Hyperimmunoglobulinemia D with periodic fever (ORPHA:343)
A rare autoinflammatory disease, and form of mevalonate kinase deficiency (MKD), characterized by periodic attacks of fever and a systemic inflammatory reaction (cervical lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia and skin manifestations.
Epidemiology
The prevalence is unknown but several hundred patients have been reported worldwide. This is unquestionably an under-representation as many patients remain undiagnosed. A founder mutation (p.V377I) may account for the large number of cases reported from the Netherlands.
Clinical description
The disease usually begins in the first year of life and rarely after 5 years of age, and involves recurrent attacks of fever with abdominal pain, vomiting and diarrhea. Joint involvement (arthralgia/arthritis), swollen lymph nodes, skin lesions (maculopapular rash, vasculitis with purpura or erythema nodosum), early-onset colitis, and headaches may also be observed. Aphthous ulcers may be found and affect the oral mucosa or more rarely the genital and rectal mucosa. Attacks usually last 3 to 7 days and recur every 2 to 8 weeks, but can vary between patients. Frequency of attacks is highest during childhood and usually decreases with age. Severity of attacks also appears to decrease with age. These attacks can occur spontaneously or can be triggered by vaccination, infection and emotional or physical stress. Growth and development is usually not affected, unlike in patients with more severe disease (mevalonic aciduria; MVA). Disease complications are rarely seen in hyperimmunoglobulinemia D with periodic fever (HIDS) patients, but can include AA-amyloidosis, hemophagocytosis, glomerulonephritis, abdominal adhesions, and very rarely joint contractures.
Etiology
HIDS is an inherited syndrome caused by mutations in the mevalonate kinase (MVK) gene (12q24). These MVK mutations lead to reduced, but not abolished enzyme activity. This in turn leads to impaired control of the production of inflammatory mediators, which in turn cause inflammatory (fever) attacks.
Diagnostic methods
Diagnosis is based on clinical manifestations of the disease along with genetic or biochemical evidence of MVK deficiency. Immunoglobulin A (IgA) and IgD levels may be elevated. However, measurement of IgD cannot confirm nor rule out the diagnosis of HIDS. During an attack, erythrocyte sedimentation rate (ESR) is increased, as well as serum C-reactive protein (CRP), IL-1, IL-6 and TNF-alpha levels. The diagnosis can be made when genetic testing reveals two pathogenic MVK mutations or when a decreased mevalonate kinase activity is found in leukocytes or fibroblasts. Measurement of urinary mevalonic acid might be useful to select patients for MVK gene-analysis or enzyme assay.
Differential diagnosis
Unlike HIDS, the severe form of MKD, MVA, results in nearly complete MVK deficiency. Other autoinflammatory disorders like familial Mediterranean fever (FMF), Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) and Muckle-Wells syndrome should be considered. In children, the clinical picture of HIDS can be indistinguishable from PFAPA syndrome.
Antenatal diagnosis
Prenatal diagnosis is theoretically possible, but is not usually done.
Genetic counseling
HIDS follows an autosomal recessive pattern of inheritance. 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 curative treatment for HIDS and currently no established standard therapy. Treatment with NSAIDs might relieve symptoms during attacks. Some patients have responded to high-dose prednisone, especially when given at the beginning of an attack. Interleukin-1 blockade with canakinumab or anakinra (IL-1 receptor antagonist) has also been successful in many cases. Etanercept has also been effective in some patients. Patients should be monitored closely for complications.
Prognosis
The prognosis in HIDS is good. Life expectancy is not shortened except in rare cases where severe infections or renal amyloidosis occur. Spontaneous complete disease remission is possible.

                            Last update: 
                            February 2016


                            - Expert reviewer(s): 
                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM