![]() Screening programs have been currently established in all 50 US-states, 4 Canadian Provinces, Israel, Switzerland and Germany, and will be introduced in various European countries within next years. New-Born Screening by Quantification of T-cell Receptor Excision Circles (TREC)Īctive infection and age > 3.5 months at HSCT are associated with poor survival after HSCT ( 4, 10, 11), underlining the importance of new-born screening (NBS) to diagnose patients as early as possible and to prevent infections ( 12, 13) (see review on Universal newborn screening for SCID). Omenn syndrome and rarely maternal GvHD require immunosuppressive drugs. In some cases, “hypomorphic mutations” of SCID-causing genes encode for proteins with some residual function, allowing for the development of few oligoclonal autoreactive T-lymphocytes, which proliferate and invade peripheral tissues and may be responsible for a so-called Omenn syndrome (definition see Table 1) with a generalized exanthema, lymphadenopathy, alopecia, hepato-/ splenomegaly, intractable diarrhea, and eosinophilia ( 9). An increased risk for post-transplant acute GvHD has been demonstrated for patients with maternal T cells detectable at diagnosis ( 8). In most cases however, maternal T-lymphocytes are detected in patient's peripheral blood without any clinical signs. T-lymphocytes transferred from the mother during pregnancy can proliferate, expand, and cause skin lesions and more rarely liver manifestations such as in GvHD following allogeneic HSCT ( 7). Signs of Immunodysregulation: Maternal Graft vs. Some patients with DNA repair defects associated with SCID, such as Ligase-4 deficiency or Cernunnos/XLF may present with microcephalia and delayed neurological development. Patients with Adenosine-Deaminase (ADA)-deficiency may present with alveolar proteinosis ( 6) and/or bone abnormalities (cupping of osteochondral junctions) detectable on the chest radiograph. Specific Features Due to the Affected Gene ![]() A chronic swelling or ulceration at the BCG injection site or a chronic diarrhea after oral Rotavirus vaccination should lead to further diagnostic steps and the formal exclusion of a T-lymphocyte deficiency. Live vaccines with attenuated microorganisms, such as Bacille Calmette-Guérin (BCG) or Rotavirus, may lead to atypical infections and can have an unwanted diagnostic value. ![]() Cytomegalovirus (CMV) infection can be particularly severe and diffuse with pulmonary, liver, cardiac, intestinal, retinal, and/or central nervous system involvement. Intestinal infections with Rota-, Noro or Adenovirus can lead to severe chronic diarrhea. Airway infections due to viral ( Respiratory Syncytial Virus, Myxovirus, Adenovirus) and opportunistic microorganisms such as Pneumocystis jirovecii (PJP) can cause severe pneumonias requiring mechanical ventilation. Opportunistic infections can suggest a defect of specific cellular immunity but non-specific bacterial infections are also frequently observed in SCID patients ( 5). Patients are classically not infected at birth, but in the absence of diagnosis, they will eventually present with severe, atypical and/or recurrent life threatening infections. Some patients may also present with leaky-SCID, usually caused by hypomorphic mutations in classical SCID causing-genes, responsible for a less severe phenotype with infections and autoimmunity. ![]() ![]() In the absence of allogenic hematopoietic stem cell transplantation (HSCT) or gene therapy (GT), patients ultimately die generally within the first year of life. Some genetic defects cause non-immunological and disease specific features. Some patients may also present with signs of immune dysregulation caused by autologous (Omenn syndrome) or allogeneic (maternal GvHD) T cells. Usually, patients are asymptomatic at birth and present within their first weeks or months of life with infections and/or failure to thrive (FTT) ( 5). The clinical presentation of patients with SCID is variable. This immunophenotypic categorization does not replace molecular identification, which is key for prognosis ( 4). SCID entities are also classified by immunophenotype, depending on the presence of B-lymphocytes and NK cells, which are usually associated with specific gene defects (genotypes) ( Table 2). ![]()
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