Does She Have SCID?

Patient Presentation
A pediatrician received a late afternoon phone call from the state’s newborn screening program, about a 4-day-old female whose neonatal screening test was presumptively positive for severe-combined immunodefiency (SCID). The parents had already been contacted and were already planning on coming to their first office visit after discharge the next day. The program coordinator had faxed full information about what the pediatrician should do during the visit and also information for the parents. “The most important part is to make sure that the repeat testing is transported right away to our hospital, so we can get the testing done correctly,” the coordinator stated. “The second most important part is to make sure that the infant isn’t around anyone who is sick because they can get sick very quickly,” she also said.

The following day, the staff brought the infant to a room immediately and weighed and measured her. The medical history showed that she was a full-term infant born to a G2P2 mother without problems during pregnancy or delivery. The baby had no problems during hospitalization. Her mother reported that she was breast-feeding about every 2-3 hours with many wet diapers. Her stools had transitioned and her mother was not concerned about jaundice. The family history was negative for any genetic diseases or children who died young or unexpectedly.

The pertinent physical exam showed an alert female with a weight of 3180 g down 6% from birth but only 2% from discharge. Her length and head circumference were 50-75%. She had no rashes, but she had a black-blue nevus over her sacrum. No abnormal physical findings were noted.

The diagnosis of a healthy appearing infant with a positive neonatal screening test was made. The repeat neonatal screening test was sent after the visit and routine care was discussed as well as infectious disease precautions were re-iterated. The next day the program coordinator called to tell the pediatrician that the repeat testing was totally normal. The original testing was a false-positive result. She asked that the pediatrician contact the family with the results and said that no special precautions needed to be followed. She wanted the family to also know that if they had other questions they could always call the program, but that she was happy that the family had a healthy infant.

Severe-combined immunodefiency (SCID) is actually a group of inherited disorders with an absence or dysfunction of T, B and NK cells that results in severe dysfunction of the immune system. SCID is a primary immunodeficiency. SCID was thought to be a rare disorder but with the advent of neonatal screening the incidence in the US general population is estimated at ~1 in 58,000 live births, but with numbers higher or lower depending on the specific population.

Patients often have failure to thrive, oral candidiasis, and diarrhea as infants as well as a variety of infectious diseases. They can also have interstitial lung disease due to Pneumocystis jiroveci or graft-vs-host disease because of maternal lymphocyte engraphment. Without treatment to reconstitute the immune system, patients usually die at < 2 years of age.

Initially SCID was classified by if the patient was T or B cell deficient or normal, with subsets of NK deficiency or not (i.e. TB NK ,TB+ NK +, etc.) Molecular genetics now has identified multiple genes that are associated with different SCID phenotypes. The genes can cause disease by affecting the hematopoietic precursor survival, cause problems with cytokine signaling, allow toxic metabolite accumulation, genetic recombination, and other mechanisms. Most SCID genes have an autosomal recessive inheritance. Thymic abnormalities are often grouped with SCID because of phenotypic and genetic similarities. DiGeorge syndrome (22q11 deletion sequence) includes congenital athymia which causes similar immunological problems because the T-cells do not have a thymus to properly develop within. DiGeorge syndrome also has other problems associated with it and a review can be found here.

Curative treatment is available through allogeneic hematopoietic stem cell transplantation and is considered the preferred treatment. Gene therapy is also potentially curative for 2 different types of SCID (ADA and IL2RG genes). Adenosine deaminase infusions are also an option for ADA deficient SCID but are not curative. Studies have shown > 90% long-term survival after transplantation when infants are < 3.5 months of age, and have a sibling match.

A review of primary immunodeficiencies can be found here.
A review of potential testing to do for a suspected immunodeficiency can be found here.

Learning Point
In the US, the Department of Health and Human Services has an advisory panel that recommends a core panel of congenital disorders that are recommended to be screened for. SCID was added to the core panel in 2010. Screening for SCID is done through TREC testing (T cell receptor excision circles) using the Guthrie blood spot cards. T cell specific confirmatory testing using flow cytometry and other testing needs to be carried out if TREC is positive.

TREC testing does not identify all forms of combined immunodeficiency or atypical SCID. Other types of testing such as KREC (kappa-deleting recombination excision circles) may increase the ability to identify other forms for SCID. Prenatal testing in high risk families is available.

Questions for Further Discussion
1. Who was “David the Bubble Boy” and what is his link to SCID?
2. What are indications for stem cell transplant?
3. What are the differences between stem cell transplant and gene therapy?
4. What disorders does your state or country test for on newborn screening?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for this topic: Immune System Disorders

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Centers for Disease Control. Severe Combined Immunodeficiency (SCID). Available from the Internet at (rev. 9/17/15, cited 10/2/18).

Gaspar HB, Hammarstrom L, Mahlaoui N, Borte M, Borte S. The case for mandatory newborn screening for severe combined immunodeficiency (SCID). J Clin Immunol. 2014 May;34(4):393-7.

Cirillo E, Giardino G, Gallo V, D’Assante R, Grasso F, Romano R, Di Lillo C, Galasso G, Pignata C. Severe combined immunodeficiency–an update. Ann N Y Acad Sci. 2015 Nov;1356:90-106.

Chinn IK, Shearer WT. Severe Combined Immunodeficiency Disorders. Immunol Allergy Clin North Am. 2015 Nov;35(4):671-94.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa