Universal SCIDS Screening Gaining Ground

Universal newborn screening for severe combined immunodeficiency syndrome is being adopted increasingly around the country.

Severe combined immunodeficiency (SCIDS) is a syndrome caused by a spectrum of mutations in genes necessary for the normal development and function of T cells, and therefore B cells. Identification of newborns with these mutations allows for early hematopoietic stem cell transplantation and a vastly improved prognosis. The evidence for an improved outcome for those identified early comes from studies comparing the outcome in first cases in a family with those in subsequent siblings who are diagnosed and transplanted earlier in life (Blood 2011;117:3243-6).

In May 2010, U.S. Secretary of Health and Human Services Kathleen Sebelius announced the addition of SCIDS to the national Recommended Uniform Screening Panel. Thus far, pilot programs for universal newborn SCIDS screening have been implemented in five states: California, Louisiana, Massachusetts, New York, and Wisconsin, and also in Puerto Rico. Another eight states, Colorado, Delaware, Florida, Iowa, Michigan, Minnesota, North Carolina, and Rhode Island, are prepared to implement SCIDS Newborn Screening Programs in the near future.

There are several types of SCIDS. Deficiency of the common gamma chain of the T-cell receptor is the most common, affecting nearly 45% of all cases. This mutation of the "cg" (for common gamma chain) gene on the X chromosome results in very low T-lymphocyte and NK-lymphocyte counts but the B-lymphocyte count is high. Only males have this type of SCIDS, but females may carry the gene.

The second-most common type, adenosine deaminase (ADA) deficiency, is caused by mutations in a gene that encodes the ADA enzyme, which is essential for the metabolic function of a variety of body cells, but especially T cells. The absence of ADA leads to accumulation of toxic metabolic by-products within lymphocytes that cause the cells to die. Infants with this type of SCIDS have the lowest total lymphocyte counts of all, and the T, B and NK-lymphocyte counts are all very low.

Another, less common SCIDS type is deficiency of the alpha chain of the IL-7 receptor, in which the infant has B and NK cells, but no T cells. However, the B cells don’t work because of the lack of T cells.

Other less frequent types include deficiency of Janus kinase 3 (JAK3), in which the infants have lab values similar to X-linked SCIDS (T, B+, NK), and deficiencies in the CD3 or CD45 chains that play key roles in T-cell function.

The classic symptoms of SCIDS are recurrent severe infections, chronic diarrhea, and failure to thrive. Persistent mucocutaneous candidiasis is a common early finding, and opportunistic infections with normally nonpathogenic organisms, such as Pneumocystis jiroveci (formerly carinii) also occur. Attenuated vaccine organisms, rotavirus and varicella, may cause severe or fatal infection. About 10 cases SCIDS presenting with persistent diarrhea following rotavirus vaccine have been reported (Vaccine 2010;28:6609-12).

The strategy for newborn SCIDS screening is based upon polymerase chain reaction quantification of T-cell receptor excision circles (TRECs) – small circles of DNA created in T-cells during their passage through the thymus – from dried blood spots (DBS) on newborn screening cards. A normal number, based on an evaluation of 5,766 Wisconsin newborns, is 708 TRECs/3.2 mm DBS (Public Health Rep. 2010;125 [Suppl 2]:88-95).

A low TREC number implies abnormal thymic function. Children with SCIDS are expected to have near zero (the screening cutoff is 25 TREC/uL). Children with an abnormally low TREC count on screening should be followed by more formal testing of T-cell number, including naive cell markers and T-cell function (mitogen stimulation) if sufficient T cells are present.

When notified about a positive test, the physician should immediately refer the infant to a center for lymphocyte subset analysis to confirm or refute the diagnosis. These infants should be "isolated" within the home by avoiding young children and any potentially contagious contacts. Prophylaxis for Pneumocystis jiroveci pneumonia could be given if a delay in further testing is likely, as well as replacement therapy with immune globulin might be indicated if assessment of humoral immunity demonstrates hypogammaglobulinemia.

Live attenuated vaccines normally given by 2 months of age, including rotavirus, bacille Calmette-Guérin, and oral poliovirus vaccine should NOT be administered to the infant, and measles-mumps-rubella and varicella vaccines should not be administered to the infant’s caregivers or family.

