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Disease Profile

Hyper-IgD syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

E85.0

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hyper IgD syndrome; Hyperimmunoglobulinemia D and periodic fever syndrome; Periodic fever Dutch type;

Categories

Congenital and Genetic Diseases; Immune System Diseases; Metabolic disorders;

Summary

Hyper IgD syndrome is the less severe form of a metabolic disorder known as mevalonate kinase deficiency. It is considered an auto-inflammatory disease, with recurrent episodic or chronic unexplained inflammation, characterized by periodic episodes of fever, and other symptoms such as joint pain, swollen lymph nodes, skin rash, headaches, and abdominal pain. Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from person to person.[1][2] These attacks can occur spontaneously or be triggered by vaccinations, infections, and/or emotional or physical stress. Growth and development is usually not affected. Hyper IgD syndrome is caused by mutations in the MVK gene which provides instructions for making the mevalonate kinase enzyme. The mutations result in the partial deficiency of the enzyme. A more severe form of maevalonate kinase deficiency is known as mevalonic aciduria.[3][4] It is inherited in an autosomal recessive manner.[1][4] Treatment is with anakinra, and other medications, but not all patients show a complete response. In most cases, the frequency of the disease's episodes decreases over time.[2] 

Symptoms

Hyper IgD syndrome is characterized by periodic high fevers that may be associated with other symptoms including:[3][5][2]

Most episodes last several days and occur periodically throughout life.[1] The frequency of episodes and their severity vary greatly from person to person.[1][3] The first attack usually takes place during infancy.[5] Patients may have no symptoms between attacks. However, in some patients, the attacks may be so frequent that the symptoms persist.[3] The attacks can occur spontaneously or be triggered by vaccinations, infections, and/or emotional or physical stress. Growth and development is usually not affected.[5][1] Disease complications sometimes seen in adults include amyloidosis, abdominal adhesions, and very rarely joint contractures.[5]

Some people seem to have an intermediate form that is more severe than hyper IgD syndrome but less severe than classic mevalonate aciduria. These people suffer from a neurological illness with or without periodic fever.[2]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abdominal pain
Pain in stomach
Stomach pain

[ more ]

0002027
Arthralgia
Joint pain
0002829
Elevated erythrocyte sedimentation rate
High ESR
0003565
Gastrointestinal hemorrhage
Gastrointestinal bleeding
0002239
Hepatomegaly
Enlarged liver
0002240
Increased circulating IgA level
0003261
Lymphadenopathy
Swollen lymph nodes
0002716
Myalgia
Muscle ache
Muscle pain

[ more ]

0003326
Recurrent fever
Intermittent fever
Increased body temperature, episodic
Episodic fever

[ more ]

0001954
30%-79% of people have these symptoms
Arthritis
Joint inflammation
0001369
Diarrhea
Watery stool
0002014
Migraine
Intermittent migraine headaches
Migraine headache
Migraine headaches

[ more ]

0002076
Papule
0200034
Recurrent aphthous stomatitis
Recurrent canker sores
0011107
Urticaria
Hives
0001025
Vasculitis
Inflammation of blood vessel
0002633
5%-29% of people have these symptoms
Acrocyanosis
Persistent blue color of hands, feet, or parts of face
0001063
Ataxia
0001251
Erythema
0010783
Global developmental delay
0001263
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Intestinal obstruction
Bowel obstruction
Intestinal blockage

[ more ]

0005214
Limitation of joint mobility
Decreased joint mobility
Decreased mobility of joints
Limited joint mobility
Limited joint motion

[ more ]

0001376
Peritonitis
0002586
Purpura
Red or purple spots on the skin
0000979
Rod-cone dystrophy
0000510
Seizure
0001250
1%-4% of people have these symptoms
Chills
0025143
Chronic diarrhea
0002028
Chronic oral candidiasis
Chronic oral thrush
0009098
Elevated urine mevalonic acid
0032638
Febrile seizure (within the age range of 3 months to 6 years)
Fever induced seizures
0002373
Headache
Headaches
0002315
Hepatosplenomegaly
Enlarged liver and spleen
0001433
Increased circulating IgD level
0410246
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Lymphadenitis
Inflammation of the lymph nodes
0002840
Molluscum contagiosum
0032163
Oral ulcer
Mouth ulcer
0000155
Renal angiomyolipoma
0006772
Serositis
0045073
Skin rash
0000988
Splenomegaly
Increased spleen size
0001744
Vomiting
Throwing up
0002013
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Leukocytosis
Elevated white blood count
High white blood count
Increased blood leukocyte number

[ more ]

