Hyperimmunoglobulin D Syndrome - Symptoms, and Treatment

Introduction

Hyperimmunoglobulin D syndrome, or mevalonate kinase deficiency, is a rare genetic disorder with recurring febrile phases associated with lymphadenopathy (swollen lymph nodes), abdominal pain, and elevated serum polyclonal immunoglobulin D levels. The syndrome can be classified into two types: classic and variant forms. Both variants exhibit similar clinical symptoms, but the classic form is seen in most cases with a known genetic defect.

What Is Hyperimmunoglobulin D Syndrome?

It is a genetic disorder inherited in an autosomal recessive (two mutated genes received from parents) pattern. The syndrome exhibits recurring episodes of clinical symptoms. In addition, the affected patients have a high amount of protein called immunoglobulin (D and A), which is used to fight infections. Mevalonic aciduria, a severe form of the syndrome, appears at birth. The patients may also show neurological symptoms and slow growth.

What Is Mevalonate Aciduria?

Mevalonate aciduria is a severe form of hyperimmunoglobulin D syndrome. In addition to clinical symptoms of hyperimmunoglobulin D syndrome, aciduria presents with symptoms of

• Growth deficiency before and after birth.

• Failure to gain weight.

• Neurological abnormalities.

• Ocular problems.

• Distinctive facial features of hypertelorism (widely spaced eyes).

• Frontal bossing (enlarged forehead).

• Long eyelashes.

• Triangular-shaped face.

• Microcephaly (reduced head circumference).

• Developmental delays (difficulty in reaching developmental milestones).

• Psychomotor delays (difficulty in muscular and mental coordination).

• Intellectual disability (below average intelligence).

• Ataxia (difficulty in voluntary muscle control causing poor coordination).

• Cataract (clouding of natural eye lens).

• Increased susceptibility to infections.

The symptoms are more frequent and severe in mevalonate aciduria. In rare instances, mevalonate aciduria can progress to life-threatening complications.

What Are the Causes of Hyperimmunoglobulin D Syndrome?

The syndrome is caused by gene mutations that code for mevalonate kinase protein. The shape of the protein is affected by making the mevalonate kinase unstable. The mevalonate kinase facilitates a chemical reaction to produce cholesterol and unsaturated lipid chains (nonsteroidal isoprenoids) in the body. The deficiency of enzymes can also be termed a metabolic disease, resulting in reduced cholesterol and unsaturated lipids in the body.

The association of enzyme deficiency with the occurrence of fever is unknown. However, the genetic defect causes a decrease in the number of molecules that control inflammation.

What Are the Trigger Factors for Hyperimmunoglobulin D Syndrome?

• Infections.

• Emotional or physical stress.

• Trauma.

• Surgery.

• Childhood vaccines.

These factors trigger the immune system, resulting in the occurrence of disease. However, episodes can occur without any trigger.

What Is the Incidence of Hyperimmunoglobulin D Syndrome?

• Most common among individuals in Western Europe (Netherlands and France) but can appear in all ethnic groups.

• All genders are equally affected.

What Are the Symptoms of Hyperimmunoglobulin D Syndrome?

The symptoms with episodes of inflammation start to appear during infancy. The symptoms can vary from mild to severe among affected patients.

• Recurrent episodes of a high fever that last three to seven days. The symptoms reappear every 2 to 12 weeks.

• Fatigue.

• Chills.

• Headache.

• Skin rash appears on all body parts, including hands and feet. They may appear as reddish spots (erythematous macules) or bumps (papules).

• Abdominal pain.

• Loss of appetite.

• Flu-like symptoms.

• Vomiting.

• Diarrhea.

• Joint pain with swelling in small and large joints.

• Enlarged liver (hepatomegaly).

• Enlarged spleen (splenomegaly).

• Muscle pain.

• Mouth sores (canker sores). The genital and rectal mucosa may develop ulcers in a few patients.

• Bleeding in the gastrointestinal tract.

• Lymphadenopathy of the neck and other body parts.

• Few patients present with cough or inflammation in the back of the throat (pharyngitis).

