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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. [ABSTRACT FROM AUTHOR]

Background: 22q11.2 deletion syndrome (22q11.2DS) is a rare disease with an important characteristic-clinical heterogeneity. The diversity of organs, regions, and systems of the body that can be affected requires periodic updating of health professionals so that they can recognize these clinical signs as belonging to 22q11.2DS. Updated professionals are equally important for the appropriate and timely clinical management of individuals with a positive diagnosis. In this context, this article aimed to map and analyze the access to healthcare for individuals with 22q11.2DS until the moment of diagnosis.Results: We analyzed the clinical data of 111 individuals with 22q11.2DS registered in the Brazilian Database on Craniofacial Anomalies (BDCA) from 2008 to 2020. In this study, individuals were diagnosed at a median age of 9 years (mean = 9.7 years). Before the genetic investigation, they accessed 68.75% of the internationally recommended evaluations available at BDCA. Recurrent 22q11.2DS clinical manifestations such as delayed neuropsychomotor development, lip and/or palate defects, cardiac malformation and/or hematological/immunological alteration co-occurred in at least 72.06% of individuals. Cardiac malformation was the only clinical alteration that lowered the median diagnostic age, corresponding to 6.5 years of age with a cardiac malformation versus 11 years of age without one (p = 0.0006).Conclusions: In Brazil, 22q11.2 DS is under-recognized, and early diagnosis and management of affected individuals are still a distant reality. In this sense, 22q11.2 DS suspicion followed by the elimination of obstacles for its diagnosis confirmation is essential to increase life expectancy and improve the quality of life of these individuals in Brazil. [ABSTRACT FROM AUTHOR]

Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T−B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia. [ABSTRACT FROM AUTHOR]

Right aortic arch (RAA) is an abnormal embryologic development of the aorta characterized by its descendance on the right side of the trachea. This anomaly is accompanied often by other intracardiac and extracardiac anomalies and it is also known for potential association with genetic aberrations, most common being 22q11.2 deletion. The aim of the study was to evaluate the incidence of chromosomal anomalies and in particular 22q11.2 deletion in RAA. Moreover, we assessed the prognosis of fetuses with isolated RAA. Our second objective was to evaluate the prevalence of hypoplastic or absent thymus in RAA fetuses diagnosed with 22q11.2 deletion. We conducted a retrospective study of all fetuses with RAA over a period of 10 years diagnosed prenatally in a tertiary referral center in Romania. A detailed ultrasound was obtained in each case. We extracted the cases that were investigated genetically and selected the cases positive for 22q11.2 deletion. These fetuses were followed up until pregnancy termination or birth to confirm the ultrasound findings. Deletion 22q11.2 was present in 23.52% (4/17) cases. The incidence was particularly high when the fetuses presented a small thymus. In conclusion, we believe that all cases of RAA, including when isolated, should be referred for genetic testing and especially 22q11.2 deletion exclusion. Also, we suggest considering hypoplastic thymus to be a soft marker for this deletion. [ABSTRACT FROM AUTHOR]

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening. [ABSTRACT FROM AUTHOR]

The objective of this work was to identify 22q11.2 chromosomal deletion in patients with cleft lip and/or cleft palate and suggestive syndromic phenotype in Colombian patients. We studied 49 patients with cleft lip and/or cleft palate, exhibiting additional clinical findings linked to 22q11.2 deletion syndrome. All patients underwent high-resolution G-banded karyotyping, multiplex ligation-dependent probe amplification, and clinical evaluation by a geneticist. Seven patients presented 22q11.2 deletion and 2 patients had other chromosomal abnormalities. In conclusion, this study contributes with new data for genetic etiology in syndromic conditions of oral fissures. [ABSTRACT FROM AUTHOR]

The DiGeorge Syndrome was first described in 1968 as a primary immunodeficiency resulting from the abnormal development of the third and fourth pharyngeal pouches during embryonic life. It is characterized by hypocalcemia due to hypoparathyroidism, heart defects, and thymic hypoplasia or aplasia. Its incidence is 1:3000 live births and, despite its high frequency, little is known about its natural history and progression. ←This is probably due to diagnostic difficulties and the great variety of names used to describe it, such as velocardiofacial, DiGeorge, and CATCH 22 Syndromes, as well as conotruncal facial anomaly. All represent the same genetic condition, chromosome 22q11.2 deletion, which might have several clinical expressions. To describe clinical and laboratorial data and phenotypic characteristics of patients with DiGeorge Syndrome. Patients underwent standard clinical and epidemiological protocol and tests to detect heart diseases, facial abnormalities, dimorphisms, neurological or behavioral disorders, recurrent infections and other comorbidities. [ABSTRACT FROM AUTHOR]

We report a 40-year-old male who presented with seizures due to hypocalcemia. Biochemical evaluation revealed the diagnosis of hypoparathyroidism. The symptom complex of dysmorphic facies and intellectual disability along with hypoparathyroidism led to a suspicion of 22q11.2 microdeletion syndrome (22q11.2DS), which was confirmed by multiplex ligation-dependent probe amplification (MLPA) analysis showing 22q11.2.21 microdeletion. [ABSTRACT FROM AUTHOR]

Introduction: Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. Objective: We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). Methods: A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence in situ hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. Results: Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). Conclusion: In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families. [ABSTRACT FROM AUTHOR]

