Using transcranial alternating current stimulation to enhance working memory skills in youths with 22q11.2 deletion syndrome: A randomized double-blind sham-controlled study.

Abnormal cognitive development, particularly working memory (WM) deficits, is among the first apparent manifestations of psychosis. Yet, cognitive impairment only shows limited response to current pharmacological treatment. Alternative interventions to target cognition are highly needed in individuals at high risk for psychosis, like carriers of 22q11.2 deletion syndrome (22q11.2DS). Here we applied theta-tuned transcranial alternating current stimulation (tACS) between frontal and temporal regions during a visual WM task in 34 deletion carriers. We conducted a double-blind sham-controlled study over three consecutive days. The stimulation parameters were derived from individual structural MRI scan and HD-EEG data acquired at baseline (Day 1) to model current intensity and individual preferential theta peak. Participants were randomized to either sham or tACS (Days 2 and 3) and then completed a visual WM task and a control task. Our findings reveal that tACS was safe and well-tolerated among participants. We found a significantly increased accuracy in the visual WM but not the control task following tACS. Moreover, this enhancement in WM accuracy was greater after tACS than during tACS, indicating stronger offline effects than online effects. Our study therefore supports the application of repeated sessions of brain stimulation in 22q11.2DS.

Clinical and Treatment History of Patients with Partial DiGeorge Syndrome and Autoimmune Cytopenia at Multiple Centers.

BACKGROUND: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES: Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS: Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS: Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS: AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.

A model for preservation of thymocyte-depleted thymus.

DiGeorge syndrome is a disorder caused by a microdeletion on the long arm of chromosome 22. Approximately 1% of patients diagnosed with DiGeorge syndrome may have an absence of a functional thymus, which characterizes the complete form of the syndrome. These patients require urgent treatment to reconstitute T cell immunity. Thymus transplantation is a promising investigational procedure for reconstitution of thymic function in infants with congenital athymia. Here, we demonstrate a possible optimization of the preparation of thymus slices for transplantation through prior depletion of thymocytes and leukocyte cell lineages followed by cryopreservation with cryoprotective media (5% dextran FP 40, 5% Me2SO, and 5% FBS) while preserving tissue architecture. Thymus fragments were stored in liquid nitrogen at -196°C for 30 days or one year. The tissue architecture of the fragments was preserved, including the distinction between medullary thymic epithelial cells (TECs), cortical TECs, and Hassall bodies. Moreover, depleted thymus fragments cryopreserved for one year were recolonized by intrathymic injections of 3×106 thymocytes per mL, demonstrating the capability of these fragments to support T cell development. Thus, this technique opens up the possibility of freezing and storing large volumes of thymus tissue for immediate transplantation into patients with DiGeorge syndrome or atypical (Omenn-like) phenotype.

The Subtlety of 22q11.2 Deletion Syndrome in a Preterm Neonate.

To date, 22q11.2 deletion syndrome (DS) is regarded as the most commonly diagnosed DS in humans. The location of the deletion on chromosome 22 affects the phenotypic presentation, which ranges from subtle to severe. Common manifestations include congenital heart defects, calcium deficiency, clefts and other midline defects, immunodeficiencies, and neurocognitive delay. This wide range of clinical manifestations can complicate diagnostic reasoning as many align with other disease processes commonly observed in preterm neonates. This article presents the case of a preterm neonate born at 25-weeks' gestation with 22q11.2 DS. The clinical presentation of this neonate included a right aortic arch, ventricular septal defect, hypocalcemia, borderline severe combined immunodeficiency, and abnormal thyroid function. The infant's hospital course is followed to highlight the challenges clinicians face when suspicious of a genetic disorder in a preterm neonate.

Chromosome 22q11.2 Deletion (DiGeorge Syndrome): Immunologic Features, Diagnosis, and Management.

PURPOSE OF REVIEW: This review focuses on immunologic findings, relationships among immunologic findings and associated conditions of autoimmunity and atopy, and management of immunologic disease in chromosome 22q11.2 deletion syndrome (22q11.2DS, historically known as DiGeorge syndrome). RECENT FINDINGS: The implementation of assessment of T cell receptor excision circles (TRECs) in newborn screening has led to increased detection of 22q11.2 deletion syndrome. While not yet applied in clinical practice, cell-free DNA screening for 22q11.2DS also has the potential to improve early detection, which may benefit prompt evaluation and management. Multiple studies have further elucidated phenotypic features and potential biomarkers associated with immunologic outcomes, including the development of autoimmune disease and atopy. The clinical presentation of 22q11.2DS is highly variable particularly with respect to immunologic manifestations. Time to recovery of immune system abnormalities is not well-defined in current literature. An understanding of the underlying causes of immunologic changes found in 22q11.2DS, and the progression and evolution of immunologic changes over the lifespan have expanded over time and with improved survival. An included case highlights the variability of presentation and potential severity of T cell lymphopenia in partial DiGeorge syndrome and demonstrates successful spontaneous immune reconstitution in partial DiGeorge syndrome despite initial severe T cell lymphopenia.

Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.

Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development.

Current practices vary widely regarding the immunological work-up and management of patients affected with defects in thymic development (DTD), which include chromosome 22q11.2 microdeletion syndrome (22q11.2del) and other causes of DiGeorge syndrome (DGS) and coloboma, heart defect, atresia choanae, retardation of growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome. Practice variations affect the initial and subsequent assessment of immune function, the terminology used to describe the condition and immune status, the accepted criteria for recommending live vaccines, and how often follow-up is needed based on the degree of immune compromise. The lack of consensus and widely varying practices highlight the need to establish updated immunological clinical practice guidelines. These guideline recommendations provide a comprehensive review for immunologists and other clinicians who manage immune aspects of this group of disorders.

Speech Telepractice and Treatment Intensity in a Cantonese-Speaking Case with 22q11.2 Deletion Syndrome Following Late Diagnosis and Management of Velopharyngeal Dysfunction.

This case report explores clinical treatment efficacy in a Cantonese-speaking child with 22q11.2 Deletion Syndrome where diagnosis and management of velopharyngeal dysfunction can be considered late. All treatment sessions were undertaken via telepractice during the peak of the COVID-19 pandemic in Hong Kong. A hybrid of specialized cleft palate speech treatment techniques and traditional treatment approaches in Speech Sound Disorders were utilized. Treatment intensity components including dose, dose form, session duration, and total intervention duration were documented.

Mesenchymal cell replacement corrects thymic hypoplasia in murine models of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common human chromosomal microdeletion, causing developmentally linked congenital malformations, thymic hypoplasia, hypoparathyroidism, and/or cardiac defects. Thymic hypoplasia leads to T cell lymphopenia, which most often results in mild SCID. Despite decades of research, the molecular underpinnings leading to thymic hypoplasia in 22q11.2DS remain unknown. Comparison of embryonic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) revealed proportions of mesenchymal, epithelial, and hematopoietic cell types similar to those of control thymuses. Yet, the small thymuses were growth restricted in fetal organ cultures. Replacement of Tbx1neo2/neo2 thymic mesenchymal cells with normal ones restored tissue growth. Comparative single-cell RNA-Seq of embryonic thymuses uncovered 17 distinct cell subsets, with transcriptome differences predominant in the 5 mesenchymal subsets from the Tbx1neo2/neo2 cell line. The transcripts affected included those for extracellular matrix proteins, consistent with the increased collagen deposition we observed in the small thymuses. Attenuating collagen cross-links with minoxidil restored thymic tissue expansion for hypoplastic lobes. In colony-forming assays, the Tbx1neo2/neo2-derived mesenchymal cells had reduced expansion potential, in contrast to the normal growth of thymic epithelial cells. These findings suggest that mesenchymal cells were causal to the small embryonic thymuses in the 22q11.2DS mouse models, which was correctable by substitution with normal mesenchyme.

Introducing thymus for promoting transplantation tolerance.

Establishing tolerance remains a central, if elusive, goal of transplantation. In solid-organ transplantation, one strategy for inducing tolerance has been cotransplantation of various forms of thymic tissue along with another organ. As one of the biological foundations of central tolerance, thymic tissue carries with it the ability to induce tolerance to any other organ or tissue from the same donor (or another donor tissue-matched to the thymic tissue) if successfully transplanted. In this review, we outline the history of this approach as well as work to date on its application in organ transplantation, concluding with future directions. We also review our experience with allogeneic processed thymus tissue for the treatment of congenital athymia, encompassing complete DiGeorge syndrome and other rare genetic disorders, and consider whether allogeneic processed thymic tissue implantation may offer a novel method for future experimentation with tolerance induction in organ transplantation.

Spectrum of Genetic T-Cell Disorders from 22q11.2DS to CHARGE.

Improved genetic testing has led to recognition of a diverse group of disorders of inborn errors of immunity that present as primarily T-cell defects. These disorders present with variable degrees of immunodeficiency, autoimmunity, multiple organ system dysfunction, and neurocognitive defects. 22q11.2 deletion syndrome, commonly known as DiGeorge syndrome, represents the most common disorder on this spectrum. In most individuals, a 3 Mb deletion of 22q11 results in haploinsufficiency of 90 known genes and clinical complications of varying severity. These include cardiac, endocrine, gastrointestinal, renal, palatal, genitourinary, and neurocognitive anomalies. Multidisciplinary treatment also includes pediatrics/general practitioners, genetic counseling, surgery, interventional therapy, and psychology/psychiatry. Chromosome 10p deletion, TBX1 mutation, CHD7 mutation, Jacobsen syndrome, and FOXN1 deficiency manifest with similar overlapping clinical presentations and T-cell defects. Recognition of the underlying disorder and pathogenesis is essential for improved outcomes. Diagnosing and treating these heterogenous conditions are a challenge and rapidly improving with new diagnostic tools. Collectively, these disorders are an example of the complex penetrance and severity of genetic disorders, importance of translational diagnostics, and a guide for multidisciplinary treatment.

