The contribution of medical burden to 22q11.2 deletion syndrome quality of life and functioning.

PURPOSE: To date, there is no systematic method to quantify the medical burden of individuals with 22q11.2 deletion syndrome (22q11.2DS). This study aimed to design a Medical Burden Scale for 22q11.2DS to evaluate the effect of medical symptoms severity on quality of life (QoL) and functioning in individuals with this syndrome. METHODS: Individuals with 22q11.2DS (n = 76) were included in the study. A multidisciplinary group of physicians determined the severity of symptoms (on a scale of 0 to 4) of 8 major medical systems affected in 22q11.2DS, as well as the level of cognitive deficits and psychiatric morbidity. Regression models were used to evaluate the impact of medical, cognitive, and psychiatric symptoms' severity on global assessment of functioning (GAF) and QoL. RESULTS: The total Medical Burden Scale score was significantly associated with both QoL and GAF scores, beyond the effect of the psychiatric and cognitive deficits. We also found that QoL and GAF scores were associated with the severity scores of specific medical systems, particularly neurological symptoms, but also cardiovascular, ear-nose-throat, endocrinology, and orthopedics. CONCLUSION: Quantifying the medical burden of 22q11.2DS individuals is feasible and indicates the overall and specific contribution of medical symptoms to QoL and functioning of 22q11.2DS individuals.

Support to caregivers who have received genetic information about neurodevelopmental and psychiatric vulnerability in their young children: A narrative review.

Diagnosis of pathogenic genetic variants associated with neurodevelopmental and psychiatric disorders (NPDs) is increasingly made early in life. This narrative review focuses on the need for, and provision of, psychological supports following genetic diagnosis. We conducted a literature search of publications on how caregivers are informed about the NPD vulnerability associated with genetic variants, challenges and unmet needs when receiving this information, and whether psychological supports are provided. Given its early recognition, the 22q11.2 deletion has been studied thoroughly for two decades, providing generalizable insights. This literature indicates the complex caregivers' needs related to learning about potential NPD vulnerabilities associated with a genetic variant, include how to communicate the diagnosis, how to identify early signs of NPDs, how to deal with stigma and a lack of medical expertise outside of specialized genetics clinics. With one exception, no publications describe psychotherapeutic support provided to parents. In the absence of support, caregivers struggle with several unmet needs regarding potential longer-term NPD implications of a genetic diagnosis. The field needs to go beyond explaining genetic diagnoses and associated vulnerabilities, and develop approaches to support caregivers with communicating and managing NPD implications across the child's lifespan.

The relationship between oxidative stress and psychotic disorders in 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. This condition is associated with a wide range of symptoms including immune and neuropsychiatric disorders. Notably, psychotic disorders including schizophrenia have a prevalence of âˆ¼ 30%. A growing body of evidence indicates that neuroinflammation and oxidative stress (OS) play a role in the pathophysiology of schizophrenia. In this study, we aim to assess the interaction between 22q11.2DS, OS and schizophrenia. METHODS: Blood samples were collected from 125 participants (including individuals with 22q11.2DS [n = 73] and healthy controls [n = 52]) from two sites: Sheba Medical Center in Israel, and University Hospital Gasthuisberg in Belgium. Baseline OS levels were evaluated by measuring Myeloperoxidase (MPO) activity. A sub-sample of the Israeli sample (n = 50) was further analyzed to examine survival of Peripheral Blood Mononuclear Cells (PBMCs) following induction of OS using vitamin K3. RESULTS: The levels of MPO were significantly higher in all individuals with 22q11.2DS, compared to healthy controls (0.346 ± 0.256 vs. 0.252 ± 0.238, p =.004). In addition, when comparing to healthy controls, the PBMCs of individuals with 22q11.2DS were less resilient to induced OS, specifically the group diagnosed with psychotic disorder (0.233 ± 0.206 for the 22q11.2DS individuals with psychotic disorders, 0.678 ± 1.162 for the 22q11.2DS individuals without psychotic disorders, and 1.428 ± 1.359 for the healthy controls, p =.003, η2 = 0.207). CONCLUSIONS: Our results suggest that dysregulation of OS mechanisms may play a role in the pathophysiology of the 22q11.2DS phenotype. The 22q11.2DS individuals with psychotic disorders were more sensitive to induction of OS, but did not present significantly different levels of OS at baseline. These results may be due to the effect of antipsychotic treatment administered to this sup-group. By elucidating novel molecular pathways, early identification of biochemical risk markers for 22q11.2DS and psychotic disorders can be detected. This can ultimately pave the way to the design of early and more precise interventions of individuals with 22q11.2DS.

Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. METHODS: Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. DISCUSSION: Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study's protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

Perinatal Diagnosis and Management of a Case with Interrupted Aortic Arch, Pulmonary Valve Dysplasia and 22q11.2 Deletion: A Case Report.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder caused by hemizygous microdeletion of the long arm of chromosome 22. It is now known to have a heterogenous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioral phenotypes and psychiatric illness. The purpose of our paper is to present the case of a fetus diagnosed with a complex association of cardiac anomalies: interrupted aortic arch type B, large malalignment-type ventricular septal defect, pulmonary valve dysplasia, and aberrant right subclavian artery for whom the result of genetic testing revealed 22q11.2 deletion. The pregnancy was regularly followed until delivery which took place in Germany so that neonatal cardiac surgery could be performed in an experienced center for cardiac malformations. The distinctivness of our report resides in the fact that it offers a complete image of a case of 22q11.2 deletion syndrome starting from the prenatal diagnosis (and emphasizing on the most relevant sonographic features) and, with parents not opting for termination of pregnancy, ending with the newborn surviving major cardiac surgery, offering thus the possibility to bring into focus postnatal outcome and future expectations in similar cases.

Clinical and Immunological Defects and Outcomes in Patients with Chromosome 22q11.2 Deletion Syndrome.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans and can present with highly variable clinical manifestations. Immune deficiencies occur because of thymic hypoplasia or aplasia. METHODS: This retrospective study included patients diagnosed with 22q11.2DS at a medical center between 2000 and 2021. We analyzed the association between clinical phenotypes, immunological abnormalities, age, and outcomes. RESULTS: Eighty-seven patients with 22q11.2DS had a median diagnostic age of 1.78 months. Patients presented with congenital heart disease (CHD; 86.2%), major infections (75.9%), and failure to thrive (FTT; 58.6%). Autoimmunity, neuropsychiatric disorders, and hypoparathyroidism were significantly associated. Neonatal seizures were associated with early diagnosis before 2 months (OR 8.56, 95% CI 1.21-60.58, P = 0.032). Immunological abnormalities included lymphopenia (93.1%), T lymphopenia (71.9%), CD4+ T lymphopenia (64.1%), a lack of hepatitis B vaccine antibodies (46.2%), and complete DiGeorge syndrome (cDGS) (2.3%). Severe lymphopenia and T lymphopenia improved at 3 years of age. Two patients with cDGS were treated with hematopoietic stem cell transplantation, and one survived. The mortality rate was 12.8% and the estimated 35-year survival probability was 77.5%. Major infections experienced > four times were significantly associated with a decreased survival rate of 60%. Patients with CHD without FTT or recurrent infections had a better 20-year survival rate (96.2%). CONCLUSIONS: CHD, major infection, and FTT were common manifestations and poor prognostic factors. Autoimmunity, neuropsychiatric disorders, and hypoparathyroidism were significantly associated. Although T lymphopenia may improve with age, patients with 22q11.2DS require lifelong monitoring for immune dysregulation.

Challenges in genetic diagnosis, co-occurrence of 22q11.2 deletion syndrome and Noonan syndrome.