Background: Microdeletion of chromosome 22q11 is associated with significant developmental anomalies, including disruption of the cardiac outflow tract, thymic/parathyroid aplasia and cleft palate. Amongst the genes within this region, TBX1 is a major candidate for many of these developmental defects. Targeted deletion of Tbx1 in the mouse has provided significant insight into the function of this transcription factor during early development of the cardiac and pharyngeal systems. However, less is known about its role during palatogenesis. To assess the influence of Tbx1 function on gene expression profile within the developing palate we performed a microarray screen using total RNA isolated from the secondary palate of E13.5 mouse embryos wild type, heterozygous and mutant for Tbx1. Results: Expression-level filtering and statistical analysis revealed a total of 577 genes differentially expressed across genotypes. Data were clustered into 3 groups based on comparison between genotypes. Group A was composed of differentially expressed genes in mutant compared to wild type (n = 89); Group B included differentially expressed genes in heterozygous compared to wild type (n = 400) and Group C included differentially expressed genes in mutant compared to heterozygous (n = 88). High-throughput quantitative real-time PCR (RT-PCR) confirmed a total of 27 genes significantly changed between wild type and mutant; and 27 genes between heterozygote and mutant. Amongst these, the majority were present in both groups A and C (26 genes). Associations existed with hypertrophic cardiomyopathy, cardiac muscle contraction, dilated cardiomyopathy, focal adhesion, tight junction and calcium signalling pathways. No significant differences in gene expression were found between wild type and heterozygous palatal shelves. Conclusions: Significant differences in gene expression profile within the secondary palate of wild type and mutant embryos is consistent with a primary role for Tbx1 during palatogenesis. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the frequency of airway anomalies in patients with 22q11.2 deletion syndrome (22q11DS). Methods: Retrospective review of patients with 22q11DS who had undergone microlaryngoscopy/bronchoscopy (MLB) for aerodigestive symptoms at a tertiary care children's hospital from 2011 to 2016. Results: Thirty patients underwent an MLB due to the following indications: aspiration (11), stridor (10), chronic respiratory failure due to ventilator dependence (8), and difficult intubation (1). Median age at MLB was 6.5 months (range, 0.25-32 months). Forty airway anomalies were identified in 20 (66%) patients. Laryngomalacia (10), tracheomalacia (8), and bronchomalcia (8) were the most common intraoperative findings, followed by laryngeal cleft (5), anterior glottic web (5), subglottic stenosis (3), and subglottic cysts (1). Synchronous airway anomalies were common and identified in 11 (55%) of the patients who had identified anomalies on MLB. Nineteen of the 20 patients required operative intervention due to the anomalies identified. Conclusions: Structural airway abnormalities are common in children with 22q11DS undergoing MLB, and synchronous anomalies can frequently exist. Providers caring for children with 22q11DS should be vigilant about airway evaluation when aerodigestive symptoms are present. [ABSTRACT FROM AUTHOR]

Aim Severe combined immunodeficiency ( SCID) is the most severe form of primary immunodeficiency and is fatal in infancy if untreated. As early diagnosis is associated with improved outcomes, SCID is an ideal condition to consider for inclusion in a newborn screening ( NBS) programme in Australia. In this feasibility study, we evaluated the EnLite Neonatal TREC kit for detection of T-cell receptor excision circles ( TRECs) from NBS dried blood spots for the identification of known SCID patients in Victoria. Methods TREC copies/ μL were measured retrospectively in 14 children diagnosed with SCID or complete DiGeorge syndrome ( CDGS) from 2005 to 2015 at the Royal Children's Hospital, Melbourne. In addition, TREC copies/ μL were measured for 501 prospective de-identified NBS cards. Results Of 14 known SCID or CDGS samples, 11 were correctly identified as presumptive positive samples with low or undetectable TREC on duplicate testing. The remaining three samples also had low or undetectable TREC on duplicate testing but were considered invalid due to insufficient β-actin DNA amplification. Of the 501 prospective NBS samples, none were identified as presumptive positive samples on duplicate testing. Conclusions The EnLite Neonatal TREC kit correctly identified known SCID or CDGS patients as presumptive positive samples, and initial cut-offs for TREC and β-actin in the Victorian NBS population were determined. A larger pilot study is required to confirm these proposed cut-offs and to evaluate the cost and implementation of this screening programme in Victoria, Australia. Overall, this study provides preliminary data to support the introduction of this assay to the NBS programme in Victoria. [ABSTRACT FROM AUTHOR]

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The diagnostic approach for adulthood parkinsonism can be challenging when atypical features hamper its classification in one of the two main parkinsonian groups: Parkinson's disease or atypical parkinsonian syndromes (APS). Atypical features are usually associated with non-sporadic neurodegenerative causes. Retrospective analysis of patients with a working clinical diagnosis of "atypical" APS and complex parkinsonism. "Atypical" APS were classified according to the diagnostic research criteria and the "4-step diagnostic approach" (Stamelou et al. 2013). When not indicated, the final aetiological diagnosis was prospectively assessed. Brain MRI of progressive supranuclear palsy (PSP) look-alikes was reviewed by a neuroradiologist. Among 18 patients enrolled, ten were assigned to the "atypical" APS and eight to the complex parkinsonism group. In the "atypical" APS group, nine patients had PSP and one had corticobasal degeneration. In the PSP group the median magnetic resonance parkinsonism index was 17.1. A final aetiological diagnosis was established for 11 patients, four from the complex parkinsonism (L-2-hidroxiglutaric aciduria and DiGeorge syndrome) and seven from the "atypical" APS (Perry syndrome, postencephalitic PSP, vascular PSP, and MTP-AT6 mitochondrial disease) group. In this study, the identification of atypical APS features, as proposed in the "4-step diagnostic approach", successfully guided the investigation of alternative diagnoses. Distinctive non-neurodegenerative etiologies causing "atypical" atypical and complex parkinsonism were uncovered, including acquired (post-encephalitis and vascular) and genetic (MTP-AT6 mitochondrial disease mimicking PSP, described for the first time) ones. In the future, accurate clinical identification and distinction between neurodegenerative and non-neurodegenerative parkinsonism etiologies will allow for refining clinical trials. • Age cut-off can be permissively higher and still be able to identify "atypical" APS. • Postencephalitic parkinsonism can mimic a PSP phenotype. • MRPI can be useful to distinguished between vascular PSP and vascular parkinsonism. • MT- ATP6 mitochondrial disease, usually associated with adult-onset SCA, was found in one PSP patient. • DiGeorge syndrome is an important cause of early-onset parkinsonism, with neuropsychiatric features. [ABSTRACT FROM AUTHOR]

