X-linked hyper-IgM syndrome

What is X-linked hyper-IgM syndrome?

X-linked hyper-IgM syndrome (OMIM 308230) is a genetic immunodeficiency syndrome that presents with bacterial and opportunistic infections from an early age. It is the most common form of hyper-IgM syndrome, accounting for approximately 70% of cases. An old name for this condition was dysgammaglobulinaemia type I with neutropenia.

Who gets X-linked hyper-IgM syndrome and why?

X-linked hyper-IgM syndrome is a rare condition, with an estimated incidence of approximately 1 case per million population.

X-linked hyper-IgM syndrome only affects males, as the defective gene is located on the X chromosome. It is inherited from the mother who is an asymptomatic carrier. Diagnosis is usually made before the age of 12 months when the male infant presents with unusual or severe infections. There may be a family history of unexplained deaths in male infants.

The genetic defect involves the gene on chromosome Xq26 coding for CD40 ligand. This molecule is expressed on activated CD4+T lymphocytes and is involved in switching B cells from making IgM antibodies to IgG and other forms of antibody. So although the problem presents as an inability of B cells to make an appropriate antibody response to infections, the defect is on T cells.

Clinical features

This condition typically presents as unusual, opportunistic or severe infections of upper and lower respiratory or gastrointestinal tracts and is often associated with failure to thrive and enlarged lymph nodes.

• Pneumonia affects over 80% of patients; Pneumocystis jiroveci pneumonia is the presenting problem in 40% (previously known as Pneumocystis carinii)
• Ear infections (otitis)
• Sinus infections (sinusitis)
• Central nervous system infections (bacterial, viral and fungal infections)
• Invasive fungal infections include candida, histoplasmosis, cryptococcosis
• Chronic diarrhoea due to cyptosporidiosis may lead to sclerosing cholangitis and liver cirrhosis

The dermatological signs include frequent and recurrent bacterial and fungal skin infections and oral ulcers.

Systemic infection with skin manifestations include cryptococcosis and histoplasmosis. Primary skin infection may be bacterial including cellulitis or viral including treatment-resistant warts, cold sores (herpes simplex)

Oral ulcers are usually not due to infections although these should be excluded. Characteristics of the ulcers include:

• recurrent, large (up to 2cm)
• may be multiple
• painful lesions may require pain relief
• typically affect the tongue and inside of the cheeks
• usually heal without scarring
• begin in early childhood – commonly in the first year
• slow to heal – 3 weeks to 3 months
• may interfere with feeding/eating and oral hygiene
• sometimes relate to episodes of neutropenia

Other features of this condition include:

• Gingivitis – streptococcal
• Stomatitis (inflamed oral mucosa)
• Thrombocytopenic purpura (bleeding due to low platelet count)
• Neutropenia which can be intermittent or persistent
• Autoimmune conditions including Coombs positive anaemia, thrombocytopenia, inflammatory bowel disease, hepatitis
• Cancer – of the biliary tree and bowel

How is X-linked hyper-IgM syndrome diagnosed?

Early diagnosis is important as untreated X-linked hyper-IgM syndrome is fatal.

The initial investigations for a patient suspected of having an immunodeficiency syndrome include immunoglobulin (antibody) levels in the blood.

In X-linked hyper-IgM syndrome:

• IgG – very low or undetectable
• IgE – very low or undetectable
• IgA – usually very low, but can be normal or high
• IgM – usually high, although normal or low levels have also been reported.
• Such a blood test result would suggest the diagnosis of a hyper-IgM syndrome.

Specific investigations for X-linked hyper-IgM syndrome are:

• Flow cytometry of activated T lymphocytes will fail to detect CD40 ligand
• DNA sequencing of the specific gene on the X chromosome should be performed to identify the mutation and confirm the diagnosis. Many different mutations have been identified in this gene.

These tests will distinguish X-linked hyper-IgM syndrome from the rarer autosomal recessive CD40-deficient syndrome, which is clinically identical. In addition, ataxia-telangiectasia can present as a hyper-IgM syndrome in infancy with the neurological symptoms and telangiectasia developing later in childhood. Congenital rubella, cancer and anti-eplileptic medications may also cause a hyper-IgM pattern of immunodeficiency.

Carrier state diagnosis should be performed on both parents, expecting the mother to have one copy of the same gene mutation (and one normal gene), and the father to have one normal gene. Prenatal diagnosis is available.

Treatment of X-linked hyper-IgM syndrome

Monthly intravenous gamma globulin should be started as soon as the diagnosis is made as this results in normal IgM levels and limits the number of severe and serious infections. However it may not prevent the opportunistic infections. In some cases it also improves growth.

Trimethoprim + sulphamethoxazole may be given prophylactically to prevent Pneumocystis jirovecii infection.

Granulocyte colony-stimulating factor (GCSF) treats the neutropenia.

Live vaccines should be avoided.

Bone marrow or umbilical cord stem cell transplant has been curative in some patients.

It has been suggested that affected boys should initially receive intravenous gamma globulin and trimethoprim + sulphamethoxazole with careful monitoring for complications of the disease. Bone marrow transplantation should be considered and performed if possible when complications develop.