Complete DiGeorge syndrome: persistence of profound immunodeficiency.

OBJECTIVE: DiGeorge syndrome is characterized by developmental defects of the heart, parathyroid glands, and thymus. The objective of this study was to determine whether T-cell function spontaneously improves in patients with DiGeorge syndrome who have profoundly depressed T-cell proliferative responses to mitogens at presentation, regardless of the T-cell count. STUDY DESIGN: We conducted a retrospective chart review of eight patients with DiGeorge syndrome who had no proliferative responses to mitogens on presentation. RESULTS: Despite lack of responsiveness of the patients' peripheral blood lymphocytes to mitogens, T cells were occasionally detected, and the patients' cells often responded to IL-2 and in mixed lymphocyte reactions. Unresponsiveness to mitogens and clinical immunodeficiency persisted without immune-based therapy. One patient is alive and well after immunoreconstitution from thymic transplantation. The others either died early of complications of their disease such as gastroesophageal reflux with aspiration (2 patients) or infection (2 patients) or died after attempts at immunorestorative therapy with IL-2, thymus transplantation, or bone marrow transplantation (3 patients). CONCLUSION: Eight patients with DiGeorge syndrome who were first seen with no mitogen responsiveness did not improve spontaneously. We recommend HLA-identical bone marrow transplantation or thymic transplantation for these patients as soon as the diagnosis is confirmed.

Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants.

OBJECTIVE: To determine the relative frequencies of the different genetic forms of severe combined immunodeficiency (SCID) and whether there are distinctive characteristics of the particular genotypes. STUDY DESIGN: The demographic, genetic, and immunologic features of 108 infants with SCID who were treated consecutively at Duke University Medical Center were analyzed. RESULTS: Eighty-nine subjects were boys and 19 were girls; there were 84 white infants, 16 black infants, and 8 Hispanic infants. Forty-nine had X-linked SCID with mutations of common cytokine receptor gamma chain (gamma c), 16 had adenosine deaminase (ADA) deficiency, 8 had Janus kinase 3 (Jak3) deficiency, 21 had unknown autosomal recessive mutations, 1 had reticular dysgenesis, 1 had cartilage hair hypoplasia, and 12 (all boys) had SCID of undetermined type. Deficiency of ADA caused the most profound lymphopenia; gamma c or Jak3 deficiency resulted in the most B cells and fewest natural killer (NK) cells; NK cells and function were highest in autosomal recessive and unknown types of SCID. CONCLUSIONS: Different SCID genotypes are associated with distinctive lymphocyte characteristics. The presence of NK function in ADA-deficient, autosomal recessive, and unknown type SCIDs, and low NK function in a majority of gamma c and Jak3 SCIDs indicates that some molecular lesions affect T, B, and NK cells (gamma c and Jak3), others primarily T cells (ADA deficiency), and others just T and B cells.

Correction of purine nucleoside phosphorylase deficiency by transplantation of allogeneic bone marrow from a sibling.

Deficiency of the purine salvage pathway enzyme purine nucleoside phosphorylase causes a combined immunodeficiency and neurologic abnormalities and is usually fatal in childhood. We report the first successful transplantation of bone marrow from a sibling with identical class II human leukocyte antigens in this condition, demonstrating correction of both lymphocyte metabolic and functional abnormalities.

Elevated IgA concentration in milk produced by mothers delivered of preterm infants.