Objective: 22q11.2 deletion syndrome (DS) or velo-cardio-facial syndrome (VCFS) is a genetic condition that has been identified as the highest genetic risk factor for developing psychotic illnesses. This unique biological nature of 22q11DS provides a valuable opportunity to explore predictive biomarkers of psychosis. In this study, we examined the relationship of cortical thickness and surface area between various brain regions and prodromal symptoms of psychosis.Methods: 75 probands with 22q11DS, 32 age-matched controls and 28 siblings underwent MRIs over 2 or 3 timepoints. Longitudinal mixed model regression analyses, with age as an interaction variable, were carried out to study the differences in longitudinal trajectories of change in average cortical thickness and surface area over 6-9years. Similar analyses were carried out to examine the relationship with positive prodromal symptoms of psychosis.Results: Significant differences were noted in the inferior and superior parietal regions in both the average thickness and longitudinal change in cortical thickness with age between the probands and controls. Significant associations were also noted between regions in the frontal cortex and positive prodromal symptoms among probands. No associations were noted with cortical surface area.Conclusion: Our results indicate that individuals with 22q11DS who develop positive prodromal symptoms demonstrate differential longitudinal trajectories of cortical thickness in some regions of the frontal lobe. Our results suggest that the pruning stage associated with adolescent brain development may be disrupted. [ABSTRACT FROM AUTHOR]

About one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia. Notably, a full-blown psychotic disorder is usually preceded by subthreshold symptoms. Therefore, it is important to identify early signs of psychosis in this population, a task that is complicated by the intellectual disabilities typically seen in 22q11.2DS. We aimed to identify subthreshold psychotic symptoms that distinguish 22q11.2DS from other neurodevelopmental disorders. The study included two independent cohorts from Tel Aviv and Philadelphia. 22q11.2DS (N=171) and typically developing (TD; N=832) individuals were enrolled at both sites and further compared to two groups with intellectual disabilities: Williams syndrome (WS; N=21) in the Tel Aviv cohort and idiopathic developmental disabilities (IDD; N=129) in the Philadelphia cohort. Participants and their primary caregivers were interviewed with the Structured Interview for Prodromal Symptoms (SIPS) and psychopathologies were assessed using standardized tools; general cognitive abilities were assessed with the Computerized Neurocognitive Battery. Negative/disorganized subthreshold syndrome was significantly more common in the 22q11.2DS group than in the WS (OR=3.90, 95% CI=1.34-11.34) or IDD (OR=5.05, 95% CI=3.01-10.08) groups. The 22q11.2DS group had higher scores than the two intellectual disabilities groups on several SIPS negative items, including avolition and decreased expression of emotion. Overall, there were few significant correlations between level of cognitive deficits and severity of negative symptoms in 22q11.2DS and only in the Tel Aviv cohort. Our findings suggest that 22q11.2DS individuals at the age of risk for developing psychosis should be closely monitored for negative symptoms. [ABSTRACT FROM AUTHOR]

Background Chromosome 22q11.2 deletion syndrome (22q11DS) is a promising model for studying psychosis risk. Direct comparisons of psychosis features between 22q11DS and nondeleted (ND) individuals are limited by inconsistency and small samples. In the largest study to date, we compare 22q11DS to ND in comorbidities, functioning, cognition, and psychosis features across the full range of overall severity. Methods ND youths ( n = 150) ages 9 to 24 years were matched to 22q11DS individuals ( n = 150) on age and sex, stratifying for presence of psychosis spectrum disorder. Individuals were evaluated for psychosis using the Structured Interview for Prodromal Syndromes, and for attention-deficit/hyperactivity, substance-related, and mood disorders. Differential item functioning analysis addressed whether 22q11DS differs from ND in the probability of clinically significant ratings while holding constant the overall level of psychosis. Results Onset of psychosis proneness was similar among 22q11DS (mean: 11.0 years) and ND (mean: 12.1 years) individuals. Accounting for higher overall psychosis symptoms, 22q11DS participants were still more likely to manifest impaired stress tolerance, avolition, and ideational richness; ND individuals were more likely to exhibit unusual thoughts, persecutory ideas, and bizarre thinking. Cognition was impaired in 22q11DS, but it did not correlate with symptoms except ideational richness. Comorbid anxiety disorders were more likely in psychosis spectrum 22q11DS; substance-related disorders were more likely in ND. Global assessment of function was similar in 22q11DS and ND individuals, except among those with low total Structured Interview for Prodromal Syndromes scores. Conclusions Individuals with 22q11DS share overarching similarities with ND individuals in psychosis symptoms and age of onset for psychosis proneness; this continues to support the 22q11DS model as a valuable window into mechanisms contributing to psychosis. [ABSTRACT FROM AUTHOR]

