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Background: Currently, there are no approved therapies to treat congenital athymia, a condition of immune deficiency resulting in high early mortality due to infection and immune dysregulation. Multiple syndromic conditions, such as complete DiGeorge syndrome, 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness) syndrome, diabetic embryopathy, other genetic variants, and FOXN1 deficiency, are associated with congenital athymia., Objective: Our aims were to study 105 patients treated with cultured thymus tissue (CTT), and in this report, to focus on the outcomes of 95 patients with treatment-naive congenital athymia., Methods: A total of 10 prospective, single-arm open-label studies with patient enrollment from 1993 to 2020 form the basis of this data set. Patients were tested after administration of CTT for T-cell development; all adverse events and infections were recorded., Results: A total of 105 patients were enrolled and received CTT (the full analysis set). Of those patients, 10 had diagnoses other than congenital athymia and/or received prior treatments. Of those 105 patients, 95 patients with treatment-naive congenital athymia were included in the efficacy analysis set (EAS). The Kaplan-Meier estimated survival rates at year 1 and year 2 after administration of CTT in the EAS were 77% (95% CI = 0.670-0.844) and 76% (95% CI = 0.657-0.834), respectively. In all, 21 patients died in the first year before developing naive T cells and 1 died in the second year after receipt of CTT; 3 subsequent deaths were not related to immunodeficiency. A few patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after year 1. The rates of infections, autologous graft-versus-host-disease manifestations, and autoimmune cytopenias all decreased approximately 1 year after administration of CTT., Conclusion: Treatment with CTT led to development of naive T cells with a 1-year survival rate of 77% and a median follow-up time of 7.6 years. Immune reconstitution sufficient to prevent infections and support survival typically develops 6 to12 months after administration of CTT., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders., (Copyright © 2020 Bhalla, Wysocki and van Oers.)

Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes including reduction in T-cell counts, combined T-B cell defects rarely requiring antibiotic prophylaxis or immunoglobulin replacement, and severe combined immunodeficiency, which is fatal without immune reconstitution. However, the prevalence of immunodeficiency in CHARGE syndrome remains unclear with few prospective studies. In this review, we examine the existing literature covering immunodeficiency associated with CHARGE syndrome, compare these with immunodeficiencies reported in 22q11.2 deletion syndrome (a condition that shares many phenotypic characteristics with CHARGE syndrome) and suggest future research priorities., (© 2017 Wiley Periodicals, Inc.)

Background: Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted., Objective: This study aims to examine and compare the immune phenotype of patients with CHARGE syndrome to those with 22q11.2 deletion and healthy controls., Methods: A total of 21 patients attended a multidisciplinary CHARGE clinic. All patients had CHD7 mutational analysis performed. Patients with CHARGE syndrome had lymphocyte subsets, immunoglobulins (IgG, A, M), functional protein, and polysaccharide vaccine responses measured at initial evaluation. A total of 55 healthy controls were prospectively recruited, whereas 40 patients with 22q11.2 deletion were retrospectively identified through medical records. A separate analysis compared serial lymphocyte counts and ionized calcium levels between patients with CHARGE syndrome and those with 22q11.2 deletion in the first 72 months of life., Results: Despite recurrent childhood ear and chest infections, only 2 children with CHARGE syndrome had an identifiable immune defect (reduced serum IgA). In contrast, T-cell lymphopenia, low immunoglobulin levels, and specific antibody deficiency were noted in patients with 22q11.2 deletion. A greater proportion of patients with 22q11.2 deletion had persistent lymphopenia (57% vs 30%) and hypocalcemia (60% vs 37.5%) compared with patients with CHARGE syndrome in the first 72 months of life., Conclusions: Although phenotypic overlap exists between CHARGE and 22q11.2 deletion syndromes, no significant immune defects were detected in this cohort of patients with CHARGE syndrome at the time of testing. Lymphopenia and hypocalcemia occur in both conditions early in life, but is more pronounced in patients with 22q11.2 deletion., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

