Definition and genetics
Hyper-IgD syndrome (HIDS) is the milder end of mevalonate kinase deficiency (MKD), a monogenic autoinflammatory disease caused by biallelic mutations in MVK (chromosome 12q24), the gene encoding mevalonate kinase. Inheritance is autosomal recessive. Reduced enzyme activity blocks the isoprenoid (cholesterol/non-sterol) biosynthesis pathway downstream of mevalonate, impairing protein prenylation of small GTPases and producing exaggerated IL-1β-driven inflammation. The disease spectrum runs from HIDS (substantial residual enzyme activity) to mevalonic aciduria (near-absent activity, with developmental and neurological involvement) at the severe end. The common V377I variant is strongly associated with the HIDS phenotype; many patients are compound heterozygotes. HIDS is most frequently reported in patients of Dutch and Western European ancestry.
Episode pattern
Onset is characteristically in infancy — usually within the first year of life. Attacks last 3–7 days and recur every 4–6 weeks, more regularly than TRAPS. A hallmark trigger is childhood vaccination; intercurrent infection, stress, trauma, and surgery also provoke attacks. The combination of very early onset and immunisation-triggered febrile episodes is an important diagnostic clue, and attack frequency tends to be highest in early childhood and to attenuate with age in many patients.
Clinical features
Abrupt high fever (often ≥38.5°C, sometimes with chills) is accompanied by tender cervical lymphadenopathy (a prominent and useful feature), prominent abdominal symptoms (pain, vomiting, diarrhoea), an erythematous maculopapular rash, aphthous oral and/or genital ulcers, arthralgia and large-joint arthritis, splenomegaly, and headache. Laboratory features during attacks include leukocytosis, raised ESR/CRP, and — diagnostically — elevated urinary mevalonic acid. Polyclonal IgD elevation (and often IgA ≥2.6 g/L) is the historical namesake but is neither sensitive nor specific (normal IgD does not exclude MKD, particularly in young infants), so it has been displaced by genetic and metabolic testing.
Diagnosis
Diagnosis is confirmed by MVK sequencing and/or demonstration of reduced mevalonate kinase activity, supported by elevated urinary mevalonic acid during attacks. Serum IgD is supportive at best. The 2019 Eurofever/PRINTO classification criteria combine genetic and clinical variables to distinguish MKD/HIDS from FMF, TRAPS, and CAPS.
See the full criteria: Hyper-IgD Syndrome
Red flags
- AA (secondary) amyloidosis — a recognised complication, though less frequent than in FMF or TRAPS; monitor inter-attack acute-phase reactants and screen for proteinuria.
- Severe-end phenotype (mevalonic aciduria) — failure to thrive, developmental delay, ataxia, cataracts, dysmorphism: warrants metabolic and neurological evaluation.
- Vaccination-triggered febrile attacks from infancy — points toward MKD over FMF/CAPS.
Management overview
Mild, infrequent attacks may be managed symptomatically (NSAIDs); short on-demand corticosteroid courses can attenuate individual attacks. Colchicine is generally ineffective. For frequent or disabling disease, modern management is IL-1-centric — IL-1 blockade (e.g. canakinumab, anakinra) is first-line, with IL-6 or TNF blockade reserved for refractory cases. Continue immunisations per programme with anticipatory guidance, as vaccine-provoked attacks are expected and self-limited. (Therapeutic classes only — confirm agent, dose, and monitoring against current formularies.)
References
- Gattorno M, et al. Ann Rheum Dis. 2019;78:1025–1032 (Eurofever/PRINTO).
- ter Haar NM, et al. Ann Rheum Dis. 2015;74:1636–1644 (SHARE).
- van der Hilst JCH, et al. Medicine (Baltimore). 2008;87:301–310.
- Nelson Textbook of Pediatrics, 21st ed.
Decision support for qualified clinicians only — verify against current primary guidelines and your clinical judgement.