Purpose: Chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome, is quite variable. Neonatal diagnosis traditionally relies on recognition of classic features and cytogenetic testing, but many patients come to attention only following identification of later onset conditions, such as hypernasal speech due to palatal insufficiency and developmental and behavioral differences including speech delay, autism, and learning disabilities that would benefit from early interventions. Newborn screening (NBS) for severe combined immunodeficiency (SCID) is now identifying infants with 22q11.2DS due to T cell lymphopenia. Here, we report findings in such neonates, underscoring the efficacy of early diagnosis. Methods: A retrospective chart review of 1350 patients with 22q11.2DS evaluated at the Children's Hospital of Philadelphia identified 11 newborns with a positive NBS for SCID. Results: Five out of 11 would have been diagnosed with 22q11.2DS without NBS, whereas early identification of 22q11.2DS in 6/11 led to the diagnosis of significant associated features including hypocalcemia, congenital heart disease (CHD), and gastroesophageal reflux disease that may have gone unrecognized and therefore untreated. Conclusions: Our findings support rapidly screening infants with a positive NBS for SCID, but without SCID, for 22q11.2DS even when typically associated features such as CHD are absent, particularly when B cells and NK cells are normal. Moreover, direct NBS for 22q11.2DS using multiplex qPCR would be equally, if not more, beneficial, as early identification of 22q11.2DS will obviate a protracted diagnostic odyssey while providing an opportunity for timely assessment and interventions as needed, even in the absence of T cell lymphopenia. [ABSTRACT FROM AUTHOR]

Neonatal hypocalcemia and congenital heart defects has been known as the first clinical manifestation of the chromosome 22q11.2 deletion syndrome (22q11DS). However, because of its wide clinical spectrum, diagnosis of 22q11DS can be delayed in children without classic symptoms. We report the case of a girl with the history of imperforate anus but without neonatal hypocalcemia or major cardiac anomaly, who was diagnosed for 22q11DS at the age of 11 after the onset of overt hypocalcemia. She was born uneventfully from phenotypically normal Korean parents. Imperforate anus and partial cleft palate were found at birth, which were surgically repaired thereafter. There was no history of neonatal hypocalcemia, and karyotyping by GTG banding was normal. At the age of 11, hypocalcemia (serum calcium, 5.0 mg/dL) and decreased parathyroid hormone level (10.8 pg/mL) was noted when she visited our Emergency Department for fever and vomiting. The 22q11DS was suspected because of her mild mental retardation and velopharyngeal insufficiency, and a microdeletion on chromosome 22q11.2 was confirmed by fluorescence in situ hybridization. The 22q11DS should be considered in the differential diagnosis of hypocalcemia at any age because of its wide clinical spectrum. [ABSTRACT FROM AUTHOR]

Objectives: To analyze a population of fetuses with prenatally diagnosed right aortic arch (RAA).Methods: Retrospective study of fetuses with RAA diagnosed prenatally between 2011 and 2015 in two referral centers.Results: Right aortic arch was found in 4.4% (46/1036) of fetuses with cardiovascular abnormalities (CVA). As an isolated anomaly, RAA was present in 30.4% of cases; in 32.6%, other CVA were detected; in 23.9%, CVA and extracardiac anomalies; and in 13.1%, only extracardiac malformations. The most common noncardiac abnormalities were thymus hypoplasia/aplasia (7/17), of which six had deletion 22q.11.2. In another three fetuses, trisomy 21 was present. One intrauterine fetal death occurred at 41 weeks of pregnancy, and two fetuses died after birth. In six of 18 infants with known follow-up, symptoms of dysphagia were reported, of which four infants underwent surgical intervention. In 12 infants, an isolated RAA was clinically silent.Conclusions: The diagnosis of RAA is an indication for a detailed examination of cardiac and noncardiac structures, including the thymus. It is advisable to consider genetic testing, together with the assessment of deletion 22q11.2, especially in the case of accompanying defects. The prognosis depends on underlying cardiac and extracardiac anomalies and possibly coexisting genetic defects. Isolated anomalies are asymptomatic. © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background 22q11.2 deletion syndrome (22q11 DS) is a genetic disorder that greatly increases risk of developing schizophrenia. We previously characterized cerebral surface morphology trajectories from late childhood to mid adolescence in a cohort of youth with 22q11 DS. Herein, we extend the study period into early adulthood, and describe further the trajectories associated with severe psychiatric symptoms in this cohort. Methods Participants included 76 youth with 22q11 DS and 30 unaffected siblings, assessed at three timepoints, during which high resolution, anatomic magnetic resonance images were acquired. High-dimensional, nonlinear warping algorithms were applied to images in order to derive characteristics of cerebral surface morphology for each participant at each timepoint. Repeated-measures, linear regressions using a mixed model were conducted, while covarying for age and sex. Results Alterations in cerebral surface morphology during late adolescence/early adulthood in individuals with 22q11 DS were observed in the lateral frontal, orbitofrontal, temporal, parietal, occipital, and cerebellar regions. An Age x Diagnosis interaction revealed that relative to unaffected siblings, individuals with 22q11 DS showed age-related surface protrusions in the prefrontal cortex (which remained stable or increased during early adulthood), and surface indentations in posterior regions (which seemed to level off during late adolescence). Symptoms of psychosis were associated with a trajectory of surface indentations in the orbitofrontal and parietal regions. Conclusions These results advance our understanding of cerebral maturation in individuals with 22q11 DS, and provide clinically relevant information about the psychiatric phenotype associated with the longitudinal trajectory of cortical surface morphology in youth with this genetic syndrome. [ABSTRACT FROM AUTHOR]