CHARGE syndrome is a variable, multiple congenital malformation syndrome. Patients with CHARGE syndrome have frequent infections that are presumed to be due to anatomical anomalies of the craniofacial region and upper airway, and cranial nerve problems resulting in swallowing difficulties and aspiration. The possible contribution of immunological abnormalities to these infections has not been systematically studied even though immune deficiencies have been described in patients with 22q11.2 deletion syndrome, a condition which shares remarkable clinical overlap with CHARGE syndrome. We assessed the frequency and nature of immune dysfunction in 24 children with genetically proven CHARGE syndrome. All patients, or their parents, completed a questionnaire on infectious history. Their immune system was extensively assessed through full blood counts, immunoglobulin levels, lymphocyte subpopulations, peripheral B- and T-cell differentiation, T-receptor excision circle (TREC) analysis, T-cell function, and vaccination responses. All CHARGE patients had a history of infections (often frequent), mainly otitis media and pneumonia, leading to frequent use of antibiotics and to hospital admissions. Decreased T-cell numbers were found in 12 (50%) patients, presumably caused by insufficient thymic output since TREC amounts were also diminished in CHARGE patients. Despite normal peripheral B-cell differentiation and immunoglobulin production in all patients, 83% of patients had insufficient antibody titers to one or more early childhood vaccinations. Based on our results, we recommend immunological evaluation of CHARGE patients with recurrent infections.

CHARGE syndrome is caused by a dominant variant in the CHD7 gene. Multiple organ systems can be affected because of haploinsufficiency of CHD7 during embryonic development. CHARGE syndrome shares many clinical features with the 22q11.2 deletion syndrome. Immunological abnormalities have been described, but are generally given little attention in studies on CHARGE syndrome. However, structured information on immunological abnormalities in CHARGE patients is necessary to develop optimal guidelines for diagnosis, treatment and follow-up in these patients. Here, we provide an overview of the current literature on immunological abnormalities in CHARGE syndrome. We also explore immunological abnormalities in comparable multiple congenital anomaly syndromes to identify common immunological phenotypes and genetic pathways that might regulate the immune system. Finally, we aim to identify gaps in our knowledge on the immunological aspects in CHARGE syndrome that need further study.

Lymphocyte counts <2000 cells/μL are associated with early death in infants with CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness) syndrome and CHD7 haploinsufficiency. Absence of recent thymic emigrants is also accompanied by an Omenn-like syndrome and infant death in CHD7 haploinsufficiency. Studies positively identifying recent thymic emigrants, in relation to CHD7 haploinsufficiency, are non-existent. Thirty two months of flow-cytometric work-up of an athymic (evaluated by four chest X-rays) infant, with a novel CHD7 deletion, demonstrated sparse (<50 cells/mm(3)) but continuous egress of recent thymic emigrants (CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+)) and homeostatic lymphocyte expansion. Infectious or autoimmune episodes (e.g., Omenn-like syndrome) were not detected (despite lymphocyte counts <2000 cells/μL) and excellent vaccination (tetanus, Haemophilus influenzae type B and pneumococcal conjugate vaccines) and proliferation (anti-CD3 and anti-CD28 stimulated) responses were recorded. Her CD4(+) T cells displayed Gaussian distributed TCR (CDR3) spectratypes (22 functional Vβ families). Her CD4(+) T cell profile was also characterized by a slightly increased proportion CD4(+) CD25(+) FoxP3(+) T cells. Since CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+) RTE are reported to be TCR diverse and to contain regulatory T cells, we found it important to report that continuously reduced numbers of CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+) RTE, in the context of CHD7 haploinsufficiency and despite severe lymphopenia, is consistent with an uneventful clinical outcome., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Chromosome 22q11 deletion is the most common chromosomal deletion syndrome and is found in the majority of patients with DiGeorge syndrome and velo-cardio-facial syndrome. Patients with CHARGE syndrome may share similar features. Cardiac malformations, speech delay, and immunodeficiency are the most common manifestations. The immunological phenotype may vary widely between patients. Severe T lymphocyte immunodeficiency is rare-thymic transplantation offers a new approach to treatment, as well as insights into thymic physiology and central tolerance. Combined partial immunodeficiency is more common, leading to recurrent sinopulmonary infection in early childhood. Autoimmunity is an increasingly recognized complication. New insights into pathophysiology are reviewed.

Phenotypic variation in CHARGE syndrome remains unexplained. A subcategory of CHARGE patients show overlapping phenotypic characteristics with DiGeorge syndrome (thymic hypo/aplasia, hypocalcemia, T-cell immunodeficiency). Very few have been tested or reported to carry a mutation of the CHD7 (chromodomain helicase DNA-binding domain) gene detected in two-thirds of CHARGE patients. In an attempt to explore the genetic background of a severe CHARGE/DiGeorge phenotype, we performed comparative genomic array hybridization in an infant carrier of a CHD7 mutation. The high-resolution comparative genomic array hybridization revealed interesting findings, including a deletion distal to the DiGeorge region and disruptions in other chromosomal regions of genes implicated in immunological and other functions possibly contributing to the patient's severe phenotype and early death.