T-B-NK+ SCID: Clinical manifestations, diagnosis, and treatment
- Morton J Cowan, MD
Morton J Cowan, MD
- Professor Emeritus of Pediatrics
- University of California, San Francisco
An extreme form of severe combined immunodeficiency disease (SCID) is the T cell negative (T-), B cell negative (B-), natural killer cell positive (NK+) SCID phenotype, which accounts for about one-quarter of all cases of SCID. Children with T-B-NK+ SCID present early in life with serious infections, failure to thrive, low to absent T and B cell numbers and function, and normal numbers and function of natural killer (NK) cells.
Autosomal recessive defects in several genes, all involved in V(D)J recombination that randomly combines variable, diverse, and joining gene segments in lymphocytes, result in this form of SCID. Some of the proteins encoded by these genes are also involved in DNA repair. Defects in these genes are associated with growth and developmental abnormalities and radiation/chemotherapy sensitivity.
The clinical manifestations, diagnosis, and treatment of T-B-NK+ SCID are reviewed here. The pathogenesis, genetic defects, and radiation sensitivity are discussed in detail separately. An overview of SCID and the different forms of SCID are also presented separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "T-B-NK+ SCID: Pathogenesis and genetics".)
T-B-NK+ SCID accounts for 20 to 30 percent of all cases of SCID [1-4]. The overall estimated incidence of SCID in the United States is 1:58,000, based upon data from universal newborn screening (NBS) in 10 states plus the Navajo Nation over a four-year period . The X-linked form of SCID accounted for only 19 percent of the identified cases, with the remainder comprised of autosomal recessive forms of SCID. Data from retrospective studies of relatively limited numbers of patients prior to the advent of NBS for SCID suggested there was an incidence of 1:500,000 for autosomal recessive SCID among outbred populations and 1:10,000 for first cousin marriages . Based on the NBS data, it appears that the true incidence for autosomal recessive SCID is closer to 1:72,500, with significantly higher rates in certain founder populations. As an example, the estimated incidence of Athabascan SCID (SCIDA) in the Navajo population is approximately 1:2000 livebirths . (See "Severe combined immunodeficiency (SCID): An overview" and "Newborn screening for primary immunodeficiencies".)
In general, children with classic T-B-NK+ SCID present early in life with features typical of all children with SCID, including serious infections and failure to thrive. In addition, many of the specific defects are accompanied by unique clinical features. There is also a theoretical increased risk of malignancy for those with defects that also involve DNA repair. Increased incidence of malignancy has not been observed in children with the classic phenotype of Artemis-deficient SCID (ART-SCID) , although Epstein-Barr virus (EBV)-associated lymphoma was reported in two children with ART-SCID and mutations of the distal exon of DLCRE1C (DNA cross-link repair protein 1C) that left a partially functioning protein and the presence of B cells . (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations'.)
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- CLINICAL MANIFESTATIONS
- Clinical variants
- - Omenn syndrome phenotype
- - Athabascan (SCIDA) phenotype
- - Other radiation sensitive SCID
- LABORATORY FINDINGS
- Evaluation for radiation sensitivity
- DIFFERENTIAL DIAGNOSIS
- Management prior to diagnosis and transplantation
- Hematopoietic cell transplantation
- - Outcomes
- - Preconditioning regimens
- General approach in T-B-NK+ SCID
- Approach in radiation-sensitive SCID
- Gene therapy