Objective: This study examined the complexity and myriad clinical manifestations and expressions of velocardiofacial syndrome (VCFS). It aimed to determine if VCFS invariably met the three disability criteria for the Compassionate Allowance List (CAL) program administered by the Social Security Administration (SSA).Methods: A systematic evaluative review of the literature found in 10 academic databases was completed. Inclusion criteria of the search terms yielded 1,383 initial manuscripts. Only 77 of articles met higher-level inclusion criteria of explicit statements reporting observed severity of symptoms and disability that this study used as evidence. The three SSA CAL criteria include duration, severity, and impact of employment. The analysis systematically reviewed papers with the objective of determining if they met one, two, or all three of the SSA CAL criteria.ResultsThe first criteria for the CAL require a condition to last beyond 12 months. From the 77 articles that met inclusion criteria, a total of 21 articles reported explicit statements that evidenced symptoms that were limited to the first criteria only. The second CAL criteria required that a condition also has negative impact on quality of life or death. Forty-nine articles demonstrated the first and second criteria, duration ≥12 months plus a negative impact on quality of life or death. The third criteria required that the condition prevents substantial gainful employment as well as duration ≥12 months plus a negative impact on quality of life or death. A total of seven articles reported all three criteria.Conclusions: The variability of symptoms related to VCFS makes it impossible to assert that all cases will meet the criteria for disability entitlements. [ABSTRACT FROM PUBLISHER]

Both CHARGE syndrome and DiGeorge anomaly are frequently accompanied by cardiovascular malformations. Some specific cardiovascular malformations such as interrupted aortic arch type B and truncus arteriosus are frequently associated with 22q11.2 deletion syndrome, while conotruncal defects and atrioventricular septal defects are overrepresented in patients with CHARGE syndrome. CHD7 gene mutation is identified in approximately two-thirds of patients with CHARGE syndrome, and chromosomal microdeletion at 22q11.2 is found in more than 95% of patients with 22q11.2 deletion syndrome. CHARGE syndrome is occasionally accompanied by DiGeorge phenotype. We report two patients with dysmorphic features of both CHARGE syndrome and 22q11.2 deletion syndrome. Although both of the two cases did not have 22q11.2 deletion, they had typical dysmorphic features of 22q11.2 deletion syndrome including cardiovascular malformations such as interrupted aortic arch type B. They also had characteristic features of CHARGE syndrome including ear malformation, genital hypoplasia, limb malformation, and endocrinological disorders. CHD7 gene mutation was confirmed in one of the two cases. When a patient with cardiovascular malformations frequently associated with 22q11.2 deletion syndrome does not have 22q11.2 deletion, we suggest that associated malformations characteristic of CHARGE syndrome should be searched for. [ABSTRACT FROM AUTHOR]

Objective: The incidence of the 22q11.2 microdeletion among children who have at least two out of five major clinical criteria for 22q11.2 deletion syndrome. Design: Prospective study. Setting: University Children's Hospital in Belgrade, Serbia between 2005 and 2014. Participants: 57 patients with clinical characteristics of 22q11.2 deletion syndrome. Methods: Standard G-banding cytogenetic analysis was performed in all children, and the 22q11.2 genomic region was examined using fluorescence in situ hybridization (FISH). For patients with no deletion detected by FISH, multiplex ligationdependent probe amplification (MLPA) analysis was also done in order to detect cryptic deletions of this region and to analyze other genomic loci associated with phenotypes resembling the syndrome. A selected group of patients diagnosed to have 22q11.2 microdeletion by FISH underwent MLPA testing in order to characterize the size and position of deletion. Outcome Measure: The frequency of 22q11.2 microdeletion among children with at least two of the five major characteristics of 22q11.2 deletion syndrome (heart malformations, facial dysmorphism, T-cell immunodeficiency, palatal clefts and hypocalcemia/hypoparathyroidism) Results: Typical 22q11.2 microdeletion was detected in 42.1% of patients; heart malformation were identified in all of them, facial dysmorphism in 79.2%, immunological problems in 63.6%, hypocalcemia in 62.5% and cleft palate in 8.3%. Conclusions: A higher detection rate compared to one-feature criterion is obtained when at least two major features of 22q11.2 deletion syndrome are taking into consideration. The criteria applied in this study could be considered by centers in lowincome countries. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to determine the prevalence and characterize the types of hearing loss in pediatric patients with 22q11.2 deletion syndrome (22q11DS). Methods Fifty-eight patients were identified via retrospective chart review performed of patients with 22q11DS between 1996 and 2014. Patient demographics, pertinent family history, associated comorbidities, and degree and type of hearing loss were gathered for each patient. A literature review of the National Library of Medicine's database with a focus on hearing loss and 22q11DS was performed. Results 22 patients (38%) were found to have hearing impairment: 68% with conductive hearing loss, 14% with sensorineural hearing loss, and 18% with mixed hearing loss. Patients with hearing loss regardless of type had a higher prevalence of developmental delay (55%), cleft palate (23%), articulation disorders (77%), and a greater need for tympanostomy tubes (73%) compared to patients with normal hearing. Temporal bone computed tomography scans of 5 patients revealed a variety of abnormalities in the middle and/or inner ears. Conclusion Hearing impairment occurs in up to 38% of 22q11DS patients of both conductive and sensorineural types, with the conductive type being the most common. These patients have a greater need for tympanostomy tubes and a higher prevalence of developmental delay and speech articulation disorders. Early hearing screening and treatment is warranted in this population. [ABSTRACT FROM AUTHOR]

