Hyper-IgM syndrome (HIGM) is a primary immunodeficiency disease characterised clinically by susceptibility to infections, decreased serum immunoglobulin (Ig) G and IgA with normal or raised IgM levels, and defective class switch recombination and somatic hypermutation. Several genetic defects can account for this congenital disorder.1 However, other primary immunodeficiency diseases can present with serum Ig levels suggestive of HIGM, ie decreased serum IgG with normal or raised IgM levels. Probably the best known of these diseases is common variable immunodeficiency; patients display a marked reduction in serum IgG and IgA levels, while in approximately half of the patients IgM is also reduced.2

Ataxia–telangiectasia (A–T) is a complex multisystem disorder clinically characterised by progressive neurological abnormalities (such as cerebellar ataxia and dysarthric speech), both cellular and humoral immunodeficiency, and oculocutaneous telangiectasias. Patients with A–T show raised serum α-fetoprotein (AFP) levels, rearrangement of chromosomes 7 and/or 14 and increased radiosensitivity. The gene responsible for A–T is named ATM (A–T mutated) and located on chromosome 11q22–23.

The humoral immunodeficiency in A–T patients can affect serum IgA and/or IgG₂ levels.3 However, 10% of patients have (mildly) raised serum IgM concentrations with deficiency of IgG and IgA.4 As the other clinical hallmarks of A–T such as cerebellar ataxia and dysarthric speech might not be present in infancy, these patients are frequently misdiagnosed as HIGM. We present eight A–T patients who showed serum Ig levels suggestive of HIGM on presentation and give an outline of this subgroup of A–T.

PATIENTS

The study has been carried out in The Netherlands in accordance with the applicable rules concerning the review of research ethics committees and informed consent.

Table 1 summarises the relevant clinical features and laboratory results of the eight A–T patients. Some data of patient 3 have been published before.5 Details of all results and mutation analyses are available to interested readers by applying directly to the corresponding author.

RESULTS

Most patients were referred at a very young age because of recurrent infections (table 1). Ocular telangiectasias were not present at time of presentation. Based on their serum Ig levels, all patients were initially diagnosed as HIGM and treated accordingly. Ultimately, all patients showed clinical features (ataxia, telangiectasia, recurrent respiratory tract infections) compatible with the diagnosis A–T. All patients had raised serum AFP levels (82–175 ng/ml). Furthermore, in seven of eight patients the diagnosis A–T was confirmed by DNA analysis.

Seven of eight A–T patients showed IgA deficiency (<0.05 g/l) and decreased serum IgG (<2.5 g/l) with normal or raised IgM levels suggestive of HIGM on presentation (table 1). Only patient 5-3 presented with a serum IgG level of 2.6 g/l, which was normal for the age of 6 months. Because of her affected siblings she was analysed while still being asymptomatic. Four months later she showed serum Ig levels suggestive of HIGM as well (table 1).

In six A–T patients absolute numbers of T lymphocytes were determined. All patients had decreased numbers at some time during their disease course.

DISCUSSION

Diagnosing A–T in very young children is frequently difficult, as characteristic clinical signs (cerebellar ataxia, dysarthric speech and ocular telangiectasias) have not yet appeared or are difficult to recognise. Recurrent infections are often the only presenting symptom. The diagnostic work-up of a child with recurrent infections will include determination of serum Ig. As 10% of A–T patients have (mildly) raised serum IgM concentrations with deficiency of IgG and IgA,4 young A–T patients presenting with infections might therefore be misdiagnosed as HIGM.

Systemic bacterial, severe viral, and opportunistic infections are uncommon in A–T patients. Nowak-Wegrzyn et al studied 100 A–T patients and reported five deaths, all of whom died at age 18 years or older.4 The A–T patients with increased serum IgM levels described in this paper showed a remarkably more severe disease course. Four patients died at a young age (patient 5-1 from hepatocellular carcinoma at 10 years of age, patient 3 from lymphoma, and patients 2 and 6 from respiratory failure at 14 and 12 years of age, respectively). Patient 2 was treated for tuberculosis and patient 4 developed disseminated granulomas. It has been reported that A–T patients with no kinase activity have a markedly more severe immunological phenotype than those with low levels of ATM activity.3 ATM protein and ATM kinase activity were lacking in patients 3 and 4. Although no attempt was made to detect ATM protein expression in the other patients it can be predicted from the type of mutation (frameshift or direct stopcodon) that no protein can be generated. In this respect all but one A–T patient can be regarded as having no functional activity of ATM (DNA analysis was not performed in patient 6).

Six A–T patients presented in this paper had reduced absolute numbers of T lymphocytes. In HIGM absolute numbers of T lymphocytes are normal. Determination of serum AFP can also be helpful as a raised serum AFP level is found in more than 90% of A–T patients and is an important diagnostic marker. However, below 1 year of age high AFP levels are physiological.6 Cytogenetic analysis for rearrangements of chromosomes 7 and/or 14 can be an additional diagnostic tool in these cases. In order not to miss the diagnosis A–T in patients presenting with serum Ig levels suggestive of HIGM, we propose to add DNA repair disorders to the list of possible causes of HIGM.