We present 14 patients with a variety of 11q-disorders. We demonstrated an increased vulnerability to infections in almost all, but with varying clinical impact. Infections started in early infancy with recurrent and/or chronic ENT and airway infections, leading to high consumption of antibiotics, but also of inhalation therapy, hospitalization and the performance of ENT-surgery. Vulnerability for both viral and bacterial infections is illustrated by the finding that almost half of patients suffered from VZV infections with multiple skin lesions leading to secondary bacterial skin infections. Also, other skin manifestations, including eczema, (candida) dermatitis, fungal skin and nail infections, and warts, were encountered regularly.
We confirm B-lymphocyte dysfunction resulting in hypogammaglobulinemia in 64% (9/14) of patients in infancy or at older age, necessitating IgRT in 6/14, as well as low B-lymphocyte numbers (8/14). [7, 8] We underline the relevant finding that low IgG is not always accompanied by low total B-lymphocyte counts and vice versa, as demonstrated in patient 11 (P11). [7, 12]
We are the first to demonstrate that T-lymphocyte dysfunction occurs in the majority of patients with 11q-disorders. We showed that decreased T-lymphocyte counts or abnormal CD4/CD8-ratio occur in 43% of our cohort and abnormal in vitro T-lymphocyte activation in 12/13 patients (92%). Especially, the abnormal responses to stimuli such as PHA, SEB, Diphteria, CMV and VZV are clinically relevant. Unfortunately, we were not able to test seroconversion for CMV. The abnormal response may be due to naivety towards CMV, HSV1 or VZV in four patients, still giving an abnormal test result in 62%. Qualitative T-lymphocyte defects have been reported in cases before [8, 12, 27], but none of the applied stimulation tests in these studies was identical to the assays we used, which makes comparisons between results difficult. We conclude that a combined primary immunodeficiency regularly occurs, which was suggested in previous case-series. [7, 8, 28–31]
Finally, although we demonstrate a disturbed granulocyte function in vitro, these findings may be interpreted as mild or irrelevant as none of the patients experienced typical infections with e.g. Aspergillus or invasive S. Aureus. It therefore remains unclear whether the need for antibiotics due to a bacterial superinfection after VZV (P2,6,9,11,14; 56%) is due to hypogammaglobulinemia only, or combined with a potential granular dysfunction (only P2,11,14 are on IgRT). In a single patient on IgRT hospitalization for possible septicemia was documented. In this patient, an isolated abnormal response to NBT was found in granulocyte function analysis (P7). Our current results do not clearly support nor rule out the hypothesis that granulocyte dysfunction is responsible for the high incidence of infections, more research in this area is indicated .
Genetically, the role of ETS1 nor FLI1 gene did not correspond with abnormal B nor T-lymphocyte number or function in our cohort. While monosomy of ETS1 and FLI1 was seen in nine patients (P1-9) and trisomy in one (P14), an abnormal B or T-lymphocyte number was only seen in seven. On the other hand, low numbers T-lymphocyte numbers were found in 1 patient and abnormal T-lymphocyte function in 3 patients, respectively, while ETS1 and FLI1 were not deleted in these patients (See Table 5). This variable phenotype-genotype may be due to incomplete penetrance, as is suggested in congenital microdeletions in two families with an identical microdeletion in 11q24.2-11q24.3. One family demonstrated persistent lymphopenia and low IgG, the other did not.  But, this variability may also be due to other genes of interest that are located on 11q. It could be hypothesized that a whole gene cluster is involved in cell proliferation and differentiation and could play a role in development of the combined immunodeficiency in 11q patients. Our two patients with interstitial deletions not involving ETS1 and FLI1 also suffer from a combined immunodeficiency. Genes of interest to be considered as modifiers are ATM, CD3, CBL and THYN1.
More in detail, the ATM gene is located on 11q22.3 (OMIM #607585). Homozygous or compound heterozygous mutations cause ataxia-telangiectasia (AT).  AT is characterized by cerebellar ataxia, telangiectasia, predisposition to malignancy and immune defects, such as thymus hypoplasia, reduced IgG and IgA-levels, and sometimes accompanied by low IgM, lymphopenia and abnormalities in T-lymphocyte maturation. Besides the autosomal recessive AT-disorder, variant-AT with residual ATM protein expression and kinase-activity have been described as leading to a milder or more variable phenotype. Often, in variant-AT-patients only one truncating mutation in ATM is found, together with a compound missense, splice variant or leaky mutation. [33, 34] Most patients have elevated alpha-fetoprotein levels (AFP). No AFP-levels are known in 11q-disorder patients.
The cluster of CD3EAP, CD3D, CD3E, CD3G, CD3Z genes are all located on 11q23.2, and regulate the synthesis of T-lymphocyte antigen receptor chains: gamma, delta, epsilon and zeta.  The genes for the alpha and beta chains are located on other chromosomes. During development, the CD3 protein complex plays an important role in the transition of thymocytes from immature precursors to the final mature CD4 + or CD8 + T-lymphocytes.  Pathogenic variants in any of these genes may cause mild to severe blockage of this development at the stage of CD4+/CD8 + lymphocytes, resulting in reduced gamma-delta T- lymphocytes or even absent T-lymphocytes causing severe combined immunodeficiency. 