Noonan syndrome (NS) is caused by pathogenic variants in genes involved in the RAS/MAPK pathway. On the other hand, 22q11.2 Deletion Syndrome (22q11.2DS) is caused by heterozygous microdeletion on chromosome 22q11.2. The clinical characteristics of both syndromes are expected to be relatively distinct, and, in fact, there is only one report of these syndromes occurring together, but on daily clinical practice and especially in early childhood phenotypes may overlap. In this study, we describe a patient with NS and 22q11.2DS features harboring a heterozygous 2.54 Mb deletion of chromosome 22q11.2 and a variant in LZTR1, c.1531G > A p.(Val511Met). In 1993, Wilson et al reported a patient with both 22q11.2DS and NS, proposing that probably more than one gene is deleted in the proband and that one of the deleted genes is responsible for Noonan's phenotype. In our patient, one of the deleted genes within the 22q11.2 region was the LZTR1 gene which was associated with NS in 2015. This case also highlights the importance of the long-term patients' follow-up to detect evolutionary changes that may appear in the phenotype and alerts clinicians of the co-occurrence of two syndromes that may manifest over time.

An examination of adaptive behavior and functional outcomes in adults with 22q11.2 deletion syndrome: A parental perspective.

22q11.2 Deletion Syndrome (22q11DS) is a genetic syndrome caused by a chromosomal microdeletion. It affects approximately 1 in 850-992 pregnancies, and its clinical manifestations include congenital heart disease, gastrointestinal symptoms, and psychiatric illnesses. The study examined the relationship between adaptive behavior and functional outcomes, educational attainment, employment, and independent living, and whether age, gender, intellectual disability, presence of psychiatric disorder, and close friendships could predict levels of adaptive behavior. Parents of adults with 22q11DS (n = 101; 48 male and 54 female) completed the Waisman Activities of Daily Living Scale, demographic details, and questions elicited employment, education, and relationships status. Analysis conducted in SPSS, included descriptive statistics, measures of association, Analysis of Variance, logistic and linear regressions. Differences in levels of overall adaptive behavior were found regarding employment and living status, but not in educational attainment. Having close friendships was associated with adaptive behavior as well as the likelihood of living independently. Further research is needed, ideally using prospective designs and purposive sampling strategies. This needs to examine how social and communication deficits impact relationship building and how they are affected by the clinical manifestations of 22q11DS. It also needs to focus on how different social structures interface with levels of adaptive behavior.

Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature.

BACKGROUND: 22q11.2 deletion syndrome (DiGeorge syndrome) is associated with multiple organ dysfunctions such as cardiac defects, immunodeficiency, and hypoplasia of parathyroid glands. Moreover, the phenotype of 22q11.2 DS has clinical variability and heterogeneity. CASE PRESENTATION: In this report, we present the case of a 35-year-old patient with a past medical history that included recurrent infections, mild learning difficulties in childhood, pediatric obesity, and cataract. He was admitted to the endocrinology department for the management of hypogonadism and hypocalcemia. During the 3-year follow-up, the patient gradually developed primary hypoparathyroidism, hypogonadism, chronic renal failure, and heart failure, and his medical condition deteriorated. Meanwhile, in order to improve clinicians' awareness of the endocrine manifestations of adult 22q11.2 DS and reduce missed diagnoses, we reviewed 28 case reports of adult 22q11.2 DS to analyze the clinical characteristics. DISCUSSION: Here, we report the case of a young man diagnosed with 22q11.2 DS presented a rare combination of multiple endocrine disorders. This is the first time that a patient with 22q11.2DS had late-onset hypogonadism caused by primary testicular failure combined with decreased pituitary gonadotropin reserve in a patient with 22q11.2DS.

Prevalence and incidence of psychotic disorders in 22q11.2 deletion syndrome: a meta-analysis.

