Recurrent infections associated with rare immunoglobulin isotypes deficiency (ORPHA:183675)
Deficiencies in immunoglobulin (Ig) isotypes (including: isolated IgG subclass deficiency, IgG sublcass deficiency with IgA deficiency and kappa chain deficiency) are primary immunodeficiencies that are often asymptomatic but can be characterized by recurrent, often pyogenic, sinopulmonary infections.
Epidemiology
Prevalence is unknown.
Clinical description
Some patients may show an increased frequency of infections in their second year of life, while for others the onset of infections may be later. There are four subclasses of IgG (IgG1, IgG2, IgG3 and IgG4), the levels of which change with age. Deficiency with IgG subclass 2 is most common in children, whereas after puberty deficiency in subclass 3 is more common. Symptomatic patients experience recurrent sinopulmonary infections, particularly with Streptococcus pneumonia and Haemophilus influenza, which present as repeated ear infections, bronchitis, pneumonia, sinusitis and diarrhea. Patients may also present with meningitis, bronchiectasis and severe, recurrent otitis media, which may lead to hearing loss. Patients with kappa chain deficiency are usually asymptomatic but symptoms can include recurrent respiratory infections and diarrhea.
Etiology
The cause and mode of transmission of deficiencies in IgG subclasses is unknown. Kappa-chain deficiency is produced by mutations in the IGKC gene (2p11).
Diagnostic methods
IgG subclass deficiency, with or without IgA deficiency, should be suspected in patients suffering from recurrent or chronic infections with encapsulated bacteria. Diagnosis is based on the number of infections (more than 6 courses of antibiotics per year given for upper and lower respiratory tract infections) and a lack of functional antibodies produced in response to vaccines and, in the case of IgG subclass deficiency, measurement of IgG subclass levels. The most common subclass deficiency is in IgG2, which may be accompanied by decreased IgG4 with or without decreased IgA levels. IgG subclass deficiency may still be a possibility even when the total IgG is normal, therefore measurement of all four IgG subclasses is required for an accurate diagnosis of IgG subclass deficiency. Diagnosis of kappa chain deficiency can be confirmed with genetic testing.
Differential diagnosis
Differential diagnoses include other primary immunodeficiencies, including 22q11 microdeletion syndrome, HLA class II deficiency and ataxia telangiectasia (see these terms). In general, infections are less severe than those in patients with marked deficiencies of IgG (all subclasses), IgA and IgM (such as X-linked agammaglobulinemia and common variable immunodeficiency; see these terms).
Genetic counseling
Transmission is autosomal recessive and point mutations in one family have been described.
Management and treatment
Treatment is based on prophylactic antibiotics and/or polyvalent immunoglobulin replacement in cases with severe or recurrent infections. Asymptomatic cases do not require treatment. Treatment in children is restricted to 8-9 months over winter with attempts to stop treatment totally in the summer in order to see if the deficit has corrected itself. For kappa chain deficiency, oral poliovaccine should not be given because of the risk of paralytic disease.
Prognosis
In children these deficiencies may be transient, while in adults they seem to be permanent. However, there is no evidence at diagnosis to predict their evolution.

                            Last update: 
                            September 2010


                            - Expert reviewer(s): 
                            Dr Anne DURANDY  - Pr Alain FISCHER  - Pr Isabelle PELLIER