Hyper IgD syndrome R77.1

HIDS and mevalonic aciduria (MA) belong to the spectrum of mevalonate kinase (MVK) deficiency (MKD). Both diseases are inherited in an autosomal recessive manner and are caused by mutations in the MVK gene, which codes for mevalonate kinase, an enzyme involved in the synthesis of non-steroidal isoprenoids and also in the caspase activation pathway. The amount of remaining enzyme activity correlates inversely with the severity of the phenotype. V377I and I268T are the most common pathogenic mutations. Most HIDS patients are heterozygous for two different variants. The presence of homozygous I268T mutations is associated with MA, the most severe phenotype.

Febrile symptoms typically occur in the first year of life.

Massive onset of fever attacks without real periodicity. The attacks last about 5-7 days. Attacks are usually associated with cervical lymphadenopathy, abdominal and joint pain and maculo-papular exanthema.

MA begins with repeated episodes of fever accompanied by severe ocular and neurological impairment, musculoskeletal abnormalities associated with growth retardation and dysmorphic features, hepatosplenomegaly, lymphadenopathy and skin lesions; other typical features include cervical or generalized lymphadenopathy, marked oral aphthae, arthralgia or non-erosive arthritis of the large joints, abdominal pain and hepatosplenomegaly.

Systemic and cutaneous symptoms are occasionally triggered by infections, vaccines or trauma.

Dermatologic symptoms: The skin is affected in about 70% of MKD patients. The cutaneous lesions are heterogeneous and typically consist of non-specific maculopapular or morbilliform rashes. Small erythematous patches, papules or erysipelas-like plaques are also common (Braun-Falco M et al. 2011). Erythema nodosum and urticarial lesions have also been described, as well as petechiae or purpura reminiscent of IgA vasculitis, erythema elevatum diutinum and Sweet syndrome. Bipolar aphthae occur in almost 50 % of patients (van der Hilst JCH et al. 2008).

Acute phase reactants, IgD and IgA levels are usually elevated during relapses. An increase in urinary mevalonic acid levels during relapses is considered a specific marker for MKD. Secondary amyloidosis was found in about 3% of patients.

Lesions are histologically variable. Endothelial swelling and perivascular inflammatory infiltrates are the most important changes. In addition, signs of leukocytoclastic or necrotizing vasculitis, Sweet-like neutrophilic lesions, erythema elevatum diutinum or erythema nodosum may also be observed.

Perivascular and linear deposits of IgD and C3 along the basement membrane have been described.

A persistent increase in serum IgD (> 100 IU/ml) measured at least twice at intervals of at least one month is diagnostic. Determination of mevalonate kinase in the blood (very specific diagnostic screening method). In case of reduced enzyme activity, molecular genetic diagnostics should be followed up.

High-dose glucocorticoids are helpful in controlling seizures in some patients, but most of them need biologic therapy to avoid adverse effects of glucocorticoids. Among the biologics, etanercept can improve symptoms in more than 50% of patients. However, IL-1 blockers are effective in the majority of cases. Anakinra has been shown to be useful when administered continuously or on demand, and canakinumab was recently approved by the FDA and EMA for the treatment of HIDS. Tocilizumab has been shown to be effective in some cases that have failed to respond to previous treatments.

1. Arkwright PD et al. (2003) Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept. Clin Exp Immunol 130: 484-488
2. Braun-Falco M et al (2011) Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges J Ger Soc Dermatol 9:232-246.

3. Drenth JP et al. (1994) Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. International Hyper IgD Study Group. Arch Dermatol 130:59-65.

4. Houten SM et al. (2003) Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet 11: 196-200

5. Houten SM et al. (2002) Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome. Hum Mol Genet 11: 3115-3124

6. van der Hilst JCH et al. (2008) Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine 87:301-310.

7. van der Meer JWM et al. (1984) Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet 1: 1087-1090