22q11.2 deletion syndrome (22q.11.2DS) might be one of the strongest genetic risk factors for psychosis, but robust estimates of prevalence and incidence of psychotic disorders in this condition are not available. To address this gap, we performed a multistep systematic PRISMA/MOOSE-compliant literature search of articles reporting prevalence (primary outcome) or incidence (secondary outcome) of psychotic disorders in 22q11.2DS samples (protocol: https://osf.io/w6hpg) using random-effects meta-analysis, subgroup analyses and meta-regressions. The pooled prevalence of psychotic disorders was 11.50% (95%CI:9.40-14.00%), largely schizophrenia (9.70%, 95%CI:6.50-14.20). Prevalence was significantly higher in samples with a mean age over 18 years, with both psychiatric and non-psychiatric comorbidities and recruited from healthcare services (compared to the community). Mean age was also significantly positively associated with prevalence in meta-regressions (p < 0.01). The pooled incidence of psychotic disorders was 10.60% (95%CI:6.60%-16.70%) at a mean follow-up time of 59.27 ± 40.55 months; meta-regressions were not significant. To our knowledge, this is the first comprehensive systematic review and meta-analysis of the prevalence and incidence of psychotic disorders in 22q11.2DS individuals. It demonstrates that around one in ten individuals with 22q11.2DS displays comorbid psychotic disorders, and around one in ten will develop psychosis in the following five years, indicating that preventive approaches should be implemented systematically in 22q11.2DS.

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

Pharyngeal epithelial deletion of Tbx1 causes caudal pharyngeal arch defect but not cardiac conotruncal anomaly.

TBX1 is a major disease gene of 22q11.2 deletion syndrome (22q11.2DS). It is expressed in all three germ layers of pharyngeal apparatus to control the complicated morphogenesis. The haploinsufficiency of pharyngeal endodermal or ectodermal, but not mesodermal Tbx1 causes aortic arch patterning defect. However, the mesodermal deletion of Tbx1 causes much severer pharyngeal and cardiovascular defect than either pharyngeal endodermal or ectodermal Tbx1 deletion does. It is inconsistent with the conventional thought that the invagination of pharyngeal epithelia drives pharyngeal segmentation. Therefore, we asked whether pharyngeal ectodermal and ectodermal Tbx1 can compensate the loss of each other. Here we carefully characterized pharyngeal epithelia-specific Fgf15Cre and Fgf15HspCre lines and used them to perform pharyngeal epithelia-specific deletion. Our data showed that the percentage of E18.5 Fgf15Cre;Tbx1flox/+ embryos with aortic arch patterning defects was similar to that of E10.5 Fgf15Cre;Tbx1flox/+ embryos with the 4th pharyngeal arch artery (PAA) defect, indicating that there is no significant recovery from the initial PAA defect, in contrast to germ line haploinsufficiency. Fgf15Cre;Tbx1flox/flox embryos had hypoplastic caudal pharyngeal arch and defective derivatives, but cardiac OFT development was not affected. The phenotypic spectrum of simultaneous Tbx1 deletion in both pharyngeal ectoderm and endoderm is strikingly similar to what presents with single pharyngeal endoderm or ectoderm-specific deletion of Tbx1. The absence of synergistic effect indicates intimate topographic interactions among pharyngeal endoderm and ectoderm, through which deletion of a gene in one tissue may disrupt the development of adjacent tissues and thereby lead to similar morphological phenotypes in either tissue-specific deletion.

