Hyper-IgD syndrome

Información en español Title

Other Names:

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

Categories:

Congenital and Genetic Diseases; Immune System Diseases; Metabolic disorders; Congenital and Genetic Diseases; Immune System Diseases; Metabolic disorders; Musculoskeletal Diseases; Skin Diseases See More

Summary 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]

Last updated: 6/26/2017

Symptoms Symptoms

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

Cold chills
Swollen lymph nodes (lymphadenopathy)
Abdominal pain
Diarrhea
Headache
Joints pain
Increased size of the liver (hepatomegaly) and/or increased size of the spleen (splenomegaly)
Skin lesions
Canker sores (aphthous ulcers)

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]

Last updated: 6/26/2017

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.

Showing of 50 |

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

Showing of 50 |

Do you have more information about symptoms of this disease? We want to hear from you.

Last updated: 2/1/2021

Do you have updated information on this disease? We want to hear from you.

Cause 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]

Last updated: 6/26/2017

Inheritance Inheritance

Hyper IgD syndrome is inherited in an autosomal recessive manner, which means both copies of the gene in each cell have mutations. The parents of a person with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.^[1]^[5]

Last updated: 6/27/2017

Treatment 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-1- or 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]

Last updated: 6/26/2017

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

Prognosis Prognosis

Life expectancy is not shortened except for in rare cases where severe infections or kidney amyloidosis occur. Between fever attacks, patients are generally free of symptoms. Attacks do continue throughout the lifetime, although there may be a slight decrease following adolescence.^[3] A long-term follow-up study showed that the frequency of the attacks decreases over time, but about half of the patients more than 20 years of age still experience six or more attacks per year, with quite an impact on quality of life.^[6]

Last updated: 6/26/2017

Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Related Diseases Related Diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Mevalonic aciduria (MVA; see this term) is also caused by a mutation in the MVK gene, but it results in a nearly complete MVK deficiency. Other autoinflammatory disorders like familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS) and Muckle-Wells syndrome (see these terms) should be eliminated. In children, the clinical picture of HIDS can be indistinguishable from periodic fever aphtosis pharyngitis adenitis (PFAPA) syndrome. Visit the Orphanet disease page for more information.

Conditions with similar signs and symptoms from Orphanet

Mevalonic aciduria (MVA; see this term) is also caused by a mutation in the MVK gene, but it results in a nearly complete MVK deficiency. Other autoinflammatory disorders like familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS) and Muckle-Wells syndrome (see these terms) should be eliminated. In children, the clinical picture of HIDS can be indistinguishable from periodic fever aphtosis pharyngitis adenitis (PFAPA) syndrome.

Visit the Orphanet disease page for more information.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

ClinicalTrials.gov lists trials that are related to Hyper-IgD syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Patient Registry

The Sterol and Isoprenoid Diseases Consortium (STAIR) is a team of doctors, nurses, research coordinators, and research labs throughout the U.S., working together to improve the lives of people with this condition through research. The Steroid and Isoprenoid Research Consortium (STAIR) has a registry for patients who wish to be contacted about clinical research opportunities.

For more information on the registry see: https://www.rarediseasesnetwork.org/cms/stair/Get-Involved/ContactRegistry

Organizations 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

FMF & AID Global Association
Schüracherstrasse 25a
8306 Brüttisellen
Switzerland
Telephone: +41 76 415 4010
E-mail: info@fmfandaid.org
Website: https://www.fmfandaid.org/
Rare Autoinflammatory Conditions Community - UK (RACC-UK)
United Kingdom
Telephone: 07377091552
E-mail: info@raccuk.com
Website: https://www.raccuk.com/

Do you know of an organization? We want to hear from you.

Learn More 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.

GARD Answers GARD Answers

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

Are there certain foods that can trigger a flare up of hyper IgD syndrome? See answer
Can you please provide me with general information about hyper IgD syndrome? See answer

Have a question? Contact a GARD Information Specialist.

References References

Hyper IgD Syndrome. National Organization for Rare Disorders (NORD). 2017; http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1169/viewAbstract.
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.
Shinawi M, Scaglia F. Hereditary Periodic Fever Syndromes. Medscape Reference. 2017; http://emedicine.medscape.com/article/952254-overview.
Hyper-IgD Syndrome. Online Mendelian Inheritance in Man (OMIM). 2013; http://omim.org/entry/260920.
Frenkel J, Simon A. Hyperimmunoglobulinemia D with recurrent fever. Orphanet. 2011; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=343.
Sönmez HE & Özen S. A clinical update on inflammasomopathies. Int Immunol. April 6, 2017; https://www.ncbi.nlm.nih.gov/pubmed/28387826.
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.