What is Hyperimmunoglobulinemia D Syndrome (HIDS)?

Hyperimmunoglobulinemia D Syndrome (HIDS)

Hyperimmunoglobulinemia D Syndrome (HIDS) is a rare autoinflammatory disorder caused by mutations in the MVK gene encoding mevalonate kinase, characterized by recurrent episodes of fever accompanied by lymphadenopathy, abdominal symptoms, and inflammatory manifestations. 1

Definition and Classification

HIDS belongs to the category of autoinflammatory syndromes, which are relatively rare disorders (representing <1% of all primary immunodeficiencies) 1. It is specifically classified as a periodic fever syndrome that must be distinguished from other similar conditions including:

• Familial Mediterranean Fever (FMF)
• Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
• Cryopyrin-Associated Periodic Syndromes (CAPS) 2

Genetics and Pathophysiology

• Inheritance pattern: Autosomal recessive 3
• Genetic cause: Mutations in the MVK gene encoding mevalonate kinase, an essential enzyme in the isoprenoid pathway 4
• Pathophysiology: Deficiency in mevalonate kinase enzyme activity leads to dysregulation of the inflammatory response 5

Clinical Features

HIDS typically presents with:

• Age of onset: Usually begins in infancy 6
• Fever pattern: Recurrent episodes lasting 3-7 days and recurring every 4-6 weeks 6
• Key clinical manifestations during attacks:
  • Fever (hallmark feature)
  • Cervical lymphadenopathy (often massive) 4
  • Hepatosplenomegaly 4
  • Abdominal pain, vomiting, and diarrhea 7
  • Skin rash 4
  • Arthralgia/arthritis 3
  • Aphthous ulcers 7

Laboratory Findings

During acute attacks:

• Elevated inflammatory markers (ESR, CRP, serum amyloid A)
• Leukocytosis 4
• Elevated serum IgD (classically >100 U/ml), though this may be normal in children under 3 years of age 6
• Elevated proinflammatory cytokines (IL-1, IL-6, TNF-α) 6
• Low mevalonate kinase enzyme activity (confirmatory test) 5

Between attacks:

• Laboratory values typically improve or normalize 4

Diagnosis

The diagnosis of HIDS is based on:

1. Clinical presentation: Recurrent fever episodes with associated symptoms
2. Laboratory findings: Elevated inflammatory markers during attacks
3. Genetic testing: Identification of biallelic pathogenic variants in the MVK gene 5
4. Enzyme activity: Measurement of mevalonate kinase activity in cultured fibroblasts (confirmatory) 5

Treatment Options

There is no established curative treatment for HIDS. Management focuses on controlling symptoms and preventing complications:

1. Acute attack management:

   • NSAIDs and corticosteroids: Often provide limited benefit 4
   • Biological agents:
     • IL-1 inhibitors (anakinra): Shown positive responses, though may require high doses 4, 6
     • TNF-α inhibitors (etanercept): Successful in some pediatric cases 6

2. Long-term management:

   • Prophylactic antibiotics for patients with recurrent infections 1
   • Biological therapies for severe cases with frequent attacks 6

Prognosis

The prognosis for HIDS is generally favorable. The frequency and severity of attacks tend to diminish with age 3. However, the disease course and severity can vary significantly between individuals 7.

Important Considerations

• HIDS must be differentiated from other periodic fever syndromes, which may present with similar symptoms 2
• Serum IgD levels may be normal in young children (under 3 years), making diagnosis challenging in this age group 6
• Novel mutations continue to be discovered, expanding the genetic and ethnic spectrum of HIDS 5
• Treatment response is variable, and therapy often needs to be individualized based on symptom severity and frequency 7

HIDS represents one of the several autoinflammatory syndromes that should be considered in patients presenting with recurrent fever episodes and inflammatory manifestations, particularly when onset is in early childhood.