Positive Family History, Infection, Low Absolute Lymphocyte Count (ALC), and Absent Thymic Shadow: Diagnostic Clues for All Molecular Forms of Severe Combined Immunodeficiency (SCID)

Abstract

Background: Severe combined immunodeficiency (SCID) is a syndrome uniformly fatal during infancy unless recognized and treated successfully by bone marrow transplantation or gene therapy. Because infants with SCID have no abnormal physical appearance, diagnosis is usually delayed unless newborn screening is performed.

Objective: In this study, we sought to evaluate the presenting features of all 172 patients with SCID transplanted at this institution over the past 31 years.

Methods: We reviewed original charts from 172 consecutive patients with classic SCID who received either T-cell-depleted HLA-haploidentical (N = 154) or HLA-identical (N = 18) nonablative related marrow transplants at Duke University Medical Center from 1982 to 2013.

Results: The mean age at presentation was 4.87 months. When there was a family history of early infant death or known SCID (37%), the mean presentation age was much earlier, 2.0 months compared with 6.6 months. Failure to thrive was common, with 84 patients (50%) having a weight less than the 5th percentile. The leading infections included oral moniliasis (43%), viral infections (35.5%), and Pneumocystis jiroveci (26%) pneumonia. The group mean absolute lymphocyte count (ALC) was 1454/cmm; 88% of the infants had an ALC less than 3000/cmm. An absent thymic shadow was seen in 92% of infants with electronic radiographic data available. An absence of T-cell function was found in all patients.

Conclusions: Infants with SCID appear normal at birth but later present with failure to thrive and/or recurrent fungal, viral, and bacterial infections. Low ALCs and an absent thymic shadow on chest x-ray are key diagnostic clues. The absence of T-cell function confirms the diagnosis.

Keywords: Absent thymic shadow; Failure to thrive infections; Lymphopenia; Severe combined immunodeficiency.

Fig 1. Percentage of SCIDs with each molecular defect

The total number and percentage of the cohort are included for each molecular type of SCID.

Fig. 2. Age at diagnosis for the various molecular types of SCID

The mean age at which the infants in each group were diagnosed is shown with standard error bars. N indicates the number of patients within each group.

Fig. 3. Absolute lymphocyte counts for molecular types of SCID

The mean absolute lymphocyte counts in each group at the time of diagnosis are shown with standard error bars. The normal lymphocyte counts are shown for healthy individuals (6 months of age).

Fig. 4

Fig. 4a. Absent thymic shadow for a patient with SCID. No thymic shadow in the cardiomediastinal contour is evident on the radiographic image Fig 4b. Present thymic shadow for a normal infant. A thymic shadow or “sail sign” is present in the right cardiomediastinal contour.

Fig. 4

Fig. 4a. Absent thymic shadow for a patient with SCID. No thymic shadow in the cardiomediastinal contour is evident on the radiographic image Fig 4b. Present thymic shadow for a normal infant. A thymic shadow or “sail sign” is present in the right cardiomediastinal contour.

Fig. 5

Fig. 5a. Levels of Immunoglobulins at diagnosis for each molecular type of SCID. Open bars indicate IgA (mg/dL), black filled bars indicate IgM (mg/dL) and gray filled bars indicated IgE (I.U./mL). Normal 6 month old infants’ immunoglobulin levels are shown for comparison. Fig. 5b. Absolute numbers of B, T and NK cells for each molecular type of SCID. Open bars indicate B cells, black filled bars indicate T cells and gray filled bars indicated NK cells. All values are lymphocytes/cmm. Normal 6 month old infants’ levels are shown for comparison. Fig. 5c. Lymphocyte proliferation at diagnosis for each Molecular Type of SCID. Patterned bars indicate media only controls. Black filled bars indicate Phytohemagglutinin (PHA) stimulated cells, open bars indicated Concanavalin (conA) stimulated cells and gray filled bars indicate Pokeweed mitogen (PWM) stimulated cells. Responses of normal 6 month old infants’ controls are shown for comparison.

Fig. 5

Fig. 5a. Levels of Immunoglobulins at diagnosis for each molecular type of SCID. Open bars indicate IgA (mg/dL), black filled bars indicate IgM (mg/dL) and gray filled bars indicated IgE (I.U./mL). Normal 6 month old infants’ immunoglobulin levels are shown for comparison. Fig. 5b. Absolute numbers of B, T and NK cells for each molecular type of SCID. Open bars indicate B cells, black filled bars indicate T cells and gray filled bars indicated NK cells. All values are lymphocytes/cmm. Normal 6 month old infants’ levels are shown for comparison. Fig. 5c. Lymphocyte proliferation at diagnosis for each Molecular Type of SCID. Patterned bars indicate media only controls. Black filled bars indicate Phytohemagglutinin (PHA) stimulated cells, open bars indicated Concanavalin (conA) stimulated cells and gray filled bars indicate Pokeweed mitogen (PWM) stimulated cells. Responses of normal 6 month old infants’ controls are shown for comparison.

Fig. 5

Fig. 5a. Levels of Immunoglobulins at diagnosis for each molecular type of SCID. Open bars indicate IgA (mg/dL), black filled bars indicate IgM (mg/dL) and gray filled bars indicated IgE (I.U./mL). Normal 6 month old infants’ immunoglobulin levels are shown for comparison. Fig. 5b. Absolute numbers of B, T and NK cells for each molecular type of SCID. Open bars indicate B cells, black filled bars indicate T cells and gray filled bars indicated NK cells. All values are lymphocytes/cmm. Normal 6 month old infants’ levels are shown for comparison. Fig. 5c. Lymphocyte proliferation at diagnosis for each Molecular Type of SCID. Patterned bars indicate media only controls. Black filled bars indicate Phytohemagglutinin (PHA) stimulated cells, open bars indicated Concanavalin (conA) stimulated cells and gray filled bars indicate Pokeweed mitogen (PWM) stimulated cells. Responses of normal 6 month old infants’ controls are shown for comparison.