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PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.

Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posteriori in patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitro immunoglobulin production were evaluated. Seventy patients (91 percent) showed clinical symptoms. Patients suffered from infections (91 percent), allergies (47 percent) and autoimmune disease (4 percent). During follow-up 41/57 children (72 percent) normalized IgG values, mostly within 24 months of age (p less than 0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p less than 0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p less than 0.01) and an inability to produce IgG in vitro (p less than 0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions.

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. Objective: Our aim was to describe the natural history of XLA. Methods: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base.Results: Data on the patients (N 5 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean followup of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung