Late-onset Combined Immunodeficiency Research Articles

Severe gastrointestinal cytomegalovirus infection in a patient diagnosed with late onset combined immunodeficiency

Late onset combined immunodeficiency (LOCID) is a rare variant of common variable immunodeficiency (CVID), typically affecting adult patients who present with opportunistic infections (OI) and/or low CD4+ T lymphocytes. Diagnostic delay is common due to the rareness of this entity, increasing morbidity and mortality. We report on a 66-year-old male who developed a severe gastrointestinal cytomegalovirus (CMV) infection, refractory to antiviral treatment and anti-cytomegalovirus specific human immunoglobulin administration, with a fatal outcome due to an undiagnosed LOCID.

ATYPICAL PRESENTATION OF X-LINKED IL-2 RECEPTOR GAMMA MUTATION CHARACTERIZED BY RECURRENT CUTANEOUS AND GENITAL WARTS

<h3>Introduction</h3> Combined immunodeficiency syndromes constitute a group of inherited immune disorders characterized by diminished lymphocyte number and function. Late onset combined immunodeficiency can be difficult to diagnose as patients initially have a less severe phenotype compared to their SCID counterparts. Here we describe a case of an atypical presentation of late onset combined immunodeficiency due to a hemizygous IL-2 receptor gamma (IL-2Rg) mutation. <h3>Case</h3> The patient is a 41-year-old male with a 25-year history of recurrent cutaneous warts of the hands and feet. At the age of 36 he developed perianal condylomata acuminata that later developed into squamous cell carcinoma. He reported no history of recurrent sinopulmonary infection, atopic disease, or autoimmunity. Immune phenotyping demonstrated normal B- and NK cell counts but CD4+ T-cell lymphopenia with poor proliferation to antigenic stimulation. Total immunoglobulins were normal but without vaccine responses. Genetic testing revealed a hemizygous variant of unknown significance in IL2Rg gene. NK cell cytotoxicity assay showed suboptimal cytotoxicity and CD8+ T-cells exhibited impaired pSTAT5 confirming the likely pathogenicity of this variant. <h3>Discussion</h3> IL-2 plays a critical role in the activation among a host of T-cells and NK cells. Deleterious mutations of the IL-2Rg gene are associated with X-linked SCID displaying a T−B+NK− phenotype. Milder phenotypes have been reported with hypomorphic mutations of IL-2Rg, with a recent report describing recurrent cutaneous warts and respiratory infections in two brothers with splice site mutations. This patient's chronic HPV infection resulted in malignant sequalae, highlighting the importance for awareness of the phenotypic heterogeneity that can occur in X-linked SCID.

Lymphoma as an Exclusion Criteria for CVID Diagnosis Revisited.

Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.

Invasive Candidiasis in a Case of Late onset Combined Immunodeficiency

Late onset combined immunodeficiency (LOCID) is a recently described variant of common variable immunodeficiency (CVID), involving adult patients presenting with opportunistic infections and/or low CD4+ lymphocyte counts. We present a case of a 38-year, male, unmar-ried, who presented with history of abdominal pain and distension, jaundice and altered sleep- wake cycle suggestive of Decompensated liver disease. Patient developed multiple opportunistic infections in ward course which on further work up turned out to be Late onset combined immunodeficiency. Clinicians should be aware of LOCID, which could be confused with HIV infection/AIDS or idiopathic CD4 lymphocytopenia.

Assessing Severity in Common variable immune deficiency (CVID) using the "Ameratunga Score- AS"

A proportion of patients with CVID evolves with a prominent T cell defect leading to a more severe phenotype with opportunistic infections, being considered by some experts as Late Onset Combined Immunodeficiency (LOCID). The aim of the study was to assess the severity of CVID using the “AS”, which focuses mainly on cumulative damage to organs such as result of infections, autoimmunity or inflammation.

All Patients With Common Variable Immunodeficiency Disorders (CVID) Should Be Routinely Offered Diagnostic Genetic Testing.

Common Variable Immunodeficiency Disorders (CVID) are a rare group of primary immunodeficiency disorders (PIDs) where late onset antibody failure leads to immune system failure (1). Onset of symptoms can occur from early childhood to the eighth decade or later (2). Current estimates suggest a prevalence between 1: 25 000 to 1: 100 000 in Caucasians (3, 4). For reasons that are unclear, CVID appears to be less frequent in Asian and African populations, although there may be ascertainment bias. The majority of patients with CVID present with recurrent and severe infections. Untreated, patients are predisposed to chronic suppuration of the respiratory tract, often resulting in chronic sinus disease and bronchiectasis. Approximately 25% of CVID patients suffer autoimmune or inflammatory sequelae, consequent to immune dysregulation (5). There is also an increased risk of malignancy (6). There is no single clinical feature or laboratory test, which is pathognomonic for CVID. The identification of CVID therefore relies on diagnostic criteria. There are currently three new sets of diagnostic criteria for CVID (7–9). The Ameratunga et al. (7) criteria require symptomatic primary hypogammaglobulinemia with relevant laboratory tests to establish the diagnosis. The threshold for IgG was set at 5 g/l for adults. The revised European Society for immunodeficiencies (8) are similar to the Ameratunga et al. criteria. The most recent International Consensus Document (9) CVID criteria claim to be able to make a definite diagnosis on the basis of a single abnormal vaccine challenge result in a patient with primary hypogammaglobulinemia (9). The latter two criteria have set the threshold for IgG at 2 sd below the mean. Although immunoglobulin levels do not follow a Gaussian distribution (10), this is generally accepted as an IgG below 7 g/l. These criteria also exclude late onset combined immunodeficiency (LOCID) from the diagnosis. The immunoglobulin levels are also required to be repeated in these latter criteria. There is ongoing debate about the utility these diagnostic criteria, the variability of IgG levels over time, the unreliability of vaccine challenge responses and flow cytometry in the diagnosis of CVID. As discussed below, this variability in protein-based assays is a strong argument for genetic testing of all patients with a CVID phenotype.

Progressive Immunodeficiency with Gradual Depletion of B and CD4⁺ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2).

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4+ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27+ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

Assessing Disease Severity in Common Variable Immunodeficiency Disorders (CVID) and CVID-Like Disorders.

Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic primary immune deficiency (PID) in adults. Current estimates suggest a prevalence of ~1:25,000, although a recent study has suggested an even greater frequency than previous estimates (1). The majority of CVID patients suffer recurrent infections because of late onset antibody failure (LOAF) leading to immune system failure (ISF). Current criteria do not allow CVID to be diagnosed before 4 years although some patients have symptoms dating back to infancy. Most patients experience recurrent or severe bacterial infections and less commonly autoimmunity as a result of CVID. Some patients present with a sarcoidosis-like disorder or enteritis (2, 3). A proportion of patients with CVID have a prominent T cell defect leading to severe viral or opportunistic infections. These patients have been deemed to have late onset combined immunodeficiency (LOCID) (4). LOCID is currently separated from CVID although I have argued LOCID should be included as a subset of CVID (5). In spite of major progress in the last decade, the genetic basis of CVID is unknown in most patients. A causative mutation has been identified in up to 30% (6). If a causative defect is identified, these patients are removed from the umbrella diagnosis of CVID and are reclassified as having a CVID-like disorder caused by a specific mutation. To fulfill a diagnosis, all current CVID criteria require exclusion of other immunodeficiencies including NFKB1, NFKB1, CTLA4 etc. It is however likely earlier series of patients with CVID included many with CVID-like disorders, whose mutations were undiscovered. We have recently discovered new genetic defects in two NZ families with CVID-like disorders. In the first family, we have confirmed the existence of quantitative epistasis in humans (7). Epistasis is the non-linear, synergistic interaction of two or more genetic loci either leading to a much more severe disorder or a novel phenotype (8, 9). The existence of epistasis was first predicted by William Bateson in 1909 but has remained highly controversial because of the lack of well characterized examples in humans (10). In this family, the synergistic interaction of TNFRSF13B/TACI and TCF3 mutations resulted in a severe immunodeficiency and systemic lupus erythematosus (SLE) in the proband (Figure ​(Figure1).1). Other members of the family who have various permutations of the two mutated genes had a milder phenotype, which was reflected in their in vitro B cell differentiation and antibody production studies (7). Open in a separate window Figure 1 Family with a digenic CVID-like disorder caused by epistatic interactions of TNFRSF13B/TACI and TCF3 genes. The proband (arrow) suffers from both a severe immunodeficiency as well as SLE. Other members are as described in our previous publications including a mild symptomatic brother (II.3) with severe hypogammaglobulinemia caused by homozygous C104R mutations of the TNFRSF13B/TACI gene. CDSS, CVID disease severity score; CS, clinical score. The CS was suggested as means of determining eligibility for SCIG/IVIG but we have used it as a surrogate marker of disease severity (5, 7, 11).