In Wisconsin, the first state to offer universal newborn SCIDS screening, 0.05% (35) newborns out of a total 71,000 had positive tests and underwent confirmatory testing. Another 0.17% (119) had initial unsatisfactory test results that required repeat. Of 194,056 newborns screened in Massachusetts during 2008-2011, 4 were identified with SCIDS. This gives us a rate of approximately 1 in 50,000 live births. Importantly, two of those four were identified prior to exhibiting any symptoms. The oldest, who had the JAK3 defect but was never ill prior to receiving a stem cell transplant, is now more than 10 months post transplant and is doing well. The second, who has been transplanted and is at home, had been hospitalized and "very ill" at the time of the screening but had not received a diagnosis (of deficiency of common gamma chain).

The latter two have also been transplanted. One was sick by 10 days of age with classic SCIDS symptoms (thrush, febrile, failure to thrive) and was admitted. The fourth was reportedly healthy at the time of the report but had been seen for a weight check because the mother was worried. She had previously lost two children who had died at 4 months of age of pneumonia.

Although early in the adoption of SCIDS screening, the Massachusetts’ experience demonstrates that infants with SCIDS can be identified early, often before signs and symptoms are present. However, most abnormal tests are not caused by SCIDS or other immune deficits, which may also be identified early as a result of TREC screening.

Dr. Pelton is chief of pediatric infectious disease and also is the coordinator of the maternal-child HIV program at Boston Medical Center. He said he had no relevant financial disclosures. 

*This story was updated December 2, 2011.

Universal newborn screening for severe combined immunodeficiency syndrome is being adopted increasingly around the country.

Severe combined immunodeficiency (SCIDS) is a syndrome caused by a spectrum of mutations in genes necessary for the normal development and function of T cells, and therefore B cells. Identification of newborns with these mutations allows for early hematopoietic stem cell transplantation and a vastly improved prognosis. The evidence for an improved outcome for those identified early comes from studies comparing the outcome in first cases in a family with those in subsequent siblings who are diagnosed and transplanted earlier in life (Blood 2011;117:3243-6).

In May 2010, U.S. Secretary of Health and Human Services Kathleen Sebelius announced the addition of SCIDS to the national Recommended Uniform Screening Panel. Thus far, pilot programs for universal newborn SCIDS screening have been implemented in five states: California, Louisiana, Massachusetts, New York, and Wisconsin, and also in Puerto Rico. Another eight states, Colorado, Delaware, Florida, Iowa, Michigan, Minnesota, North Carolina, and Rhode Island, are prepared to implement SCIDS Newborn Screening Programs in the near future.

There are several types of SCIDS. Deficiency of the common gamma chain of the T-cell receptor is the most common, affecting nearly 45% of all cases. This mutation of the "cg" (for common gamma chain) gene on the X chromosome results in very low T-lymphocyte and NK-lymphocyte counts but the B-lymphocyte count is high. Only males have this type of SCIDS, but females may carry the gene.

The second-most common type, adenosine deaminase (ADA) deficiency, is caused by mutations in a gene that encodes the ADA enzyme, which is essential for the metabolic function of a variety of body cells, but especially T cells. The absence of ADA leads to accumulation of toxic metabolic by-products within lymphocytes that cause the cells to die. Infants with this type of SCIDS have the lowest total lymphocyte counts of all, and the T, B and NK-lymphocyte counts are all very low.

Another, less common SCIDS type is deficiency of the alpha chain of the IL-7 receptor, in which the infant has B and NK cells, but no T cells. However, the B cells don’t work because of the lack of T cells.

Other less frequent types include deficiency of Janus kinase 3 (JAK3), in which the infants have lab values similar to X-linked SCIDS (T, B+, NK), and deficiencies in the CD3 or CD45 chains that play key roles in T-cell function.

The classic symptoms of SCIDS are recurrent severe infections, chronic diarrhea, and failure to thrive. Persistent mucocutaneous candidiasis is a common early finding, and opportunistic infections with normally nonpathogenic organisms, such as Pneumocystis jiroveci (formerly carinii) also occur. Attenuated vaccine organisms, rotavirus and varicella, may cause severe or fatal infection. About 10 cases SCIDS presenting with persistent diarrhea following rotavirus vaccine have been reported (Vaccine 2010;28:6609-12).

