Hyperimmunoglobulin D syndrome

Overview

Hyperimmunoglobulin D syndrome (HIDS) is a rare hereditary autoinflammatory disorder characterized by recurrent episodes of fever and systemic inflammation. It is considered a subtype of mevalonate kinase deficiency (MKD), caused by a partial deficiency of the enzyme mevalonate kinase. HIDS typically presents in infancy or early childhood and is marked by periodic fevers accompanied by symptoms such as abdominal pain, joint pain, and skin rashes. Despite its name, not all patients have elevated levels of immunoglobulin D (IgD).

Causes

HIDS is caused by mutations in the MVK gene, which encodes the enzyme mevalonate kinase. This enzyme is involved in the biosynthesis of cholesterol and other isoprenoids. Mutations in MVK result in reduced enzyme activity, leading to an abnormal inflammatory response. HIDS follows an autosomal recessive inheritance pattern, meaning a person must inherit two defective copies of the gene (one from each parent) to develop the condition.

Symptoms

The hallmark of HIDS is periodic febrile episodes that may occur every few weeks and last 3 to 7 days. Common symptoms during attacks include:

• High fever

• Abdominal pain, vomiting, and diarrhea

• Swollen lymph nodes, especially in the neck

• Joint pain and swelling (arthralgia or arthritis)

• Skin rashes (often red and raised)

• Mouth ulcers

• Fatigue and general malaise

Between attacks, individuals may appear completely healthy. The frequency and severity of episodes can vary greatly from person to person.

Diagnosis

Diagnosing HIDS involves a combination of clinical history, laboratory findings, and genetic testing. Diagnostic steps include:

• Elevated serum IgD levels: Often above 100 IU/mL (though not always elevated in all cases)

• Increased inflammatory markers: Such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) during fever episodes

• Elevated urinary mevalonic acid: Especially during febrile episodes

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

It is also important to rule out other periodic fever syndromes such as familial Mediterranean fever (FMF) or tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

Treatment

There is no cure for HIDS, but treatment aims to reduce the frequency and severity of attacks and improve quality of life. Common treatment options include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs): To manage pain and inflammation during episodes

• Corticosteroids: Sometimes used to shorten fever duration, though not recommended for long-term use

• Biologic agents: IL-1 inhibitors (e.g., anakinra, canakinumab) and TNF-alpha inhibitors to control inflammation and prevent flares

• Supportive care: Includes hydration, rest, and monitoring during febrile episodes

Treatment is usually individualized based on symptom severity and patient response.

Prognosis

The long-term outlook for individuals with Hyperimmunoglobulin D syndrome is generally favorable. While the condition is chronic and can significantly impact quality of life, it is not typically life-threatening. Symptoms often decrease in severity or frequency with age, and many individuals experience improvement in adulthood. With proper diagnosis and management, most patients can lead full and active lives. Ongoing medical care and monitoring are important to adjust treatments as needed.