Campylobacter infection in adult patients with primary antibody deficiency

Campylobacter infection in adult patients with primary antibody deficiency

Keeping it in the family: the case for considering late-onset combined immunodeficiency a subset of common variable immunodeficiency disorders

ABSTRACTIntroduction: Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune defect in adults. Within the broad spectrum of CVID, a proportion of patients present with a predominant T cell phenotype associated with increased mortality. These patients are termed late-onset combined immunodeficiency (LOCID) and are currently separated from patients suffering from CVID.Areas covered: We have recently codiscovered a new CVID-like disorder caused by mutations of the NFKB1 gene. Members of this non-consanguineous New Zealand kindred have a very diverse spectrum of phenotypes in spite of carrying the identical mutation. The proband appears to have the autoimmune variant. The proband’s recently deceased sister best matched LOCID while other family members are less severely affected, including one asymptomatic adult brother, who has an affected daughter. Differences in genetics was one of the main arguments for separating these disorders in the past.Expert commentary: Given the recent advances in the understanding of the genetic basis of these conditions, we present the case that LOCID should now be considered a subset of CVID, rather than a separate disorder. At a clinical level, this distinction is less important but it is imperative these patients are carefully evaluated, the relevant complications are treated, and they are offered prognostic information.

PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects

V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation. We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies. We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes. The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective invivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity duringprehematopoietic stem cell transplantation conditioning.

All IBD is Not Necessarily Sporadic IBD; A Case of Primary Immunodeficiency Mimicking Small Bowel Crohnʼs Disease

The gastrointestinal (GI) tract is the largest immunological organ in the body. The GI tract contains majority of the lymphocytes and produces large amounts of immunoglobulin, protecting us from exposure to pathogens. There are over 150 heterogeneous primary immunodeficiencies and most of them are inherited. Immune defects can occur in the T cell line (cellular), B cell line (humoral), or both T and B cell lines. Dysfunction in immunity can lead to mucosal inflammation and GI distress. Thus, it is not uncommon for immunocompromised patients to present with GI symptoms. Immunocompetent and immunocompromised patients with gastrointestinal diseases can present with similar symptoms. However, immunocompromised patients have distinct histologic features and do not respond to conventional therapies. Therefore, it is critical for gastroenterologists to correctly diagnose and treat patients with immunodeficiency. Therapy for primary immunodeficiency: antibiotics, immunoglobulins, and rarely bone marrow transplantation. Herein, we report a 63-year-old male who was transferred from an outside hospital (OSH) for evaluation of Crohn Disease refractory to steroids and anti-TNF therapy. OSH work up revealed that this patient had recent exposure to Giardia. On admission, the patient was severely malnourished (albumin 0.9) with diffuse anasarca. He had multiple vitamin deficiencies due to malabsorption. MRE revealed active inflammatory small bowel disease. His hospital course was complicated by multiple infections, requiring intubation and broad spectrum antibiotics. Labs further revealed CD4 count 235, decreased absolute B cells, decreased immunoglobulins, decreased T regulatory cells, and absent NK function, suggestive of late onset combined immunodeficiency. His jejunal biopsies appeared similar to graft-versus-host disease. His biopsies were not consistent with Crohn Disease, lymphoma, or autoimmune enteropathy. He was started on monthly IVIG and sirolimus with partial recovery of his NK function. His infections resolved and he was discharged with TPN to rehab. Whole genomic sequencing was sent to determine a possible genetic link to his disease and is currently pending. This case demonstrates the importance of incorporating basic immunological work up in the assessment of patients with gut inflammation. It also suggests that individuals who present with an infection followed by gut inflammation may be more likely to have an immunodeficiency as opposed to sporadic IBD.

