HUMAN SEVERE COMBINED IMMUNODEFICIENCY (SCID): GENETIC, PHENOTYPIC AND FUNCTIONAL DIVERSITY IN 95 INFANTS. • 41

Abstract

Severe combined immunodeficiency (SCID) is a rare, fatal syndrome of diverse genetic etiology characterized by profound deficiencies of T and B cell function. In the U.S., it affects primarily male infants. Some are due to mutations in the genes encoding adenosine deaminase (ADA), the common gamma chain (Yc) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, or Janus kinase 3 (Jak3). However, for a significant proportion of SCID's, the molecular basis remains unknown. In an effort to identify unique phenotypic and/or functional features that could help identify fundamental causes, we analyzed the clinical, genetic and immunologic features of 95 SCID infants who presented consecutively to this institution between August of 1965 and December of 1995. Eighty (84%) were male and 15 (16%) female; 74 (78%) were white, 13 (14%) black, and 8 (8%) Hispanic. The 95 infants fit 7 categories: 16 (17%) were ADA deficient; 6 (6.3%) had Jak3 deficiency; 16 (17%) had autosomal recessive inheritance of unknown molecular cause; 1 (1.2%) had reticular dysgenesis; 1 (1.2%) had cartilage hair hypoplasia; 38 (40%) had X-linked SCID; and 17 (18%) (all males) had SCID of unknown type. Numbers of total lymphocytes and the various lymphocyte phenotypes distinguished the groups: ADA deficient SCID's had the lowest numbers of total lymphocytes; B cells were present in highest number and NK cells in lowest number in X-linked and Jak3-deficient SCIDs. Mean numbers of NK cells were highest in autosomal recessive and unknown types of SCID. All types were profoundly deficient in T cells. NK function was tested in 60 and found to be normal in 25. Although the family history was positive in only 34% of X-linked cases, it is likely that as many as two-thirds of the boys with SCID have mutations in Yc. The presence of NK function in ADA deficient, autosomal recessive, and some SCID's of unknown type, and abnormally low NK numbers and function in a majority of X-linked and Jak3-deficient SCID's implies that some molecular lesions affect T, B and NK cells (Yc and Jak3 mutations), but that others affect only T cells (ADA deficiency), and others T and B cells (possible recombinase abnormalities). The findings in this group of SCID's, the largest reported in the U.S., argue against a common lineage for T and NK cells and may provide clues as to the molecular bases of SCID in the 35 (37%) infants who did not have X-linked SCID, Jak3 deficiency or ADA deficiency.