Background and Objectives. The diversity of clinical presentations makes the diagnosis of DiGeorge syndrome (DGS) a diagnostic challenge. The objective of our study was to report the clinical presentation of DGS in the post-childhood period. Methods. A retrospective study, investigating patients diagnosed clinically and genetically with DGS at Sheba Medical Center during the period of 2010-2013. Post-childhood period was defined as age >10 years. Results. During the study period, 29 patients were diagnosed with DGS. Nine (31%) patients with DGS were diagnosed in their post-childhood period. The basis for clinical suspicion was diverse. However, once the suspicion was brought to attention, additional symptoms consistent with DGS were noted at up to 88% of patients who presented characteristic of facial features and developmental delay. Conclusion. Our research shows that diagnosing DGS patients in the post-childhood period is not uncommon. Characteristic facial features and developmental delay, although not leading presenting symptoms, are found very frequently in patients with DGS. [ABSTRACT FROM AUTHOR]

Our patient presented with congenital heart disease (CHD: Tetralogy of Fallot), hypocalcemia, hypoparathyroidism, and facial dysmorphisms. Suspecting DiGeorge syndrome (DGS), a fluorescence in situ hybridization (FISH) analysis for 22q11.2 deletion was made. The child had a hemizygous deletion in the 22q11.2 region, diagnostic of DGS. Unfortunately, the patient succumbed to the heart disease. DGS is the most common microdeletion syndrome, and probably underrecognized due to the varied manifestations. This case stresses the importance of a detailed physical examination and a high index of suspicion for diagnosing this genetic condition. Timely diagnosis can help manage and monitor these patients better and also offer prenatal diagnosis in the next pregnancy. [ABSTRACT FROM AUTHOR]

The chromosome 22q11.2 region has long been implicated in genomic diseases. Some genomic regions exhibit numerous low copy repeats with high identity in which they provide increased genomic instability and mediate deletions and duplications in many disorders. DiGeorge Syndrome is the most common deletion syndrome and reciprocal duplications could be occurring in half of the frequency of microdeletions. We described five patients with phenotypic variability that carries deletions or reciprocal duplications at 22q11.2 detected by Chromosomal Microarray Analysis. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had clinical indication to global developmental delay and a normal karyotype. We observed in our study three microdeletions and two microduplications in 22q11.2 region with variable intervals containing known genes and unstudied transcripts as well as the LCRs that are often flanking and within this genomic rearrangement. The identification of these variants is of particular interest because it may provide insight into genes or genomic regions that are crucial for specific phenotypic manifestations and are useful to assist in the quest for understanding the mechanisms subjacent to genomic deletions and duplications. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the performance of a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for the detection of fetal 22q11.2 deletion syndrome in clinical practice, assess clinical follow-up and review patient choices for women with high-risk results.Methods: In this study, 21 948 samples were submitted for screening for 22q11.2 deletion syndrome using a SNP-based NIPT and subsequently evaluated. Follow-up was conducted for all cases with a high-risk result.Results: Ninety-five cases were reported as high risk for fetal 22q11.2 deletion. Diagnostic testing results were available for 61 (64.2%) cases, which confirmed 11 (18.0%) true positives and identified 50 (82.0%) false positives, resulting in a positive predictive value (PPV) of 18.0%. Information regarding invasive testing was available for 84 (88.4%) high-risk cases: 57.1% (48/84) had invasive testing and 42.9% (36/84) did not. Ultrasound anomalies were present in 81.8% of true-positive and 18.0% of false-positive cases. Two additional cases were high risk for a maternal 22q11.2 deletion; one was confirmed by diagnostic testing and one had a positive family history. There were three pregnancy terminations related to screening results of 22q11.2 deletion, two of which were confirmed as true positive by invasive testing.Conclusions: Clinical experience with this SNP-based non-invasive screening test for 22q11.2 deletion syndrome indicates that these deletions have a frequency of approximately 1 in 1000 in the referral population with most identifiable through this test. Use of this screening method requires the availability of counseling and other management resources for high-risk pregnancies. [ABSTRACT FROM AUTHOR]

Introduction: Heterotopic ossification is defined as the formation of trabecular bone that forms outside the normal sites of the skeletal structure, materializing in soft tissue where it does not usually exist. Methods/Case Report: This is a case report of a 27-dayold baby with a diagnosis of DiGeorge syndrome who developed heterotopic ossification on the dorsum of his right hand. Discussion: Heterotopic ossification in the pediatric population is a rare finding. Very few cases were published in the literature, and we find it important to increase the knowledge on such cases and discuss possible causes with the treatment used with our patient. Results: General treatments of heterotopic ossification include ruling out superimposed infection, physiotherapy to prevent joint involvement, warm compressors during the active phase of development of heterotopic ossification. If the swelling persists to the point that it interferes significantly with the functional capacity of the patient or becomes a cosmetic concern, the only treatment option remaining would be surgery. [ABSTRACT FROM AUTHOR]

Abstract: Now widely adopted, SCID newborn screening has proven effective for early identification and treatment of SCID. In addition, screening has improved our understanding of SCID and related disorders, which are more diverse than originally believed. Newborn screening for SCID illustrates how adding new disorders to newborn screening panels can be enormously beneficial if evidence‐based guidelines are adhered to and if mechanisms are in place to track outcomes and learn along the way. These lessons should guide all additions to newborn screening, including those involving sequencing. [ABSTRACT FROM AUTHOR]