Abstract 3689: Jak3 mutations in colorectal neoplasia- Preliminary data on a not so silent minority

Abstract As a tumorigenesis model, colorectal cancer is associated with multiple gene mutations accumulating progressively but also has mutations that may alter disease course and provide a therapeutic target. Good examples of this are EGFR and VEGF. In melanoma, PD-1 interactions involving the immunobiome are therapeutically important. We conducted a study to detect potential mutations that might enhance therapy in colorectal cancer guided by expression of p87, a product of innate immune system Paneth cells. Methods: Adnab-9 immunohistochemistry or ELISA was used to define significant p87 Adenoma-associated antigen field effects (FE) in 10 patients with &amp;gt;1cm large high grade dysplastic adenomas (LHiGDA) and 3 with smaller high grade dysplastic adenomas (SHiGDA). We postulated that SHiGDA are not immunologically recognized by host defenses leading to negative outcomes. We used Ion Torrent™ sequencing (ITS) to find mutations in DNA (QiaAmp kit) extracted from 4 normal-appearing colonic segments taken from 1 patient in each group. Novel mutations found on ITS would then be sought using PCR with appropriate primers and subsequent sequencing of the PCR product circulating DNA extracted from available serum samples. These samples were taken from the Large- and SHiGDA groups described above and from 17 patients undergoing colonoscopy for diverse indications. Results: p87 FE were found in 40% of 10 LHiGDA and 0% of 3 SHiGDA patients. The ITS in the 2 representative patients showed unique mutational fields in: KRAS, APC, p53 in the LHiGDA and Jak3, PIK3Ca, p53, APC in the SHiGDA patient, both of whom lacked p87 FE. PCR using the Jak3 primers used in the ITS and subsequent sequencing revealed the same non-synonymous mutation in the serum of a FAP patient after colonic resection and an additional colonic segment of the selected ShiGDA patient but not in his serum. Other Jak3 mutations were found in 1 of 8 LHiGDA, 1 (the selected patient) of 3 SHiGDA, 1 of 7 patients with FAP and 1 of 10 colonoscopy patients with a family history of colorectal cancer with a FE and an untoward outcome. The selected SHiGDA patient subsequently contracted and died of NSCLC adenocarcinoma. The positive LHiGDA and FAP patients had a severely dysplastic anal condyloma and severe pancreatitis, respectively. Overall, the non-synonymous mutation occurring in the non-FAP SHiGDA patient occurred in the absence of p87 FE. Conclusions: In this pilot study we demonstrate the presence of Jak3 mutations likely associated with the lack of p87 expression in patients with high grade dysplastic adenomas and 1 FAP patient. Most of these patients had a clinical course which may have differed from their group members suggesting an altered immune system milieu. If confirmed in SHiGDA and FAP, Jak 3 mutations, associated with the SCID and late onset combined immunodeficiency, may allow for intervention with currently available medications to potentially avert a deleterious clinical outcome. Citation Format: Martin Tobi, Xiaoping Zhao, Darshana Jhala, Rebecca Rodriguez, Fadi Antaki, Edi Levi, Paula Sochacki, John Lieb, MaryAnn Rambus, Tapan Ganguly, Martin Bluth, Michael J. Lawson. Jak3 mutations in colorectal neoplasia- Preliminary data on a not so silent minority [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3689. doi:10.1158/1538-7445.AM2017-3689

Exclusion of Patients with a Severe T-Cell Defect Improves the Definition of Common Variable Immunodeficiency

In 2014, the European Society for Immune Deficiencies (ESID) revised the common variable immunodeficiency (CVID) diagnosis criteria by incorporating new clinical and biological markers. The new definition appeared more restrictive but had not yet been evaluated in a large cohort of patients. The objective of this study was to evaluate the impact of this new definition in a large cohort of patients with primary hypogammaglobulinemia. Evaluation of 3 different CVID definitions (ESID/Pan-American Group for Immunodeficiency [PAGID] 1999, ESID 2014, DEFI 2015) in 521 patients included in the French DEFI study with a diagnosis of primary hypogammaglobulinemia. Using the ESID/PAGID 1999 definition, 351 patients were classified as CVID. The new ESID 2014 definition excluded 62 (18%) patients. Most of them (n= 56; 90%) had a less severe disease, whereas 6 (10%) presented with a severe disease with major T-cell defect. We propose different criteria (occurrence of opportunistic infection or very low naive CD4+ T-cell count) to define this population with severe T-cell defect. Sixty-two patients fulfilled these criteria, represented 20% of the initial CVID population but accounted for 77% of the deaths, with a 5-year overall survival of 67.6% (95% confidence interval, 51.0-79.6), and were considered as late onset combined immunodeficiency (LOCID). The new ESID definition for CVID still fails to exclude a large number of patients with severe T-cell defect. We propose a new definition (DEFI 2015) that excluded more patients with a T-cell defect and consider these patients as LOCID. This population has a poor outcome and should be considered as a distinct group requiring specific care.