0001974
Neutrophilia
Increased blood neutrophil counts
0011897
Nyctalopia
Night blindness
Night-blindness
Poor night vision

[ more ]

0000662
Optic disc pallor
0000543
Vertigo
Dizzy spell
0002321

Cause

Hyper IgD syndrome is caused by mutations in the gene MVK which encodes the enzyme mevalonate kinase. The mutations lead to a partial deficiency of the enzyme mevalonate kinase.[3][5] This enzyme converts a substance called mevalonic acid into mevalonate-5-phosphate. This conversion is the second step in a pathway that makes cholesterol. The cholesterol is later converted into steroid hormones and bile acids. Steroid hormones are needed for normal development and reproduction, and bile acids are used to digest fats. The enzyme also helps to produce other substances that are necessary for certain cellular functions, such as cell growth, cell maturation (differentiation), formation of the cell's structural framework (the cytoskeleton), gene activity (expression), and protein production and modification. A role for this pathway in inflammation is still not completely understood, but it is known that the mevalonate pathway produces cholesterol, and also some compounds which are necessary for the proper interaction and function of these proteins.[6]

Treatment

The mainstay of the treatment of hyper IgD is anakinra, but not all patients show a complete response. Usually five to seven daily injections are sufficient to prevent an early relapse. Anakinra can also be used to prevent vaccine-induced attacks in patients that need immunizations.[6]

In 2015, a group of experts from different countries proposed recommendations for the management of several anti-inflammatory diseases including hyper IgD syndrome. Recommendations include:[7]

  • NSAIDs may provide symptom relief during inflammatory attacks
  • Short-term glucocorticoids, with or without NSAIDs, may be effective for alleviating inflammatory attacks
  • Short-term IL-1 blocking agents (anakinra or canakinumab) may be effective for ending inflammatory attacks and should be considered to limit or prevent steroid side effects or as a maintenance therapy
  • If one IL-1-blocking agent at an adequate dose is ineffective or not well tolerated, a switch to another IL-1-blocking agent or another biological agent (including TNF-α blockers (etanercept (Enbrel), rituximab, o infliximab) or IL-6 blockade (tocilizumab) should be considered.
  • If TNF-α blocker is ineffective or intolerable, a switch to another biological agent (including an IL-1or IL-6-blocking agent) should be considered.

In selected cases with severe disease that does not improve, and poor quality of life, referral to a specialist center for consideration of allogeneic hematopoietic stem cell transplantation is recommended.[7]

Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and infectious disease specialist (to evaluate periodic fever).[3] 

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

  • Canakinumab(Brand name: Ilaris) Manufactured by Novartis Pharmaceuticals Corporation
    FDA-approved indication: Treatment for Familial Mediterranean Fever (FMF) in adult and pediatric patients; for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients; and for Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.
    National Library of Medicine Drug Information Portal

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • DermNet NZ is an online resource about skin diseases developed by the New Zealand Dermatological Society Incorporated. DermNet NZ provides information about this condition.
    • The Doctor's Doctor provides information about hyper IgD syndrome. Click on the link to view this information.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • The Merck Manual for health care professionals provides information on Hyper-IgD syndrome.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Hyper-IgD syndrome. Click on the link to view a sample search on this topic.

        Selected Full-Text Journal Articles

        • The Orphanet Journal of Rare Diseases has published an article with information on this condition. This journal is affiliated with the Orphanet reference portal for information on rare diseases and orphan drugs.

          References

          1. Hyper IgD Syndrome. National Organization for Rare Disorders (NORD). 2017; https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1169/viewAbstract.
          2. Jos W M & van der Meer AS. The challenge of autoinflammatory syndromes with an emphasis on hyper-IgD syndrome. Rheumatology. 2016; 55(2):23-29. https://www.ncbi.nlm.nih.gov/pubmed/27856657.
          3. Shinawi M, Scaglia F. Hereditary Periodic Fever Syndromes. Medscape Reference. 2017; https://emedicine.medscape.com/article/952254-overview.
          4. Hyper-IgD Syndrome. Online Mendelian Inheritance in Man (OMIM). 2013; https://omim.org/entry/260920.
          5. Frenkel J, Simon A. Hyperimmunoglobulinemia D with recurrent fever. Orphanet. 2011; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=343.
          6. Sönmez HE & Özen S. A clinical update on inflammasomopathies. Int Immunol. April 6, 2017; https://www.ncbi.nlm.nih.gov/pubmed/28387826.
          7. Ozen S & Demir S. Monogenic Periodic Fever Syndromes: Treatment Options for the Pediatric Patient. Paediatr Drugs. May 11, 2017; https://www.ncbi.nlm.nih.gov/pubmed/28497352.

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