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Hyperimmunoglobulin D syndrome: Pathophysiology

Yoram C Padeh, MD
Arye Rubinstein, MD
Section Editor
Jordan S Orange, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


Hyperimmunoglobulin D syndrome (HIDS) is a rare genetic disorder characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level (MIM #260920). The syndrome can be further categorized into classic and variant forms. The genetic defect is known in the classic form, which makes up 75 percent of cases. The variant form has similar clinical manifestations, although its genetic basis is unknown [1].

This topic reviews the genetics and pathophysiology of HIDS. The clinical manifestations, diagnosis, and management of this disorder are discussed in detail separately. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)


Classic HIDS is caused by mevalonate kinase (MVK) deficiency and is inherited as an autosomal-recessive trait [2-6]. Most patients are compound heterozygous for two different mutations in the MVK gene. However, some patients may be homozygous for the same defect on both alleles. Patients with similar clinical features but lacking mutant MVK genes are referred to as having variant HIDS. (See 'Variant HIDS' below.)

Mevalonate kinase — The MVK gene (MIM *251170) is located on the long arm of chromosome 12 (12q24) [7]. The gene product, MVK, is a cytosolic protein that is localized to the peroxisome [8,9]. It is an enzyme in the cholesterol synthesis pathway. This pathway is responsible for the synthesis of sterol products, such as cholesterol and its derivatives, as well as nonsterol isoprenoids, including prenylated proteins, heme A, dolichol, and ubiquinone-10 [10,11]. MVK is one enzyme downstream of the highly regulated hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase enzyme (figure 1).

Compound heterozygous MVK mutations in HIDS patients usually consist of one allele with a mutation that causes mevalonic aciduria when present in a homozygous state (eg, H20P, I268T, or A334T mutation) [12] (see "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Mevalonic aciduria (MEVA)'). The other allele has a mutation that is not typical for mevalonic aciduria. The V377I mutation is the second most common mutation in patients with HIDS (52 to >90 percent) [7,13-15]. In the remaining HIDS patients without the V377I mutation, the second mutation probably causes a similar enzymatic defect, leading to residual MVK activity [2].

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Literature review current through: Nov 2017. | This topic last updated: Jun 13, 2016.
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