Hyper-IgD syndrome

Overview

Hyper-IgD syndrome (HIDS) is a rare autoinflammatory disorder classified under periodic fever syndromes. It is characterized by recurrent episodes of fever, abdominal pain, joint pain, and elevated levels of immunoglobulin D (IgD) in the blood. HIDS typically begins in infancy or early childhood and is part of a group of conditions known as mevalonate kinase deficiency (MKD), with varying severity. Although the condition can cause significant discomfort, it is not typically life-threatening.

Causes

Hyper-IgD syndrome is caused by mutations in the MVK gene, which provides instructions for making the enzyme mevalonate kinase. This enzyme is involved in cholesterol and isoprenoid biosynthesis. When defective, it leads to an inflammatory response that triggers periodic fever episodes. HIDS is inherited in an autosomal recessive pattern, meaning an individual must inherit two mutated copies of the gene—one from each parent—to be affected.

Symptoms

The hallmark of HIDS is periodic febrile episodes, often accompanied by systemic symptoms. These episodes can last several days and recur every few weeks. Common symptoms include:

• Recurrent high fevers, often lasting 3 to 7 days

• Abdominal pain, nausea, vomiting, and diarrhea

• Swollen and painful lymph nodes, especially in the neck

• Joint pain and swelling (arthralgia or arthritis)

• Skin rashes

• Mouth ulcers

• Headaches and fatigue

While IgD levels are elevated in many cases, some patients may have normal IgD levels and still exhibit typical symptoms, particularly in early infancy.

Diagnosis

Diagnosis of Hyper-IgD syndrome is based on clinical presentation, laboratory findings, and genetic testing. Diagnostic steps may include:

• Blood tests: Elevated serum IgD (typically >100 IU/mL), increased inflammatory markers such as CRP and ESR during attacks

• Urine tests: May show increased mevalonic acid levels, especially during febrile episodes

• Genetic testing: Identification of biallelic mutations in the MVK gene confirms the diagnosis

• Exclusion of other periodic fever syndromes: Such as familial Mediterranean fever (FMF) or TRAPS

Diagnosis can be challenging due to the variability of symptoms and overlap with other conditions.

Treatment

There is no definitive cure for Hyper-IgD syndrome, but various treatments can reduce the frequency and severity of symptoms. Common treatment strategies include:

• Non-steroidal anti-inflammatory drugs (NSAIDs): For pain and inflammation during febrile episodes

• Corticosteroids: Sometimes used to shorten the duration of attacks

• Biologic therapies: Such as IL-1 inhibitors (anakinra, canakinumab) or TNF-alpha inhibitors to prevent or reduce attacks

• Statins: In some cases, to reduce mevalonate pathway intermediates (with limited efficacy)

Treatment is personalized based on symptom severity and patient response.

Prognosis

The long-term outlook for individuals with Hyper-IgD syndrome is generally good. While the condition can cause recurrent and disruptive symptoms, it does not typically shorten life expectancy. With proper management, many patients can lead normal or near-normal lives. Inflammation may decrease with age, and some individuals experience a reduction in symptoms during adulthood. Early diagnosis and targeted therapy can significantly improve quality of life and reduce disease burden.