Purpose: Complete DiGeorge syndrome (cDGS) describes a subset of patients with DiGeorge syndrome that have thymic aplasia, and thus are at risk for severe opportunistic infections. Patients with cDGS and mycobacterial infection have not previously been described. We present this case to illustrate that patients with cDGS are at risk for nontuberculous mycobacterial infections and to discuss further antimicrobial prophylaxis prior to thymic transplantation. Methods: A 13-month old male was identified as T cell deficient by the T cell receptor excision circle (TREC) assay on newborn screening, and was subsequently confirmed to have cDGS. He presented with fever and cough, and was treated for chronic aspiration pneumonia as well as Pneumocystis jirovecii infection without significant improvement. It was only after biopsy of mediastinal lymph nodes seen on CT that the diagnosis of disseminated Mycobacterium kansasii was made. We reviewed the literature regarding atypical mycobacterial infections and prophylaxis used in other immunocompromised patients, as well as the current data regarding cDGS detection through TREC newborn screening. Results: Multiple cases of cDGS have been diagnosed via TREC newborn screening, however this is the first patient with cDGS and disseminated mycobacterial infection to be reported in literature. Thymic transplantation is the definitive treatment of choice for cDGS. Prophylaxis with either clarithromycin or azithromycin has been shown to reduce mycobacterial infections in children with advanced human immunodeficiency virus infection. Conclusions: Children with cDGS should receive thymic transplantion as soon as possible, but prior to this are at risk for nontuberculous mycobacterial infections. Severe, opportunistic infections may require invasive testing for diagnosis in patients with cDGS. Antimicrobial prophylaxis should be considered to prevent disseminated mycobacterial infection in these patients. [ABSTRACT FROM AUTHOR]

: DiGeorge syndrome (DGS) presents with a wide spectrum of thymic pathologies. Nationwide neonatal screening programs of lymphocyte production using T-cell recombination excision circles (TREC) have repeatedly identified patients with DGS. We tested what proportion of DGS patients could be identified at birth by combined TREC and kappa-deleting element recombination circle (KREC) screening. Furthermore, we followed TREC/KREC levels in peripheral blood (PB) to monitor postnatal changes in lymphocyte production. Methods: TREC/KREC copies were assessed by quantitative PCR (qPCR) and were related to the albumin control gene in dry blood spots (DBSs) from control (n = 56), severe immunodeficiency syndrome (SCID, n = 10) and DGS (n = 13) newborns. PB was evaluated in DGS children (n = 32), in diagnostic samples from SCID babies (n = 5) and in 91 controls. Results: All but one DGS patient had TREC levels in the normal range at birth, albeit quantitative TREC values were significantly lower in the DGS cohort. One patient had slightly reduced KREC at birth. Postnatal DGS samples revealed reduced TREC numbers in 5 of 32 (16%) patients, whereas KREC copy numbers were similar to controls. Both TREC and KREC levels showed a more pronounced decrease with age in DGS patients than in controls (p<0.0001 for both in a linear model). DGS patients had higher percentages of NK cells at the expense of T cells (p<0.0001). The patients with reduced TREC levels had repeated infections in infancy and developed allergy and/or autoimmunity, but they were not strikingly different from other patients. In 12 DGS patients with paired DBS and blood samples, the TREC/KREC levels were mostly stable or increased and showed similar kinetics in respective patients. Conclusions: The combined TREC/KREC approach with correction via control gene identified 1 of 13 (8%) of DiGeorge syndrome patients at birth in our cohort. The majority of patients had TREC/KREC levels in the normal range. [ABSTRACT FROM AUTHOR]

DiGeorge syndrome (DGS) is one of the most frequently seen chromosomal abnormalities. The major genetic cause of DGS is a microdeletion on chromosome 22q11.2. Majority of the cases are diagnosed during their childhood. DGS is rarely considered and diagnosed in adulthood. Herein, we report the first case of a patient with DGS and azoospermia in the literature. Our patient was a 35-year-old male with mild dysmorphic features, hypernasal voice, mental retardation, and azoospermia. His laboratory tests and echocardiographic assessments were normal. Clinical clues to DGS were hypernasal voice and dysmorphic features with mild mental retardation. The diagnosis of DGS was confirmed by fluorescence in situ hybridization (FISH). Negative effects of cognitive disorders on reproductivity are already known; however, we haven't find any studies in the literature that evaluated infertile patients with DGS using semen analysis, apart from these potential unfavourable effectc of cognitive disorders. Coexistence of DGS and azoospermia may be completely coincidental, but azoospermia can be also one of the unknown clinical features of this syndrome. Many patients with a mild phenotype of DGS may be underdiagnosed. DGS should be considered in adults who have mental, behavioral, or psychiatric disorders with mild dysmorphic features, even in the absence of classical features. [ABSTRACT FROM AUTHOR]

The article presents case studies related to adult hemophagocytic lymphohistiocytosis (HLH) diagnosis. Discussed is the case of 44-year-old man with DiGeorge syndrome as well as the 58-year-old woman on immunosuppressive therapy for organ transplant. Also noted is the case of a 14-year-old girl with idiopathic Epstein-Barr virus-driven disease.

Purpose: To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS). Methods: The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency. Results: During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as 'other'. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant's DNA. Conclusions: Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy. [ABSTRACT FROM AUTHOR]

Background Children with 22q11.2 deletion syndrome (22q11 DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. Method Guardians of children with 22q11 DS were recruited through two medical genetics clinics. Consenting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11 DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. Results Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social-behavioural and cognitive outcomes in children with 22q11 DS. Conclusion Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11 DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11 DS. [ABSTRACT FROM AUTHOR]

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The article presents a case study of a 20-year-old woman with recurrent left frontal headaches and left facial pain. She was diagnosed with velocardiofacial syndrome, which had also been noted shortly her birth. She underwent left functional endoscopic sinus surgery, wherein extensive pneumatization of the left ethmoid sinus was inferiorly encountered. The article also discusses velocardiofacial syndrome, a genetic, multiple-anomaly disease associated with a deletion of DNA from chromosome 22.

