Late-Onset and Hypomorphic Presentation of Severe Combined Immune Deficiency

Typically, SCID presents early in infancy, within the first few months of life, with severe infections, failure to thrive, and other life-threatening complications. Less severe or late-onset presentations, ranging from “leaky” SCID to late-onset combined-immunodeficiency (LOCID), caused by variants in the same genes usually associated with classical SCID, are increasingly being recognized. On the one hand, SCID is a genetically heterogeneous disease, meaning that variants in many genes can cause the same phenotype; on the other hand, there is emerging evidence of genetic pleiotropism, meaning that variants in the same gene can present with different clinical phenotypes. The main mechanisms responsible for atypical SCID presentations are hypomorphic variants, mosaicism, and somatic reversion. Hypomorphic variants reduce the quantity or stability of mRNA or protein or result in functional defect. Hypomorphic variants have been described in several SCID genes, such as RAG1, RAG2, IL2RG, ADA, CORO1A, DCLRE1C, AK2, PRKDC, LIG4, and ZAP70 resulting in milder forms of the disease with variable clinical phenotypes. Mosaicism and somatic reversion, specifically in Wiskott-Aldrich syndrome and IL2RG deficiency, have been documented as a phenomenon where the affected variant is confined in some lineages or when the affected individuals undergo a spontaneous genetic correction, leading to improved immune function and milder clinical manifestations compared to classical presentation of the disease. These delayed presentations can be very challenging on many levels, from the diagnosis to the clinical management. Diagnostically, the routine immunological tests can show borderline values and functional tests can be hard to interpret. Newborn screening sensitivity might also be reduced. Genetically, hypomorphic variants are more often “variants of uncertain significance” and are generally harder to classify than null variants. Moreover, somatic reversion and mosaicism can be easily missed by standard sequencing technologies. The shift from conventional clinical classifications to molecular diagnostics is changing the therapeutic approach of patients with SCID. Hematopoietic stem cell transplantation (HSCT) represents the main and life-saving strategy for most SCIDs, offering the potential for immune reconstitution and long-term survival. Tailored interventions (specific targeted-therapies and gene therapy) guided by genetic understanding are now available strategies in some defects.