What is Hyper-IgD Syndrome / Hyperimmunoglobulinemia D With Recurrent Fever (HIDS)

Hyper-IgD Syndrome (HIDS), also known as mevalonate kinase deficiency (MKD), is a rare autoinflammatory disorder characterized by lifelong recurrent episodes of fever and systemic inflammation. It is caused by genetic mutations that impair the mevalonate kinase enzyme, leading to an overactive immune response rather than an immune deficiency.

What causes Hyper-IgD Syndrome?

Hyper-IgD Syndrome is an autosomal recessive genetic disorder caused by mutations in the MVK gene. This gene provides instructions for producing the enzyme mevalonate kinase. When this enzyme is deficient, the body cannot properly process mevalonic acid, leading to a buildup of toxic intermediates and a lack of downstream products like cholesterol and isoprenoids. This biochemical imbalance triggers the innate immune system to release inflammatory proteins, specifically interleukin-1 beta, resulting in the characteristic fever episodes seen in Hyper-IgD Syndrome.

What are the symptoms and body systems affected?

While fever is the hallmark, Hyper-IgD Syndrome impacts multiple organ systems during flare-ups. Symptoms typically begin in early infancy, often within the first year of life. Common clinical features include:

• Recurrent fevers lasting 3 to 7 days, often triggered by stress, vaccination, or minor trauma.


• Painful lymphadenopathy (swollen lymph nodes) in the neck.


• Abdominal pain, vomiting, and diarrhea.


• Skin rashes, which can appear as maculopapular, urticarial, or nodular lesions.


• Arthralgia (joint pain) or arthritis affecting large joints.

How common is Hyper-IgD Syndrome?

Hyper-IgD Syndrome is exceptionally rare, with a prevalence estimated at less than 1 in 1,000,000 in the general population, though it is more frequently diagnosed in individuals of Western European descent, particularly those with Dutch ancestry. Because of its rarity, it is often misdiagnosed as recurrent infections or other periodic fever syndromes. Currently, our DiseaseMaps.org community includes 6 members who have been diagnosed with Hyper-IgD Syndrome and are sharing their personal experiences.

How is it differentiated from other conditions?

Unlike many other periodic fever syndromes, Hyper-IgD Syndrome is distinguished by the persistent elevation of immunoglobulin D (IgD) in the blood during and between episodes. However, because IgD levels can be normal in some patients, the definitive diagnosis of Hyper-IgD Syndrome relies on molecular genetic testing of the MVK gene and measuring mevalonic acid levels in the urine during a fever flare.

Next steps

• Consult with a specialist in pediatric rheumatology or immunology for genetic testing.


• Maintain a detailed symptom diary to track fever triggers and duration.


• Join the DiseaseMaps.org community to connect with other families navigating Hyper-IgD Syndrome.


• Ask your doctor about specialized anti-inflammatory treatments, such as IL-1 inhibitors.

Medical disclaimer: This content is for educational purposes only and does not constitute professional medical advice, diagnosis, or treatment.

References

• NIH Genetic and Rare Diseases Information Center (GARD): Mevalonate Kinase Deficiency.


• Orphanet: Hyperimmunoglobulinemia D with periodic fever syndrome.


• OMIM (Online Mendelian Inheritance in Man): Mevalonate Kinase Deficiency; MKD.


• Auto-Inflammatory Alliance: Information on HIDS/MKD.