Hyper-IgD syndrome: causes, symptoms, diagnosis, treatment, and prognosis

Hyper-IgD syndrome (HIDS), also known as hyperimmunoglobulinemia D with periodic fever, is a rare autosomal recessive disorder characterized by repeated periodic hyperthermia, obvious abdominal pain, and multiple skin lesions, with significant increase of IgD in serum. The disease occurs mostly in persons aged less than 10 years, mostly less than 1 year, without gender differences.


Causes

The disease is an autosomal recessive disorder caused by mutations of the mevalonate kinase (MVK) gene located at 12q24. MVK is involved in the synthesis of cholesterol and non-sterol isoprene. The concentration of MVK in patients does not decrease, but its activity significantly declines. The decrease of MVK activity leads to the lack of isoprene, which leads to excessive synthesis of interleukin-1β, promoting the rise of body temperature. Elevated body temperature further reduces MVK activity, resulting in a vicious circle. Elevated IgD may be only an epiphenomenon of HIDS rather than a causal cause, and can be seen in a variety of severe inflammatory reactions and hereditary periodic fever syndrome. Infection and immunization may be the inducement of the disease.


Signs and Symptoms

Significantly elevated IgD concentration in serum is a characteristic of this disease. The disease can persist for lifetime, but the symptoms can be alleviated and the number of episodes can be reduced after puberty.

Systemic symptoms

Patients often have long-term periodic fever. Prodromal symptoms include chills (76%), abdominal pain (72%), vomiting (56%), diarrhea (82%), polyarthritis (80%), non-destructive arthritis (68%), and headache (52%). Subsequently, high fever, generally above 39 °C, occurs repeatedly and periodically. The frequency of episodes ranges from once a week to twice a year, with an average interval of about 4 - 8 weeks. The average duration of each episode is 5 - 8 days (1 - 42 days). Lymphadenopathy (94%) and splenomegaly can be found in physical examinations. Few patients have serositis. Patients are fully healthy in the intermittent stages.

Skin lesions

82% of patients have skin lesions. The most common are erythema, followed by red papules. There are wheals, red nodules, and erythema annulare centrifugum in few patients, and purpura or erysipelas and erythema elevatum diutinum in very few patients. Typical rashes are many 0.5 - 2.0cm in size erythema. Large erythema can be annular, with irregular edges, and small isolated papules can also be present. Very few patients have pain and pruritus, but most patients are asymptomatic. Skin lesions are widely distributed, mostly in the trunk, rarely in the extremities, occasionally in the hips, waist, neck, and buttocks. Most of these rashes occur during fever and are absent in the intermittent stages. Not every fever is with rashes, and the rash morphology in every fever may be not the same.

Other manifestations

Cervical lymphadenopathy, multiple joint involvements in symmetrical arthritis, abdominal pain with diarrhea or constipation, vomiting, and hepatosplenomegaly may be present. Pleural involvement and amyloidosis are less common.

Laboratory examinations

There are elevated polyclonal IgD (>60mg/L or >100IU/mL, normal <15mg/L), leukocyte count ((10 - 20) × 109/L), and erythrocyte sedimentation rate. There are circulating IgD immune complexes before, during, and after episodes. There is no correlation between the concentration of IgD in serum and the incidence and extent of rashes. In 82% of patients, IgA can be increased, and sometimes only IgA but not IgD is increased. Bone marrow puncture reveals a large number of plasma cells containing IgD. Very few patients have elevated concentrations of C1q, C3, and C4. C-reactive protein is elevated. Urinary mevalonate is increased at onset. The discharge of neopterin in urine is also increased and is consistent with the activity of the disease.


Histopathology

The main pathological changes are in the dermis and are manifested by vasculitis in the capillaries and postcapillary venules. Vascular endothelial cells swelling, mononuclear cell infiltration and fibrinoid degeneration on the vascular wall, lymphocyte infiltration around the blood vessels, karyorrhexis, and estravasation of erythrocytes can be seen.

In direct immunofluorescence, perivascular IgD and C3 deposition in the upper dermis in most patients can be seen. IgD deposition is not significantly associated with IgD concentration in serum.


Diagnosis

Diagnostic considerations include:

  • Elevated erythrocyte sedimentation rate, elevated white blood cell count, and increased IgA during fever, sudden fever (at least 38.5 °C), repeated attacks
  • Persistent IgD elevation (> 100 IU/ml), 2 examinations required with an interval of at least 1 month
  • Enlargement of cervical lymph nodes
  • Abdominal discomfort (vomiting, diarrhea, abdominal pain)
  • Skin manifestations (erythema, papules)
  • Arthralgia or arthritis or both
  • Splenomegaly

Clinically, a family medical history can assist in the diagnosis. On the basis of elevated IgD in serological examination, elevated urinary mevalonate at onset, and mutated MVK gene, the disease can be diagnosed.


Treatment

There is no specific treatment for this disease, and there is no drug to prevent episodes. Therefore, clinical treatment is mainly symptomatic.

Colchicine, immunoglobulin, cyclosporine, naproxen, and thalidomide can alleviate symptoms. Some patients with joint manifestations are treated effectively with non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids. Dapsone is effective for erythema elevatum diutinum. Simvastatin can relieve inflammation, shorten fever duration, and reduce urinary mevalonate, without adverse reactions. TNF-α antagonist can alleviate symptoms of acute HIDS. Etanercept and anakinra have been reported to be effective. There are reports that allogeneic bone marrow transplantation is effective.


Prognosis

The disease lasts for lifetime, but does not affect life expectancy. The frequency and severity of episodes may decrease while aging, and the disease may not occur for months or even years.