Hyperimmunoglobulinemia D With Periodic Fever

A rare autoinflammatory disease characterized by periodic attacks of fever and a systemic inflammatory reaction (cervical lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgias and skin signs).

Epidemiology

The prevalence is unknown but the estimated incidence is at around 200 patients worldwide.

Clinical description

The disease usually begins in the first year of life and consists of recurrent attacks of fever along with abdominal pain, vomiting and diarrhea. Joint involvement (arthralgias/arthritis), swollen lymph nodes, skin lesions, and headaches are also observed. Attacks usually last 3-7 days and recur every 2-8 weeks but can vary between patients. Frequency of attacks is highest during childhood and usually decreases with age. These attacks can occur spontaneously or be triggered by vaccinations, infections, emotional or physical stress. Growth and development is usually not affected in HIDS patients. Disease complications sometimes seen in adults include amyloidosis, abdominal adhesions and very rarely joint contractures.

Etiology

HIDS is an autosomal recessively inherited syndrome caused by mutations in the mevalonate kinase (MVK) gene. Due to this mutation HIDS patients have MVK enzymes with reduced, but not abolished activity.

Diagnostic methods

Diagnosis is based on clinical characteristics of the disease along with genetic or biochemical proof of a MVK deficiency. Serum IgD values are often elevated (although IgD levels are often normal in patients under the age of 3). Elevated IgA levels are also noted in 80% of patients. During an attack, erythrocyte sedimentation rate is increased as well as serum C-reactive protein (CRP), IL-1, IL-6 and TNF-alpha levels. Genetic testing will reveal a mutation in the MVK gene in all patients with HIDS.

Differential diagnosis

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.

Antenatal diagnosis

Antenatal diagnosis is theoretically possible, but not usually done.

Genetic counseling

When a couple has an affected child, there is a 25% recurrence risk in a next child. Genetic counselling is therefore recommended.

Management and treatment

There is no cure for HIDS and currently no established treatment. Some patients have responded to high-dose prednisone. Anakinra (an IL-1 receptor antagonist) has also been successful in some cases as has the TNF-alpha inhibitor etanercept.

Prognosis

HIDS has a good prognosis. Life expectancy is not shortened except for in rare cases where severe infections or renal amyloidosis occur.