Immunodeficienze primitive: cosa c’è di nuovo

The field of primary immunodeficiencies (PID) has been characterized in the last decades by a rapid evolution that has led to a considerable expansion of knowledge, and, subsequently, to a nosografic re-classification of the different forms. The importance of defining in a timely manner the alarm signals and signs of presentation of the different forms has always been pointed out for an early diagnosis. From a clinical standpoint, the alterations of the immune system have been typically associated with an increased susceptibility of patients with PID to severe, non-selective, infections, frequently affecting multiple tissues and supported by uncommon and opportunistic germs. In addition, in the past, PID have been stereotyped as severe disorders, characterized by an early onset in the first two years of life, with typical symptoms such as failure to thrive, intractable diarrhea, recurrent and severe infections resistant to treatment, multiple organ and cutaneous abscesses. Moreover, the recovery from whichever infection was considered sufficient to rule out a PID. For a long time, it was assumed that a defective immune system, not able to respond to non-self antigens, was necessarily not able to respond to self-antigens as well. Therefore, it was thought that autoimmunity could not occur in patients with primary immunodeficiencies. These “dogmas” have been confuted, with the recent identification of novel forms of PIDs, characterized by peculiar clinical phenotypes. Along with typical forms of cellular, humoral or combined immunodeficiencies presenting with a range of clinical signs indicative of defective immune responses, several cases have been reported which are characterized by atypical clinical signs, that are less suggestive of an underlying immunodeficiency. In this review, we approach the differential diagnosis of novel PIDs based on four presenting signs, and discuss novel and recently identified underlying genetic defects, with the aim to alert not only the immunologist but also the pediatrician for an early recognition of such complex disorders.