The strategy for newborn SCIDS screening is based upon polymerase chain reaction quantification of T-cell receptor excision circles (TRECs) – small circles of DNA created in T-cells during their passage through the thymus – from dried blood spots (DBS) on newborn screening cards. A normal number, based on an evaluation of 5,766 Wisconsin newborns, is 708 TRECs/3.2 mm DBS (Public Health Rep. 2010;125 [Suppl 2]:88-95).

A low TREC number implies abnormal thymic function. Children with SCIDS are expected to have near zero (the screening cutoff is 25 TREC/uL). Children with an abnormally low TREC count on screening should be followed by more formal testing of T-cell number, including naive cell markers and T-cell function (mitogen stimulation) if sufficient T cells are present.

When notified about a positive test, the physician should immediately refer the infant to a center for lymphocyte subset analysis to confirm or refute the diagnosis. These infants should be "isolated" within the home by avoiding young children and any potentially contagious contacts. Prophylaxis for Pneumocystis jiroveci pneumonia could be given if a delay in further testing is likely, as well as replacement therapy with immune globulin might be indicated if assessment of humoral immunity demonstrates hypogammaglobulinemia.

Live attenuated vaccines normally given by 2 months of age, including rotavirus, bacille Calmette-Guérin, and oral poliovirus vaccine should NOT be administered to the infant, and measles-mumps-rubella and varicella vaccines should not be administered to the infant’s caregivers or family.

In Wisconsin, the first state to offer universal newborn SCIDS screening, 0.05% (35) newborns out of a total 71,000 had positive tests and underwent confirmatory testing. Another 0.17% (119) had initial unsatisfactory test results that required repeat. Of 194,056 newborns screened in Massachusetts during 2008-2011, 4 were identified with SCIDS. This gives us a rate of approximately 1 in 50,000 live births. Importantly, two of those four were identified prior to exhibiting any symptoms. The oldest, who had the JAK3 defect but was never ill prior to receiving a stem cell transplant, is now more than 10 months post transplant and is doing well. The second, who has been transplanted and is at home, had been hospitalized and "very ill" at the time of the screening but had not received a diagnosis (of deficiency of common gamma chain).

The latter two have also been transplanted. One was sick by 10 days of age with classic SCIDS symptoms (thrush, febrile, failure to thrive) and was admitted. The fourth was reportedly healthy at the time of the report but had been seen for a weight check because the mother was worried. She had previously lost two children who had died at 4 months of age of pneumonia.

Although early in the adoption of SCIDS screening, the Massachusetts’ experience demonstrates that infants with SCIDS can be identified early, often before signs and symptoms are present. However, most abnormal tests are not caused by SCIDS or other immune deficits, which may also be identified early as a result of TREC screening.

Dr. Pelton is chief of pediatric infectious disease and also is the coordinator of the maternal-child HIV program at Boston Medical Center. He said he had no relevant financial disclosures. 

*This story was updated December 2, 2011.

Universal newborn screening for severe combined immunodeficiency syndrome is being adopted increasingly around the country.

Severe combined immunodeficiency (SCIDS) is a syndrome caused by a spectrum of mutations in genes necessary for the normal development and function of T cells, and therefore B cells. Identification of newborns with these mutations allows for early hematopoietic stem cell transplantation and a vastly improved prognosis. The evidence for an improved outcome for those identified early comes from studies comparing the outcome in first cases in a family with those in subsequent siblings who are diagnosed and transplanted earlier in life (Blood 2011;117:3243-6).

In May 2010, U.S. Secretary of Health and Human Services Kathleen Sebelius announced the addition of SCIDS to the national Recommended Uniform Screening Panel. Thus far, pilot programs for universal newborn SCIDS screening have been implemented in five states: California, Louisiana, Massachusetts, New York, and Wisconsin, and also in Puerto Rico. Another eight states, Colorado, Delaware, Florida, Iowa, Michigan, Minnesota, North Carolina, and Rhode Island, are prepared to implement SCIDS Newborn Screening Programs in the near future.

There are several types of SCIDS. Deficiency of the common gamma chain of the T-cell receptor is the most common, affecting nearly 45% of all cases. This mutation of the "cg" (for common gamma chain) gene on the X chromosome results in very low T-lymphocyte and NK-lymphocyte counts but the B-lymphocyte count is high. Only males have this type of SCIDS, but females may carry the gene.

