Newborn screening

About 40-50% of babies with abnormal TREC results are confirmed through follow-up testing to have a T cell deficiency. Some states perform another TREC test with a different blood sample to confirm the initial abnormal results, while others proceed directly to the next tier of testing described below.

To determine if the number of T cells in the baby’s blood is actually low, a follow-up test, called immunophenotyping, is performed on another blood sample from the baby. In this test, T cells and other types of lymphocytes, including B cells and natural killer cells, are counted directly. Experts recommend also measuring the proportion naïve to memory T cells during this test to determine if any residual T cells could be from the baby’s mother (T cells from the baby should be mostly naïve T cells). If the baby has no or low numbers of T cells by immunophenotyping, or the T cells they do have are likely from their mother, they are confirmed to have T cell deficiency. Again, further testing and evaluation are needed to determine why the baby has a T cell deficiency.

In about one-third of cases, the T cell deficiency is ultimately determined to be caused by a type of SCID. 

However, in most cases, the T cell deficiency is caused by another condition. Other conditions that may cause low T cell numbers include:

• Birth defects of the heart or digestive tract.
• Premature birth (mainly infants born before 30 weeks).
• Other primary immunodeficiencies.
  • Transient lymphopenia of infancy.
  • Idiopathic T cell lymphopenia.
  • Combined immunodeficiency (leaky SCID).
  • DiGeorge/22q11.2 deletion syndrome.
  • Ataxia-telangiectasia.
  • CHARGE syndrome.
  • DOCK8 deficient hyper-IgE syndrome.
  • Jacobsen syndrome.
  • FOXN1 gene variant causing poor thymus development, but not complete deficiency of the protein.
• Disorders in the lymphatic system, which can cause a loss of T cells outside of the lymphatic system and the bloodstream.
• Temporary immunosuppression from maternal medication or certain viral exposures during pregnancy.
• Down syndrome (trisomy 21).
• Leukemia.
• HIV/AIDS.

Other conditions that can cause abnormal TREC results are often not as severe as SCID, but it's important to find out about them and test for them. If your child is diagnosed with low T cells and it’s not SCID, continue to pursue testing and medical intervention. Keep in mind that some of the medical steps taken overlap those of SCID, at least in the beginning. 

Infants definitively diagnosed with SCID are immediately sent for treatment appropriate for their diagnosis. Children without a definitive diagnosis also require ongoing evaluation and follow-up with a specialist to ensure the reason for their low T cells is understood and appropriately treated.

Babies with confirmed T cell deficiency—both those with SCID and those with non-SCID T cell deficiency—need to be evaluated by a clinical immunologist. Clinical immunologists have undergone specialty training in recognizing, diagnosing, and treating disorders associated with low T cells. The clinical immunologist can determine if the baby’s low T cell count requires further evaluation and treatment.

It is also important to note that some infants who have abnormal TREC results and confirmed low T cells at birth eventually normalize over time, without suffering from serious infections or poor health outcomes. However, all babies with T cell deficiency should be evaluated by a clinical immunologist to help families and pediatricians decide the best treatment and monitoring plan for each baby’s individual needs.

SCID and non-SCID conditions associated with low T cells may require continued care by a clinical immunologist who has the knowledge and experience to recognize which treatments are most likely to address each patient’s unique needs. 

The most important thing to remember is that if your baby has a low T cell count, you should always follow up with a skilled clinical immunologist. For help finding a clinical immunologist, use IDF’s Clinician Finder or the Primary Immune Deficiency Treatment Consortium (PIDTC) website.

If a baby has a confirmed T cell deficiency, additional, more definitive testing will be done to establish a diagnosis. These tests can include measures of T cell function, determining whether any T cells seen in the baby’s blood are from the mother, and genetic tests.

If the TREC test shows low T cells instead of no T cells at all, a test of T cell function may be done to determine how well the baby’s T cells work. The most common type of T cell function test is called lymphocyte proliferation to mitogens. Mitogens are plant-derived chemicals that stimulate healthy, functional T cells to divide and multiply. Most laboratories will check at least two of the three following mitogens – phytohemagglutinin, pokeweed, or concanavalin A. By measuring the T cells’ ability to divide when mixed with the mitogen, the test helps determine if the baby’s T cells are functioning normally.

Since low T cells can arise from chromosomal problems (such as Down syndrome or 22q11.2 deletion syndrome), doctors may order blood tests to evaluate the size, shape, and number of the baby’s chromosomes. Tests that can identify chromosomal problems include karyotype, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray. 

Genetic testing may also be done, especially if there is a high suspicion of SCID. Most genetic testing laboratories offer a SCID panel that analyzes the baby’s DNA for variants in a number of genes known to cause SCID. However, these panels are not standardized and include different numbers of genes and/or variants depending on the laboratory, so they may not test for all known SCID-causing genetic variants. Healthcare providers usually have to get prior authorization from the baby’s insurance provider before ordering any genetic testing.

Sometimes, no disease-causing variants are identified through these panels. The baby’s doctor may recommend more extensive genetic testing, such as whole exome or whole genome sequencing, which looks for variants in a larger number of genes (whole exome sequencing) or in all of the baby’s DNA (whole genome sequencing).