Sixteen patients were identified, one patient declined participation, and one passed away before study initiation. We included 14 patients (P), with a median age of 9.1 years (IQR 5.6–17.4; range 0–40), and four males (29%). Patients 1, 2, 7, and 11 of our cohort have been investigated in an earlier publication by Dalm et al. They correspond with the patients 2, 6, 5, and 4 . Twelve presented with an interstitial or terminal 11q deletion, two with 11q duplication, one interstitial, and one terminal. The extent and location of the involved regions varied widely, and in three patients’ additional chromosomal abnormalities were observed. During follow-up, one patient (P7) passed away (Table 1).
Clinically, all patients were immunized according to recommendations of the Dutch National Institute for Public Health and the Environment (RIVM) (https://rijksvaccinatieprogramma.nl/vaccinaties/vaccinatieschema). This does not involve varicella or rotavirus vaccines. Frequent infections were reported in the majority of patients, especially during childhood (12/14; 86%) and most often affecting upper and lower respiratory tract (RTI). These infections required frequent or prophylactic antibiotic treatment (7/12; 70%). Nine required ear-nose-throat (ENT) interventions such as ear tubes or adeno-tonsillectomy (9/14; 64%). Five required (5/14; 36%) therapy with inhaled β2 agonists, and three (3/14; 21%) were hospitalized for oxygen supplementation as supportive measures in case of infectious complications. Six patients (6/14; 43%) were on intravenous or subcutaneous IgRT because of hypogammaglobulinemia. All six patients on IgRT reported less infections and an improved physical condition (Table 2).
Complicated viral infections leading to hospitalization were confirmed for respiratory syncytial virus (RSV), picornavirus, para-influenza virus, and rhinovirus. Complicated and prolonged varicella zoster virus (VZV) infection occurred in 5/14 (36%). Four of 14 patients (29%) suffered from gastro-enteritis requiring hospitalization because of dehydration. Rotavirus was confirmed in two of these episodes. Fungal infections, most often in the diaper area or the nails, were reported in 4/14 (29%), persistent warts by two patients (2/14; 14%), and chronic eczema by six (43%), which resolved in patient P11 and 14 after IgRT was initiated.
Immunological laboratory results are presented in Table 3. Low leucocyte counts were seen in two patients (P2, 7): 2.8 and 3.2 × 10E9/L respectively (normal range 3.8–9.8 × E109/L). In five (36%), an absolute lymphopenia was observed (mean 0.78; absolute range 0.63–0.95 compared to age-dependent normal ranges).
The total numbers of T lymphocytes and B lymphocytes were normal or elevated in four patients (4/14; 29%), and all had IgG levels within the reference range. Total B lymphocyte counts were low in eight patients (57%, normal reference > 0.20 × 10E9/L). In five (5/8, 63%), T lymphocyte numbers were also low. Remarkably, all eight patients with low B lymphocyte counts presented with clinically relevant and increased number of infections, regardless of IgG levels (P1-3.7–10.14). The absence of an association between total number of B lymphocytes and function is illustrated in P11, who had a hypogammaglobulinemia from infancy with normal but steadily decreasing B lymphocyte count up to the age of 18 years (from 1.68 × 10E9/L at age 1, to 0.21 × 10E9/L at age 18). Low IgG levels were found in six patients (6/14; 43%), all corrected on IgRT. A concomitant low IgM (2/6) sometimes with combined low IgM and IgA (2/6) was seen in four (4/6, 67%). Only low IgM levels were seen in three patients (3/14; 21%), of whom two were < 2 years of age at time of inclusion. One patient had a low combined IgA and IgM (P12).
Total T lymphocyte counts were low in five patients (5/14, 36%). In one patient, both CD4 + and CD8 + T lymphocytes were decreased (1/5), while in two only CD4 + and in two only CD8 + T lymphocytes were decreased (normal reference CD4 + > 0.3 × 10E9/L, CD8 + > 0.2 × 10E9/L), resulting in an abnormal CD4:CD8 ratio in four (P1, 6, 8, 9). T lymphocyte function was evaluated in 13 patients using an OX40-based test. (Table 4) In general, only two patients showed a normal response to all stimuli (P6, 13). T lymphocytes from ten patients showed at least one abnormal response to the various stimuli (83%). For the viral agonists, T lymphocytes of all patients on IgRT failed in CMV response (5/5, 100%). Also, T lymphocytes of three patients (not on IgRT, but with a history of frequent viral upper airway and ENT infections) failed on CMV-response (P9-10, 12). As this assay is a functional test, diminished responses are either due to an intrinsic T lymphocyte defect, or due to the fact that a patient has not yet encountered CMV. Unfortunately, data of seroconversion were missing. Medical history was certain for 13 patients for VZV. Of these 13, three patients with a history of VZV infection demonstrated an abnormal T lymphocyte response (P3, 7, 2; 3/12; 25%). Despite the fact that all patients were vaccinated, an impaired response to the conjugated vaccine against tetanus was observed in two patients (P1&2; 2/12; 7%). All responded well to diphtheria and also to tuberculin. For the Toll-like receptor (TLR) agonists, five patients showed abnormal result after aspecific T cell stimulation with the superantigen SEB (through TLR2) or the mitogen PHA (through TLR4) (P3,1,7,2,9; 4/12, 33%).
Neutrophil granulocyte counts were normal in all 14 patients. Neutrophil granulocyte function was abnormal in four patients (P13, 7, 2, 9; 4/14, 29%). Two patients (P2, 7), who responded with a lower than normal oxidative burst, presented with a history of frequent infections and antibiotic usage, but none of the patients had opportunistic infections with microbes that are pathognomonic for neutrophil dysfunction, e.g., invasive S. aureus, Aspergillus, Nocardia, Burkholderia, or Serratia. Both patients are currently on IgRT. The two other patients (P9, 13) showed abnormal responses in chemotaxis, of whom patient 13 (P13) with a trisomy only reported chronic (diaper) dermatitis and ENT infections in infancy, and patient 9 (P9) reported an increased infectious burden in ENT and RT, but is not on IgRT due to normal IgG levels.
ETS1 and FLI1 involvement did not correlate to patients with immunodeficiency of B nor T lymphocyte dysfunction in our cohort (see Table 5).