Interleukin-2 receptor common gamma chain (IL2RG) defects present a diagnostic challenge

Severe combined immunodeficiency (SCID) represents a rare group of primary immunodeficiency disorders (PIDs) characterized by a reduced number of T lymphocytes in association with a functional or quantitative defect in B lymphocytes, natural killer cells, or both. Patients with SCID may have known or yet unidentified genetic alterations explaining their phenotype. Mutations in the IL2RG gene, which encodes the common gamma chain of the interleukin-2 receptor, cause X-linked SCID (X-SCID) as well as X-linked combined immunodeficiency and remain the most common cause of SCID. This protein is an important signaling component of many interleukin receptors, including those of interleukin-2, -4, -7, and -21, and has therefore been commonly known as the common gamma chain. More than 300 mutations in the IL2RG gene have been identified in X-SCID. These mutations are located on the long arm of the X chromosome at position 13.1 (Shearer et al. 2014; Pérez-Simón 2015). The following mutational hot spots in IL2RG have been reported, at codons p.Arg224, p.Arg226, p.Arg285, and p.Arg289 (Puck et al. 1997).

Transplacental maternal engraftment (TME) is defined as the presence of maternal T cells in peripheral blood before bone marrow transplantation. The human placenta allows for bidirectional passage of nucleated cells between mother and fetus, and in healthy infants the immune system eradicates maternal cells. Patients with SCID lack the functional immunity required to reject circulating maternal T cells, resulting in persistent TME in up to 40% of these patients (Fischer et al. 1997; Liu et al. 2016). Although TME can be asymptomatic, some infants with SCID and TME can have clinical symptoms of graft-versus-host disease (GvHD) at diagnosis. The presentation of maternal engraftment can range from a fine maculopapular erythema to generalized erythroderma and alopecia. Liver, gastrointestinal, and hematologic involvement may be observed (Wahlstrom et al. 2017). A newly diagnosed patient with SCID presenting with detectable T cells is evaluated for chimerism by HLA typing of T cells and non-T cells (Müller et al. 2001). In patients with engraftment, maternal T cells are characterized by phenotype and function in response to mitogen stimulation (Müller et al. 2001). The presence of TME may persist post-transplantation, in which the patient should be assessed for signs of acute GvHD with repeat phenotypic and functional T cell analysis (Wahlstrom et al. 2017). TME has also been an impediment to proper infant immune evaluation as well as genetic analysis. Genetic testing is extremely important in SCID as early diagnosis allows for life-saving interventions such as bone marrow transplantation, which results in a higher survival rate when administered during the first 3 months of life (Kwan et al. 2014; Wahlstrom et al. 2015). In addition, proper molecular diagnosis aids in the important task of family genetic counseling.

Here, we present a patient with TME that posed a challenge to both genetic diagnosis and genetic counselling, and whose evaluation resulted in the identification of a novel mutation.

Our patient, now 25 years old, was diagnosed with SCID at 5 months of age. His clinical history was significant for maternal engraftment, failure to thrive and recurrent infections including pneumonitis and pneumocystis jiroveci. Pertinent laboratory workup revealed a low mitogenic response and the lymphocyte subsets were irrelevant due to maternal engraftment. His parents were of English decent. He was one of the first patients world-wide to receive a matched unrelated bone marrow transplantation at 1 year of age. His conditioning consisted of Busulfan and Cyclophosphamide. He had an uneventful transplant course with the exception of mild cutaneous GvHD. His engraftment was full and rapid with no complications. He continues to do extremely well 2 decades later, with no episodes of infections, autoimmunity, or atopy. His engraftment remains solid and immune reconstitution is complete.

Patients with SCID may have unknown genetic mutations explaining their phenotype. Gene defects account for approximately 85% of SCID cases. Prior to newborn screening and in the absence of family history of SCID, most patients came to medical attention with failure to thrive, recurrent and opportunistic infections, such as our case. Over the years, genetic analysis has become an important component of an evaluation of a patient with SCID as it impacts prenatal diagnosis, treatment course, and prognosis. Further, the importance of genetic analysis in family members of such patients needs to be emphasized for family planning and subsequent genetic counselling. Our patient underwent next generation sequencing (SCID panel) 2 decades following his SCID diagnosis, confirming a suspected mutation in IL2RG. Subsequently, his mother and sister underwent molecular genetic testing which revealed mosaicism (<1%) in the mother and no deletion in the sister. This extremely low level of mosaicism was the result of a post-zygotic mutation in the mother, hence only some of her cells were affected. As the sister had no deletion detected, her risk of being mosaic was extremely low and she is therefore unlikely to pass on the mutation to her children.

Our patient poses no risk to passing on his mutation to his male children given his X-linked condition, but his risk of passing on the mutation to his female children is 100%. Thus, none of the patient’s offspring will develop SCID, but female descendants will be carriers of the pathogenic variant.

This case report describes a novel mutation in IL2RG, emphasizing the complexity of genetic analysis in SCID patients and their family members, and the importance of pursuing a molecular diagnosis. Next generation sequencing appears superior to traditional methods in providing answers for family planning and subsequent genetic counselling.