Primary immunodeficiency is increasingly recognised in both children and adults. Although clearly defined disorders are individually rare, collectively they form a significant group. The molecular basis of several disorders has been known for over a decade, but in the past 10 years there has been a massive increase in the definition of defects underlying many immunodeficiencies.

Management of immunodeficiency has historically consisted of supportive treatment, including antibiotics, immunoglobulin (Ig) replacement, and in some cases, immunomodulation and immunosuppression. Bone marrow transplantation has been standard treatment for the past 20 years, but only for clearly defined cases of severe combined immunodeficiency (SCID) and a few other disorders known to have a very poor outlook without bone marrow transplantation. Accumulating worldwide experience is now providing evidence for poor long term prognoses in many other situations, even with optimal medical treatment. Bone marrow transplantation is therefore being considered for increasing numbers of children affected by these disorders, and, in parallel with this, there is a pressing need to define individual disorders as accurately and as early as possible.

The recent increase in knowledge of the molecular defects underlying many immunodeficiencies has led to several improvements in diagnosis and management.

First, precise molecular diagnosis is now possible in many cases, allowing earlier decisions to be made about the most appropriate management. This is particularly applicable in children who have evidence of combined (cellular and humoral) immunodeficiency, but with “milder” clinical phenotypes than infants with classical SCID. Some of these children are found to have identical molecular defects to those causing SCID, and in these cases the long term outlook is now known to be poor enough to justify bone marrow transplantation at an early stage.

Second, accurate carrier detection and first trimester prenatal diagnosis are possible in any family where the precise mutation has been …