Less Common Symptoms:

• Conjunctivitis (inflammation in the outer membrane of the eyeball and inner eyelid).

• Uveitis (inflammation in the middle layer of the eye).

• Optic neuritis (inflammation of the optic nerve).

• Retinitis pigmentosa (damage to the retina causes severe vision impairment).

• Colitis (inflammation of the colon).

• Disseminated superficial actinic porokeratosis (skin disorder with defective keratinization resulting in dry patches in arms and legs).

The symptoms are of sudden onset. The patients may not show symptoms between episodes, but some may present with fatigue, headache, and mouth ulcers. Joint and skin problems persist for a few days after episodic attacks.

How to Diagnose Hyperimmunoglobulin D Syndrome?

• Identification of clinical symptoms like recurrent fevers not associated with infections.

• Blood test to identify inflammation.

• Test to identify elevated levels of immunoglobulins D and A in blood. The test is not a confirmatory test to detect the syndrome.

• Elevation in the erythrocyte sedimentation rate is seen.

• Elevations of C-reactive protein, IL-1 (interleukin-1), IL-6, and TNF-alpha levels occur.

• Urine test to identify high levels of mevalonic acid.

• Genetic test to detect defective mevalonate kinase gene. Molecular genetic testing is a technique used in defective gene identification.

How to Treat Hyperimmunoglobulin D Syndrome?

Doctors cannot cure genetic conditions completely, but doctors can treat symptoms.

• Steroids or NSAIDs (nonsteroidal anti-inflammatory drugs) like Ibuprofen and Naproxen can help during episodic attacks.

• New biological treatment can cause regression of disease and reduce frequency. For example, interleukin-1 or tumor necrosis factor that blocks inflammatory proteins.

• Interleukin-1 blockers (Anakinra) are used at the start of the episode “on demand.”

• In patients with severe disease, frequent attacks are prevented by Canakinumab (an interleukin-1 blocker) and Etanercept (a tumor necrosis factor blocker).

• Anakinra shots are given under the skin before the onset of episodes.

• Canakinumab shots are taken once a month to reduce disease frequency.

• Genetic counseling is recommended for expectant parents with a family history.

• Hematopoietic stem transplantation is the only curative treatment. However, the high risk of morbidity and mortality has restricted its use in patients with severe complications or mevalonate aciduria.

What Are the Complications of Hyperimmunoglobulin D Syndrome?

• Amyloidosis may develop in rare instances. It is an inflammatory condition where proteins are deposited in major organs. Kidneys show amyloid deposition, followed by intestines, skin, and heart. There is a progressive loss of kidney function.

• Children with high fever may develop seizures.

• Adult patients may develop depression.

• Some patients may develop renal complications like angiomyolipomas (a benign non-cancerous tumor of the kidney).

• Pneumococcal infections.

• Joint contractures (limitations in a full range of motion of joints).

• Abdominal adhesions (bands of scar-like tissue that form in the abdomen).

What Is the Differential Diagnosis of Hyperimmunoglobulin D Syndrome?

• Familial Mediterranean fever - A rare, inherited inflammatory disease with recurrent episodes of fever and inflammation of membranes that line organs (abdomen and lungs).

• TNF (Tumor Necrosis Factor) - Receptor-associated periodic syndrome, a condition that is an autosomal dominant inflammatory disorder characterized by periodic fever episodes, arthralgia, abdominal pain, myalgia, and skin rash.

• Familial cold urticaria and Muckle-Wells syndrome.

• Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) are indistinguishable from hyperimmunoglobulin D syndrome in children. It is a rare condition with repeated episodes of fever, canker sores, reddened throat, and inflammation of glands in the neck.

What Is the Prognosis for Hyperimmunoglobulin D Syndrome?

The syndrome is a lifelong disease with a good prognosis. The symptoms lessen with aging and resolve by adulthood. However, children affected by the syndrome may miss school during episodic fever attacks.

Conclusion

The disease is an inflammatory condition that regresses with age. In rare cases, the disease can cause severe complications among affected individuals. The trigger factor and mechanism of the disease are unknown. Studies are being conducted to establish newer treatment modalities to manage the disease effectively.