In 2009, a federally funded clinical and research consortium ( PID- NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies ( PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency ( CVID), the most prevalent PID. [ABSTRACT FROM AUTHOR]

The article presents an overview of the clinical features of velocardiofacial syndrome, which is the most common microdeletion syndrome. A discussion of an increase which has been seen in the number of children with the syndrome as a result of advances which have been made in diagnostic testing is presented. An increase which has been seen in the number of young children with the syndrome who are referred for early intervention services is discussed. The early development of children with the syndrome and strategies for effective early intervention services for children with the syndrome are examined. Strategies that lead to successful outcomes for children with the syndrome are explored.

Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up. In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys was also performed. In addition, multiplex ligation probe amplification assay was performed to detect deletion size. Phenotypic features leading to the genetic diagnosis were noted. The patients showed a variety of organ malformations including 39 with heart anomalies. Only 20 individuals had been diagnosed with 22q11.2 DS in the first year of life. Four patients had renal and five males had genital malformations. The increased infection susceptibility (excluding otitis media) and most feeding difficulties subsided during early childhood. Speech difficulties started early and were a major problem for many patients at least until 10 years of age. Ten patients developed kyphoscoliosis in late childhood. In teenagers and adults, abnormal social behavior, learning disabilities, and psychiatric symptoms dominated. Our study which also includes adult patients emphasizes a marked change in challenges in individuals with the 22q11.2 deletion syndrome with increasing age. [ABSTRACT FROM AUTHOR]

What's Already Known about This Topic?Aneuploidy screening using cell free DNA (cfDNA) has recently been expanded to include selected microdeletions. However, validation has been limited, and the real‐world positive‐predictive value is unknown. What Does This Study Add?Here we describe three cases of false positive cfDNA microdeletions because of small, non‐pathogenic copy number variants near the region of interest. These findings elucidate one mechanism of false‐positive results with this screening test and suggest that additional validation is necessary before wider use in clinical practice. [ABSTRACT FROM AUTHOR]

Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to identify previously undiagnosed patients as they reach reproductive age and to refer them for genetic counseling. To date, most deletions are de novo, secondary to homologous recombination between low-copy repeat sequences located within 22q11.2. Nonetheless, both somatic and germ line mosaicism has been observed giving unaffected parents a small risk of recurrence. Once present though there is a 50% chance for a person with this contiguous deletion to have an affected child. With this in mind, a variety of prenatal monitoring techniques, as well as, preimplantation genetic diagnosis are available depending on the specific level of risk. [ABSTRACT FROM AUTHOR]

Several recurrent, constitutional genomic disorders are present on chromosome 22q. These include the translocations and deletions associated with DiGeorge and velocardiofacial syndrome and the translocations that give rise to the recurrent t(11;22) supernumerary der(22) syndrome (Emanuel syndrome). The rearrangement breakpoints on 22q cluster around the chromosome-specific segmental duplications of proximal 22q11, which are involved in the etiology of these disorders. While the deletions are the result of nonallelic homologous recombination (NAHR) between low copy repeats or segmental duplications within 22q11, the t(11;22) is the result of rearrangement between palindromic AT-rich repeats on 11q and 22q. Here we describe the mechanisms responsible for these recurrent rearrangements, discuss the recurrent deletion endpoints that are the result of NAHR between chromosome 22q specific low copy repeats as well as present current diagnostic approaches to deletion detection. [ABSTRACT FROM AUTHOR]

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), the most common micro-deletion disorder in humans, is characterized by craniofacial, parathyroid, and thymic defects as well as cardiac outflow tract malformations. Most patients have a similar hemizygous 3 million base pair deletion on 22q11.2. Studies in mouse have shown that Tbx1, a T-box containing transcription factor present on the deleted region, is likely responsible for the etiology of the syndrome. Furthermore, mutations in TBX1 have been found in rare non-deleted patients. Despite having the same sized deletion, most VCFS/DGS patients exhibit significant clinical variability. Stochastic, environmental and genetic factors likely modify the phenotype of patients with the disorder. Here, we review mouse genetics studies, which may help identify possible genetic modifiers for the physical malformations in VCFS/DGS. [ABSTRACT FROM AUTHOR]

In this article, I present an updated account that attempts to explain, in cognitive processing and neural terms, the nonverbal intellectual impairments experienced by most children with deletions of chromosome 22q11.2. Specifically, I propose that this genetic syndrome leads to early developmental changes in the structure and function of clearly delineated neural circuits for basic spatiotemporal cognition. This dysfunction then cascades into impairments in basic magnitude and then numerical processes, because of the central role that representations of space and time play in their construction. I propose that this takes the form of "spatiotemporal hypergranularity"; the increase in grain size and thus reduced resolution of mental representations of spatial and temporal information. The result is that spatiotemporal processes develop atypically and thereby produce the characteristic impairments in nonverbal cognitive domains that are a hallmark feature of chromosome 22q11.2 deletion syndrome. If this hypothesis driven account is supported by future research, the results will create a neurocognitive explanation of spatiotemporal and numerical impairments in the syndrome that is specific enough to be directly translated into the development of targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]