aciduaria (MA) - neonatal onset - severe [slideplayer.com]

  Rarely, affected individuals with hyperimmunoglobulinemia D syndrome develop neonatal-onset chronic hepatitis or colitis, erosive polyarthritis or Sjögren syndrome, amyloidosis, renal angiomyolipoma, or neurologic symptoms only. [medlink.com]

  Goldbach-Mansky R, Dailey NJ, Canna SW et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355:581–589 PubMedCentral PubMed CrossRef Google Scholar 15. [link.springer.com]

  They include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystemic inflammatory disease (NOMID). [aetna.com]

  It is close to a highly conserved region with characteristics of an ATP-binding site between amino acids 329 and 344. 7 Transplantation was proposed because of the neonatal onset, the severe clinical course, and the life-threatening, recurrent febrile [nejm.org]

• Ataxia

  The third patient is a 6-year-old boy who presented at the age of 5 years with cerebellar ataxia and retinal dystrophy. [ncbi.nlm.nih.gov]

  Their speech was dysarthric, fine motor skills were impaired as result of cerebellar ataxia, and they had moderate mental retardation. [doi.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]

• Cerebellar Ataxia

  The third patient is a 6-year-old boy who presented at the age of 5 years with cerebellar ataxia and retinal dystrophy. [ncbi.nlm.nih.gov]

  Their speech was dysarthric, fine motor skills were impaired as result of cerebellar ataxia, and they had moderate mental retardation. [doi.org]

• Seizure

  One sibling, from the age of 10 years onwards, suffered from complex partial seizures that were controlled with levetiracetam and lamotrigine. [doi.org]

  Seizure 0001250 Short stature Decreased body height Small stature [ more ] 0004322 Splenomegaly Increased spleen size 0001744 Triangular face Face with broad temples and narrow chin Triangular facial shape [ more ] 0000325 30%-79% of people have these [rarediseases.info.nih.gov]

  Seizures may develop during infancy or later in childhood. [rarediseasesnetwork.org]

• Neurologic Manifestation

  Neurological manifestations of the Mendelian-inherited autoinflammatory syndromes. Dev Med Child Neurol 2009; 51: 420-428. Shendi HM, Walsh D, Edgar JDM. [dermnetnz.org]

  This patient also had a p.V377I mutation and had a mild clinical pattern, with no reported musculoskeletal or neurologic manifestations. [onlinelibrary.wiley.com]

  In the cerebral form of X-ALD, early development is entirely normal, and the first neurologic manifestations most commonly occur at 4-8 years of age. [emedicine.medscape.com]

• Lymphocytic Infiltrate

  The most frequent histopathologic finding is a non-specific perivascular lymphocytic infiltrate with some neutrophils. But vasculitis, Sweet’s-like changes, spongiosis and epidermotropism have all been reported. [dermatologyadvisor.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]