The second-most common type, adenosine deaminase (ADA) deficiency, is caused by mutations in a gene that encodes the ADA enzyme, which is essential for the metabolic function of a variety of body cells, but especially T cells. The absence of ADA leads to accumulation of toxic metabolic by-products within lymphocytes that cause the cells to die. Infants with this type of SCIDS have the lowest total lymphocyte counts of all, and the T, B and NK-lymphocyte counts are all very low.

Another, less common SCIDS type is deficiency of the alpha chain of the IL-7 receptor, in which the infant has B and NK cells, but no T cells. However, the B cells don’t work because of the lack of T cells.

Other less frequent types include deficiency of Janus kinase 3 (JAK3), in which the infants have lab values similar to X-linked SCIDS (T, B+, NK), and deficiencies in the CD3 or CD45 chains that play key roles in T-cell function.

The classic symptoms of SCIDS are recurrent severe infections, chronic diarrhea, and failure to thrive. Persistent mucocutaneous candidiasis is a common early finding, and opportunistic infections with normally nonpathogenic organisms, such as Pneumocystis jiroveci (formerly carinii) also occur. Attenuated vaccine organisms, rotavirus and varicella, may cause severe or fatal infection. About 10 cases SCIDS presenting with persistent diarrhea following rotavirus vaccine have been reported (Vaccine 2010;28:6609-12).

The strategy for newborn SCIDS screening is based upon polymerase chain reaction quantification of T-cell receptor excision circles (TRECs) – small circles of DNA created in T-cells during their passage through the thymus – from dried blood spots (DBS) on newborn screening cards. A normal number, based on an evaluation of 5,766 Wisconsin newborns, is 708 TRECs/3.2 mm DBS (Public Health Rep. 2010;125 [Suppl 2]:88-95).

A low TREC number implies abnormal thymic function. Children with SCIDS are expected to have near zero (the screening cutoff is 25 TREC/uL). Children with an abnormally low TREC count on screening should be followed by more formal testing of T-cell number, including naive cell markers and T-cell function (mitogen stimulation) if sufficient T cells are present.

When notified about a positive test, the physician should immediately refer the infant to a center for lymphocyte subset analysis to confirm or refute the diagnosis. These infants should be "isolated" within the home by avoiding young children and any potentially contagious contacts. Prophylaxis for Pneumocystis jiroveci pneumonia could be given if a delay in further testing is likely, as well as replacement therapy with immune globulin might be indicated if assessment of humoral immunity demonstrates hypogammaglobulinemia.

Live attenuated vaccines normally given by 2 months of age, including rotavirus, bacille Calmette-Guérin, and oral poliovirus vaccine should NOT be administered to the infant, and measles-mumps-rubella and varicella vaccines should not be administered to the infant’s caregivers or family.

In Wisconsin, the first state to offer universal newborn SCIDS screening, 0.05% (35) newborns out of a total 71,000 had positive tests and underwent confirmatory testing. Another 0.17% (119) had initial unsatisfactory test results that required repeat. Of 194,056 newborns screened in Massachusetts during 2008-2011, 4 were identified with SCIDS. This gives us a rate of approximately 1 in 50,000 live births. Importantly, two of those four were identified prior to exhibiting any symptoms. The oldest, who had the JAK3 defect but was never ill prior to receiving a stem cell transplant, is now more than 10 months post transplant and is doing well. The second, who has been transplanted and is at home, had been hospitalized and "very ill" at the time of the screening but had not received a diagnosis (of deficiency of common gamma chain).

The latter two have also been transplanted. One was sick by 10 days of age with classic SCIDS symptoms (thrush, febrile, failure to thrive) and was admitted. The fourth was reportedly healthy at the time of the report but had been seen for a weight check because the mother was worried. She had previously lost two children who had died at 4 months of age of pneumonia.

Although early in the adoption of SCIDS screening, the Massachusetts’ experience demonstrates that infants with SCIDS can be identified early, often before signs and symptoms are present. However, most abnormal tests are not caused by SCIDS or other immune deficits, which may also be identified early as a result of TREC screening.

Dr. Pelton is chief of pediatric infectious disease and also is the coordinator of the maternal-child HIV program at Boston Medical Center. He said he had no relevant financial disclosures. 

*This story was updated December 2, 2011.