Autologous Human Cytomegalovirus-Specific Cytotoxic T Cells as Rescue Therapy for Ulcerative Enteritis in Primary Immunodeficiency

Patients affected by primary immunodeficiency usually undergo a wide range of infections, including reactivation of latent ones. Here we report two cases suffering from late-onset combined immunodeficiency in which ulcerative enteritis due to human Cytomegalovirus caused a life-threatening malabsorption syndrome. The assessment of the viral load was carried out on both blood and mucosal samples by quantitative real-time polymerase chain reaction assay. The generation of autologous virus-specific cytotoxic T cell lines was performed according to Good Manufacturing Practice protocol after peripheral blood mononuclear cells were collected through a single leukapheresis. In both patients, the viral load resulted negligible in peripheral blood, but very high in mucosal specimens (range 1.064 - 1.031.692 copies/10(5) cells). After two rounds of antiviral therapy proved unsuccessful, the generation of virus-specific cytotoxic T cell lines was carried out despite severe lymphopenia, and their infusion resulted safe and durably effective in healing intestinal ulcerations and resetting the viral load. Virus-specific cellular therapy was useful in reconstituting specific immunity and treating severe human Cytomegalovirus-related enteritis in patients with primary immunodeficiency.

Late Onset Combined Immunodeficiency Presenting with Recurrent Pneumocystis jiroveci Pneumonia.

Late onset combined immunodeficiency (LOCID) is a recently described variant of common variable immunodeficiency (CVID), involving adult patients presenting with opportunistic infections and/or low CD4+ lymphocyte counts. A 36-year-old male with unremarkable past medical history presented with fever, respiratory failure, and lymphocytopenia. He was found to have Pneumocystis jiroveci pneumonia (PJP), subsequently complicated by recurrent hospital-acquired Pseudomonas aeruginosa pneumonia and immune reconstitution phenomena, attributed to restoration of immunoglobulin levels. Clinicians should be aware of LOCID, which could be confused with HIV infection/AIDS or idiopathic CD4 lymphocytopenia. In the English bibliography there is only one case report, where PJP was the initial presentation of CVID (that case would probably be classified as LOCID). Phenomena of immune reconstitution are described in various settings, including primary immunodeficiency, manifesting as temporary clinical and radiologic deterioration and leading to misperceptions of therapeutic failure and/or presence of alternative/additional diagnoses.

Terminal Deletion of 11q with Significant Late-Onset Combined Immune Deficiency

We report a 45-year old female adult patient with terminal deletion of chromosome 11q resulting in clinical phenotype of late-onset combined immunodeficiency. We describe the clinical phenotype and discuss the similarities between our patient and those with chromosome 22q11.2 deletion syndrome. Immunological evaluation included immunoglobulin levels, vaccine responses, number and function of T, NK and B cell subsets and comparative genomic hybridization test of blood and fibroblasts. The patient suffered from recurrent pneumococcal pneumonia and genital and cutaneous condylomas. She had a history of learning difficulties, dysmorphic features, autoimmune thyroiditis, chronic thrombocytopenia and severe asthma. We found Paris-Trousseau type thrombocytopenia, B-, T- and NK-lymphopenia, T cell oligoclonality and IgG hypogammaglobulinemia with inability to respond to pneumococcal polysaccharide, tetanus and diphtheria vaccines. A terminal deletion of chromosome 11q compatible with partial Jacobsen syndrome was found. This confirms Jacobsen syndrome as a chromosome deletion syndrome able to cause combined immunodeficiency.