From ATLANTA Medicine, 2012, Pediatrics, Vol. 83, No. 2
“Newborn Screening Saves Lives.”(1) This is a headline that is music to the ears of clinicians and public health laboratories. Since the advent of newborn screening using heel-stick blood spotted on filter cards in 1981, more than 40 different conditions can be detected using tandem mass spectrometry to diagnose metabolic disorders and DNA analysis to identify mutations associated with cystic fibrosis and hemoglobinopathies. In 2010, the U.S. Department of Health and Human Services recommended the addition of Severe Combined Immunodeficiency (SCID) to the panel of primary conditions for newborn screening.(2)
SCID, popularly known as the “boy in the bubble” disease, is a congenital immune defect caused by more than 20 distinct single gene mutations. All infants with SCID have severe T cell lymphopenia at birth, and affected infants develop severe, life-threatening infections. Infants with SCID appear perfectly well at birth but begin to develop recurrent infections in the first few months of life. In addition to bacterial and viral infections, infants with SCID develop fungal and opportunistic infections (pneumocystis) and frequently have a severe erythematous, eczematous rash. As a result of the infections and malabsorption, failure to thrive is also a common feature of these disorders.
Without immune reconstitution, SCID is uniformly fatal with very few infants surviving beyond the first year of life. Previous studies estimate the birth prevalence of SCID at 1:100,000 live births,(3) but clinical immunologists have long felt that this is an underestimate of prevalence and that many cases are missed.
Immune reconstitution for this immunodeficiency is done through a bone marrow or hematopoietic stem cell transplant (HSCT). Transplants can be performed in the first months of life; if performed before 3.5 months of age, the rate of success is greater than 95 percent.(4) Outcomes after transplantation are dependent on the age of the infant at transplant, the type of SCID, the donor and the presence of uncontrolled infection. It is clear that early intervention is critical for a good outcome.
SCID is the first primary immunodeficiency disease(PIDD) to be recommended for newborn screening(NBS). For a disorder to be considered a candidate for newborn screening, it must have significant impact (eg: life threatening), effective therapies must be available, early(presymptomatic) intervention must be important, and a sensitive and specific (and inexpensive) screening test must be available. In 2005, Chan and Puck (5) published a report of a method measuring T cell receptor excision circles(TREC) DNA using a quantitative PCR from dried blood spots (DBS). They demonstrated that this assay reliably identified infants with SCID.
In 2008, Wisconsin added the TREC assay to their NBS program. Currently five states are screening for SCID by measuring TRECs in newborn DBS. To date they have screened more than 900,000 infants and identified more than 24 cases of SCID. This suggests that the birth prevalence is approximately 1:38,000 (personal communication ACMG), more than twice as high as previous estimates.
Newborn screening for SCID is a first in many ways. Not only is it the first PIDD to be recommended for NBS, but it is the first NBS test to use a DNA-based assay as the primary screening test. An abnormal screening test reports the absence of TREC DNA in the DBS, this must then be confirmed by obtaining a blood sample and measuring the numbers of T, B and NK lymphocyte subsets by flow cytometry. Referral to a center with experience caring for children with Primary Immunodeficiencies is recommended. Any infant with suspected SCID should not be given any live vaccines and may be started on antibiotic prophylaxis and receive gamma globulins (IVIG or SCIG).
At this time, at least 10 states are preparing to add newborn screening for SCID to their state panels. The American College of Medical Genetics and Genomics(ACMG) publishes the ACT sheet providing information regarding the screening test, as well as resources for practitioners. In addition, standards for performing the TREC assay are in preparation.
In the state of Georgia, the Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies at the Emory Children’s Center is the preeminent referral center for patients with a suspected PIDD. The director of the center, Dr. Lisa Kobrynski, is a nationally recognized expert in the diagnosis and treatment of PIDD, including newborn screening for SCID. Fortunately for children in Georgia, the Jeffrey Modell Foundation (JMF) center has teamed up with the Blood and Marrow Transplant (BMT) unit at Children’s Healthcare of Atlanta at Egleston to provide life-saving transplants. Each year one to two new infants with SCID are diagnosed and treated at Emory Children’s Center and Children’s.
Obstetricians, pediatricians and neonatologists should be aware of the implementation of SCID screening in their state. They should be prepared to respond if an infant in their care is identified through newborn screening and they should become familiar with the specialized centers in their state that will ultimately provide care for these infants. Early detection and early initiation of therapy is key. This is one test that truly will save lives.
1. “Newborn Screening Saves Lives”: legislation passed April 2008 to expand
state newborn screening programs and establish a national clearing house for data.
2. Watson, MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, howell RR. Newborn
Screening advisory Groups, Newborn Screening: towards a uniform screening
panel and system. Genet Med 2006; 8:1s-250s.
3. Kalman L, Lindegren ML, Kobrynski L et al. Mutations in genes required for
T cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS and ADA
and severe combined immunodeficiency: HuGE review. Genet Med 2004;6:16-26.
4. Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell
transplantation for severe combined immunodeficiency in the neonatal period
leads to superior thymic output and improved survival. Blood 2002;99:872-8.
5. Chan K, Puck JM. Development of population-based newborn screening for
severe combined immunodeficiency. J Allergy Clin Immunol. 2005;115(2):391–398.
Lisa Kobrynski, M.D., M.P.H. is Associate Professor of Pediatrics, Emory University School of Medicine. She is the Director, Jeffrey Modell Foundation Center for the Diagnosis and Treatment of Primary Immunodeficiencies.