Concentrations of immunoglobulins G, M, and A were measured by double-antibody radioimmunoassay in morning milk samples collected during the first month postpartum from 35 mothers delivered of preterm infants and 14 mothers delivered of term infants. Mean concentrations of IgG (1.8, to 2.8 mg/gm protein) and IgM (2.8 to 11.7 mg/gm protein) were similar in milk from both groups of mothers. In contrast, IgA was present in significantly higher concentrations throughout the first month postpartum in milk from mothers delivered of preterm infants than in milk from those giving birth at term (P less than 0.01). To determine the effect of milk flow on IgA concentration, IgA was also measured in complete 24-hour milk collections; milk from mothers with preterm deliveries again contained significantly higher concentrations of IgA than milk from mothers with term deliveries (P less than 0.01). This higher IgA concentration was not secondary to method of milk expression. The concentration of IgA was found, however, to vary inversely with milk volume (P less than 0.01). Although mean values of milk volumes for the groups were not statistically different, the overall lower volumes of milk produced by mothers giving birth preterm resulted in comparable total IgA production per 24 hours. There were no differences in serum IgA concentrations of preterm infants fed their own mother's milk and comparable infants fed a cow milk formula, suggesting that IgA in milk is not absorbed from the intestine in significant amounts.

Serum IgD concentrations in normal infants, children, and adults and in patients with elevated IgE.

Earlier studies of serum immunoglobulin D concentrations were hampered by the insensitivity of single radial diffusion, since most normal individuals have IgD concentrations in a range below or near the limit of sensitivity of that method. Using a sensitive double-antibody radioimmunoassay, we measured serum IgD in normal individuals from 28 weeks' gestational age to 70 years of age and in several groups of diseased individuals, many of whom had elevated serum IgE concentrations. The group mean serum IgD concentration in children one to 20 years of age was 13.65 IU/ml. Premature and term neonates had levels that did not differ significantly from each other (0.22 and 0.14 IU/ml, respectively), but that were far lower than serum IgD concentrations in normal children one to 20 years of age (P = less than 10-9), indicating that mature levels of IgD are achieved sometime during the first year of life. Normal adults aged 21 to 70 years, atopic children with or without eczema, children with serum IgE values greater than 2,000 IU/ml, and children with cystic fibrosis all had group mean IgD concentrations that did not differ significantly from that of normal children. In contrast, 20 patients with the hyper IgE syndrome had a mean serum IgD concentration of 94.22 IU/ml, significantly higher than the normal or any other group mean (P = less than 10-5).

Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up.

The clinical and immunologic features of 11 patients with transient hypogammaglobulinemia of infancy are reported and compared with those of the 16 patients previously reported. Seven were re-evaluated three to ten years after infancy. Two groups were identified: six who were found by screening relatives of patients with other types of immunodeficiency and five whose sera were sent because the patients were having frequent or unusual infections. Those in the first group had no significant health problems during early infancy or childhood. In the second group recurrent infection was a problem during early infancy but not in later years; the latter patients also frequently had other health problems. Serum immunoglobulin concentrations were entirely normal at the last evaluation in five of the six THI patients with immunodeficient relatives. In the second group, the concentrations of one or more immunoglobulin classes, although greatly increased, were still below the normal range. All 11 patients were found to be capable of synthesizing antibodies to human type A and B erythrocytes and to diphtheria and tetanus toxoids, usually by 6 to 11 months of age, and well before immunoglobulin concentrations became normal. Lymphocyte studies in vitro showed no abnormalities in the percentages of cells in the different subpopulations or in their responses to the mitogens. None of the patients was given immune serum globulin replacement therapy and none experienced serious infections during their period of follow-up. The finding of only 11 cases of THI among over 10,000 patients whose sera were sent for immunoglobulin studies over a 12-year period suggests that this is not a common entity.

Severe combined immunodeficiency with leukopenia (reticular dysgenesis) in siblings: immunologic and histopathologic findings.

The hematologic and histologic features of two, nontwin, male siblings with severe combined immunodeficiency and variable granulocytopenia are compared to the four previously reported cases of reticular dysgenesis. These sibs died at 50 and 3 days of age, respectively, with Pseudomonas sepsis and congenital cytomegalovirus infection, respectively. A maternal uncle has selective IgA deficiency. Cord blood from the second sib contained a normal percentage of E-rosetting lymphocytes; however, these lymphocytes failed to respond to mitogenic stimulation in vitro. Erythrocyte and lymphocyte levels of adenosine deaminase were elevated in the father and the second sib. Serum immunoglobulin concentrations were low in both siblings.