Severe combined immunodeficiency (SCID) is defined as the inability of hematopoietic stem cells to differentiate into mature T cells, with or without B and natural killer (NK) cells. The most common genes involved include IL2RG, RAG1/RAG2, and ADA. The estimated incidence of SCID in the United States is 1 in 58,000 live births, but with the inclusion of SCID on the newborn screen (NBS), initiated between 2010 and 2018, survival has improved significantly through early identification and intervention. If intervention is performed before 3.5 months of age, survival increases to 94% compared with after 3.5 months of age with a survival rate of 70%.
A 7-month-old female was admitted for acute respiratory failure secondary to bocavirus infection. The development of leukopenia, deteriorating clinical status, and lack of a completed NBS prompted a workup for an inborn error of immunity. Quantitative immunoglobulins were undetectable with low lymphocyte counts (Table 1). Flow cytometry showed markedly decreased B cells and T cells but retained NK cells, consistent with T-B-NK+SCID and concerning for RAG1-mutated SCID. A genetic panel revealed two pathogenic variants in RAG1:(c.1682G>A, a missense variant, and c.2487_2488delinsTT, a nonsense variant) (Table 2), confirming as autosomal recessive SCID. With improvement of respiratory status, intravenous immunoglobulin (IVIG) and anti-fungal and Mycobacterium avium complex prophylaxis were initiated. She continues monthly IVIG, prophylactic antibiotics and antifungals, and clinical monitoring while waiting for allogeneic hematopoietic stem cell transplant (HSCT). A pretransplant chest computed tomography scan revealed pulmonary nodules. At one year of age, she awaits HSCT, delayed for treatment of presumed fungal infection.
Lymphocyte count.
| Absolute Count (mm3) | Reference Range7 (mm3) | Percentage (%) of total lymphocytes (unless otherwise noted) | |
|---|---|---|---|
| Absolute Lymphocyte Count | 264 | 3,400 - 9,000 | |
| CD3 | 140 | 1,900 - 5,900 | 53.1 |
| CD4 | 122 | 1,400 - 4,300 | 46% of CD3 |
| CD8 | 10 | 500 - 1,700 | 3.8% of CD3 |
| CD19 | <1 | 610 - 2,600 | 0.05 |
| CD16/56 | 119 | 160 - 950 | 45.2 |
| CD45RA of CD4 | 6 | 396-3,111 | 5.1% of CD4 |
| CD45RA of CD8 | 2 | 264-1,421 | 14.9% of CD8 |
| CD3 RA/RO | 0.1 |
| Absolute Count (mm3) | Reference Range7 (mm3) | Percentage (%) of total lymphocytes (unless otherwise noted) | |
|---|---|---|---|
| Absolute Lymphocyte Count | 264 | 3,400 - 9,000 | |
| CD3 | 140 | 1,900 - 5,900 | 53.1 |
| CD4 | 122 | 1,400 - 4,300 | 46% of CD3 |
| CD8 | 10 | 500 - 1,700 | 3.8% of CD3 |
| CD19 | <1 | 610 - 2,600 | 0.05 |
| CD16/56 | 119 | 160 - 950 | 45.2 |
| CD45RA of CD4 | 6 | 396-3,111 | 5.1% of CD4 |
| CD45RA of CD8 | 2 | 264-1,421 | 14.9% of CD8 |
| CD3 RA/RO | 0.1 |
RAG1 variants description.
| Variant 1 | Variant 2 | |
|---|---|---|
| Sequence Change | c.1682G>A | c.2487_2488delinsTT |
| Amino Acid Change | p.Arg561His | p.Arg829_Lys830delinsSer* |
| Classification | Pathogenic | Pathogenic |
| Zygosity | Heterozygous | Heterozygous |
| Type of Variant | Missense | Non-sense |
| GnomAD Frequency | 0.003% | Absent |
| ClinVar | 5 entries- Likely pathogenic/pathogenic (Variation ID: 13143) | 5 entries- pathogenic (Variation ID: 1034220) |
| Experimental Studies | Shown affects RAG1 function | Not applicable |
| Other Evidence | - Observed in other individuals with SCID8,10 | Observed in other individuals with SCID |
| - Other variants that disrupt p.Arg561 amino acid residue have been determined pathogenic |
| Variant 1 | Variant 2 | |
|---|---|---|
| Sequence Change | c.1682G>A | c.2487_2488delinsTT |
| Amino Acid Change | p.Arg561His | p.Arg829_Lys830delinsSer* |
| Classification | Pathogenic | Pathogenic |
| Zygosity | Heterozygous | Heterozygous |
| Type of Variant | Missense | Non-sense |
| GnomAD Frequency | 0.003% | Absent |
| ClinVar | 5 entries- Likely pathogenic/pathogenic (Variation ID: 13143) | 5 entries- pathogenic (Variation ID: 1034220) |
| Experimental Studies | Shown affects RAG1 function | Not applicable |
| Other Evidence | - Observed in other individuals with SCID8,10 | Observed in other individuals with SCID |
| - Other variants that disrupt p.Arg561 amino acid residue have been determined pathogenic |
Newborn screening would likely have prompted earlier diagnosis and treatment of this patient, including reverse isolation, antimicrobial prophylaxis, and earlier preparation for transplant. This patient’s survival and long-term immune reconstitution may be impaired given that HSCT was not able to be performed before 3.5 months of age.
This case demonstrates the necessity of newborn screening, prompt confirmatory testing, including genetic panels, immune function testing, and HSCT in the diagnosis and management of SCID. With public skepticism of medical interventions rising, it emphasizes advocating for continued education and utilization of the NBS among providers and the public.