Reflections of parents of children with 22q11.2 Deletion Syndrome on the experience of receiving psychiatric genetic counseling: 'Awareness to Act'.

Individuals with 22q11.2 deletion syndrome (22qDS) have a 25%-41% risk for a psychotic disorder. Although early intervention for psychiatric conditions leads to the best long-term outcomes, healthcare providers often provide inadequate information about these issues and psychiatric services are underused by this population. We conducted semi-structured interviews with parents of children with 22qDS a month after they received psychiatric genetic counseling (pGC), to evaluate outcomes and perceived value of pGC with respect to parents' needs. Using grounded theory, we generated a theoretical framework of the process of building parental awareness of psychiatric risks associated with 22qDS and protective and management strategies for mental health (MH). Parents described how after their child's diagnosis with 22qDS, a variety of barriers stalled their building awareness of psychiatric risk and protective/management strategies: dealing with the immediate symptoms of 22qDS; child's young age; parental fear and stigma; and missing MH guidance. These barriers led them to carry the burden of worrying over missing emerging psychiatric symptoms and the stress over advocating for their child's MH. Parents indicated pGC was beneficial in that led them to achieve an 'awareness to act,' feeling confident in being alert and equipped to protect and/or manage their child's MH.

Evaluation and Maintenance of Behavioral Interventions for 22q11.2 Deletion Syndrome.

22q11.2-deletion syndrome is a genetic disorder caused by a small deletion of chromosome 22. This deletion often results in developmental delays, learning disabilities, medical conditions, and comorbid psychiatric conditions. Patients with 22q11.2DS may present with a variety of behavioral phenotypes including obsessiveness and rigidity, poor social skills, and anxiety. In some cases, the phenotype can consist of destructive and inappropriate behavior including harming self and others. Behavioral difficulties are reported as one of the most challenging aspects of 22q11.2-deletion syndrome for families of patients, however, few studies have examined behavioral interventions as a possible therapeutic treatment for this population. Using principles derived from operant-behavioral psychology, we conducted functional assessments to determine the environmental correlates of destructive and inappropriate behaviors in two adult men with 22q11.2-deletion syndrome. Subsequently, behavioral interventions based on differential reinforcement were incorporated into each participant's natural environment to eliminate these behaviors. Significant reductions in destructive and inappropriate behavior were observed with both participants and therapeutic gains were maintained at follow-up. We discuss the role of behavioral interventions in combination with appropriate psychotropic medication when addressing challenging behaviors in this population.

Experience with cultured thymus tissue in 105 children.

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.

Percutaneous Enteral Feeding in Patients With 22q11.2 Deletion Syndrome.

OBJECTIVE: To describe the incidence of percutaneous enteral feeding in patients with 22q11.2 deletion syndrome (22q11.2 DS) and determine factors associated with the need for percutaneous enteral feeding tube placement. DESIGN: Retrospective chart review. METHODS: The records of a 22q11.2 DS clinic and pediatric otolaryngology clinic at a tertiary pediatric hospital were reviewed from January 1, 2009, to December 31, 2019. All patients with confirmed 22q11.2 deletion were identified. Cardiac, otolaryngological, and feeding characteristics were recorded along with surgical history. A patient was defined to have a G-tube if the history was significant for any percutaneous gastric feeding tube placement, including a gastrostomy tube, gastrostomyjejunostomy tube, or a Mickey button. RESULTS: One hundred ninety patients with confirmed 22q11.2 DS by genetic testing were included. Thirty-three percent (n = 63) required G-tube placement. G-tube placement was associated with cardiac diagnosis (P < .01), history of cardiac surgery (P < .01), aspiration (P < .01), nasopharyngeal reflux (P < .01), subglottic stenosis (P < .01), laryngeal web (P = .003), and tracheostomy (P < .01). This suggests these conditions are associated with higher rates of G-tube placement in the 22q11.2 DS population. CONCLUSIONS: Patients with 22q11.2 DS often require supplemental nutritional support in the form of G-tube feeding, most often in the first year of life. Congenital heart abnormalities and surgery along with tracheostomy, subglottic stenosis, laryngeal web, aspiration, and nasopharyngeal reflux are significantly associated with the need for G-tube placement. Understanding associations between comorbid conditions and G-tube placement, especially those involving the head and neck, may assist with counseling of patients with 22q11.2 DS.

Clinical Manifestations of 22q11.2 Deletion Syndrome.

DiGeorge syndrome (DGS), also known as "22q11.2 deletion syndrome" (22q11DS) (MIM # 192430 # 188400), is a genetic disorder caused by hemizygous microdeletion of the long arm of chromosome 22. In the last decades, the introduction of fluorescence in situ hybridization assays, and in selected cases the use of multiplex ligation-dependent probe amplification, has allowed the detection of chromosomal microdeletions that could not be previously identified using standard karyotype analysis. The aim of this review is to address cardiovascular and systemic involvement in children with DGS, provide genotype-phenotype correlations, and discuss their medical management and therapeutic options.