The CBL gene, located on 11q23.3 encodes for an E3 ubiquitin ligase acting as a regulator in the tyrosine kinase signaling pathway.  CBL plays a role in lymphocyte development and activation: in T-lymphocytes by regulating development of the thymocyte and thymic selection, in B-lymphocytes by regulating receptor signaling thresholds in order to stimulate B-lymphocyte maturation. [38, 39] Heterozygous pathogenic variants in patients may lead to juvenile myelomonocytic leukemia or Noonan-like syndrome with cardiac defects and lymphedema. Besides single nucleotide variants, Hanson et al. describe this entity as the result of uniparental isodisomy of 11q23 in this case, underlining the possible influence of this gene for the clinical phenotype of 11q-disorders. 
The THYN1 gene, located on 11q25, encodes for thymocyte nuclear protein 1, which is expressed in the thymus.  This gene may be involved in the induction of apoptosis or T-lymphocyte regulation.  As yet, we are not aware of diseases in humans caused by mutations this gene.
Our study has several limitations. Firstly, we describe only a small cohort of 14 patients in whom the genetic defects on chromosome 11q vary considerably and concurrent chromosomal abnormalities occur. This reflects medical practice as 11q-disorders are a rare continuous gene syndrome, but makes extrapolation of results to all 11q-disorder patients more challenging. In our cohort, seven patients had the ‘classical’ Jacobsen syndrome (11q23.3-terminal deletion syndrome). Three patients had additional chromosomal abnormalities, of whom patient 14 (P14) had a combination of partial trisomy of 11q and partial trisomy of 22q, also referred to as Emanuel syndrome. No clear primary immune deficiency has yet been reported to occur in Emanuel syndrome, but frequent ENT-infections are reported in cases and are mentioned by the Unique patient organization to occur “in a minority”.  The trisomy of 11q23.3 in our patient may give rise to hypogammaglobulinemia and T-lymphocyte dysfunction, but the 22q11 region can also cause T-lymphocyte dysfunctions or T-lymphocytopenia as is seen in other chromosome 22q abnormalities and in one case-report of a child with a 22q11.2 microduplication.  No hypogammaglobulinemia was seen in this child. [47, 48] We therefore feel that it is unclear whether the hypogammaglobulinemia and abnormal T-lymphocyte function in our patient (P14) are only due to terminal 11q-duplication or that the concurrent 22q11-duplication may also play a role. We decided to include this patient in our cohort, as the effect of 11q cannot be ruled out and it is essential to be aware that 11q-trisomy patients with Emanuel syndrome may be prone to a combined primary immune deficiency as well. More research in this specific patient group is needed.
Also, although a study design with a standardized protocol was followed, we were not able to avoid missing values with regard to clinical data and laboratory test results. The large volumes of blood necessary for laboratory tests certainly played a role in this regard. Still, we think that study results are applicable to other 11q-patients as specific clinical symptoms and immunological laboratory results were more frequently observed than expected in the general population.
Lastly, we were not able to organize serological testing for CMV infections retrospectively due to ongoing IgRT or lack of stored plasma. Therefore, it is more difficult to draw definite conclusions on the results of the OX40-based T-lymphocyte function test. We consequently recommend treating physicians to test EBV, CMV seroconversion before T-lymphocyte function is tested or before IgRT is started to enable more clear conclusions in the near future.
Overall, we conclude that patients with partial 11q-deletion or 11q-trisomy regardless of involvement of genes as ETS1 or FLI1, have a risk of a combined primary immunodeficiency, consisting of both quantitative and qualitative defects. We therefore recommend regular immunological screening by testing IgG, IgA, IgM, response to immunization and B and T-lymphocyte counts in all patients with 11q-disorders. It is important to realize that lymphocyte dysfunction does not always correlate with B- and T-lymphocyte count. Immunological abnormalities may develop over time and need repetitive testing, or may present at birth. When newborn screening by T-lymphocyte receptor excision circle (TREC) is performed, T-lymphopenia should promptly lead to further investigation involving 11q-analysis. . In case of a humoral immunodeficiency, prophylactic antibiotics and/or IgRT should be considered based on number and severity of infectious complications and potential end-organ damage, including bronchiectasis. In case of chronic fungal infections, especially affecting skin or nails, local treatment or systemic prophylaxis is indicated. Physicians should be aware that fungal infections and prolonged viral infections may still occur while on IgRT therapy.
As many questions remain in this intriguing immunological field, future research should focus on further pathophysiological understanding of this combined immunodeficiency in patients with 11q-disorders which can be seen as a model to identify modifiers of immunological function in various disorders. Focus should be on other candidate genes, that can influence the immunological dysfunctions seen in patients with 11q-disorders.