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Hyperimmunoglobulinemia D syndrome
Other Resources UpToDate PubMed

Hyperimmunoglobulinemia D syndrome

Contributors: Christine S. Ahn MD, FAAD, William W. Huang MD, MPH, FAAD, Susan Burgin MD
Other Resources UpToDate PubMed


Hyperimmunoglobulin D with periodic fever syndrome (HIDS), also known as mevalonate kinase deficiency (MKD), is a monogenic autoinflammatory syndrome characterized by recurrent fevers and systemic symptoms. HIDS is inherited in an autosomal recessive manner and is seen equally in both males and females. It is caused by a mutation in the MVK gene, which encodes for the enzyme mevalonate kinase, a key enzyme in the cholesterol biosynthesis pathway. The majority of patients have compound heterozygous mutations. Although the exact etiology of the inflammation is not fully understood, there are elevated levels of interleukin-1 beta (IL-1β) in association with inflammation.

HIDS typically presents in infancy with a median age of onset of 6 months. The primary manifestation of HIDS is recurrent febrile attacks occurring at varied intervals with duration of 3-7 days. Frequent triggers of febrile attacks include vaccinations, illness, and emotional stress. The attacks may begin with a prodrome of headache and malaise followed by the onset of a high fever, often 40°C (104°F) or higher. Patients may also experience tender cervical lymphadenopathy, abdominal pain, diarrhea, vomiting, arthralgias or nonerosive arthritis, splenomegaly, oral or genital ulcers, and pharyngitis. Cutaneous manifestations are observed in about 70% of patients with HIDS; however, skin findings do not necessarily occur with every febrile attack. The skin findings include erythema nodosum, vasculitis, urticarial lesions, and a morbilliform eruption.

Although a few cases of associated amyloidosis have been reported, amyloidosis is not typically seen with HIDS.

Note: It is rare for symptoms to first manifest in those older than 5 years of age, so other periodic fever syndromes should be considered first in such cases.


D82.8 – Immunodeficiency associated with other specified major defects

403834003 – Hyper-immunoglobulin D periodic fever syndrome

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Differential Diagnosis & Pitfalls

  • Familial Mediterranean fever – Erysipelas-like skin findings.
  • Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) – Longer duration of febrile attacks, autosomal dominant inheritance.
  • Cryopyrin-associated periodic syndromes (CAPS) such as Muckle-Wells syndrome – Associated with deafness; attacks may be induced by cold.
  • Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome – Diagnosis of exclusion; rarely has skin manifestations.
  • Juvenile idiopathic arthritis
  • Malignancy including lymphoma
It is rare for symptoms to first manifest in those older than 5 years, so other periodic fever syndromes should be considered first in such cases.

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Last Reviewed:04/19/2018
Last Updated:01/17/2022
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Hyperimmunoglobulinemia D syndrome
Hyperimmunoglobulinemia D syndrome : Abdominal pain, Cervical lymphadenopathy, Headache, Rash, Recurring fever episodes, Lower legs
Clinical image of Hyperimmunoglobulinemia D syndrome
Erythematous and brownish nodules and plaques on the leg that were tender to palpation.
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