Vitamin D status and the immune assessment in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is characterized by a heterogeneous phenotype, including alterations in phospho-calcium metabolism and immunodeficiency. We analyzed vitamin D status and the immune assessment, focusing on T cell subpopulations and dendritic cells (DCs) in a cohort of 17 pediatric 22q11.2DS patients and 17 age-matched healthy subjects. As antigen-presenting cells, DCs are the main target of vitamin D, promoting a tolerogenic T cell response. Patients were subdivided into three groups according to the parameters of phospho-calcium metabolism and serum levels of 25OHD: normal values, vitamin D deficiency and hypoparathyroidism. Different degrees of T cell deficiency, ranging from normal to partial T cell numbers, were observed in the cohort of patients. The group with vitamin D deficiency showed a significant reduction of naive T cells and a significant increase of central memory T cells compared to controls. In this group the number of circulating DCs was significantly reduced. DC decrease affected both myeloid and plasmacytoid DC subsets (mDCs and pDCs), with the most relevant reduction involving pDCs. A direct correlation between 25OHD levels and recent thymic emigrant (RTE) and DC number was identified. Despite the limited cohort analyzed, our results show that deficiency of the pDC subset in patients with 22q11.2DS may be included among the causative factors of the progressive increase of risk of autoimmune diseases in these patients. As most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, we suggest a potential role of vitamin D supplementation in preventing autoimmune or proinflammatory diseases in 22q11.2DS.

Exploring the potential association among sleep disturbances, cognitive impairments, and immune activation in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.

[Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention]. / Prise en charge pédopsychiatrique des patients présentant un syndrome microdélétionnel 22q11.2 : du soin à la prévention.

22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.

Gene expression profiling in the developing secondary palate in the absence of Tbx1 function.

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.

Club foot in association with the 22q11.2 deletion syndrome: An observational study.

The 22q11.2 Deletion Syndrome (22q11.2DS) occurs in ~1:3,000-6,000 individuals. Features less typically associated with 22q11.2DS, such as orthopedic manifestations, may be overlooked or may not lead to appropriate diagnostic testing. Club foot has a general population prevalence of ~1:1,000 and has been occasionally described in association with 22q11.2DS. Our hypothesis is that the prevalence of club foot is higher in patients with 22q11.2DS. We performed a retrospective review in two specialized 22q11.2DS centers to determine the prevalence of club foot. "True club foot" requires treatment (either conservative or surgical), therefore we only included those patients with proof of treatment. We investigated whether congenital heart disease (CHD) and/or cleft palate were associated with the presence of club foot within 22q11.2DS. The records of 1,466 patients were reviewed. Of these, 48 (3.3%) had confirmation of club foot (95% Confidence Interval: 2.4-4.3): 22 (46%) had a bilateral, 12 (25%) left, and 14 (29%) right club foot. Within our study, neither a CHD and/or a cleft palate were associated with a club foot. The prevalence of club foot in 22q11.2DS is 30 times higher than that observed in the general population. This suggests the diagnosis of club foot, especially in the face of other typically associated abnormalities of 22q11.2DS, should provoke consideration of 22q11.2DS as an underlying diagnosis, particularly in the neonatal setting.

Neurologic challenges in 22q11.2 deletion syndrome.

Children with 22q11.2 deletion syndrome often come to medical attention due to signs and symptoms of neurologic dysfunction. It is imperative to understand the expected neurologic development of patients with this diagnosis in order to be alert for the potential neurologic complications, including cortical malformations, tethered cord, epilepsy, and movement disorders. We present an update of brain imaging findings from the CHOP 22q and You Center, a review of the current literature, and our current management practices for neurological issues.

Neurodevelopmental outcome in 22q11.2 deletion syndrome and management.

The 22q11.2 deletion syndrome (22q11.2 DS) places affected individuals at an increased risk for neurodevelopmental/cognitive, behavioral and social-emotional difficulties. Poor cognitive functioning and intellectual disabilities, attention and executive functioning deficits, learning disorders, emotional dysregulation and impairments in social processing are common among individuals with 22q11.2 DS. Identifying risk and protective/resilience factors that can be detected in early life and can predict neurodevelopmental outcomes for people with 22q11.2 DS is of significant clinical relevance and might allow for early detection and intervention. Given the focus of this review, we will discuss the possible contributing factors that influence the neurodevelopmental outcome in 22q1.2 DS, the cognitive phenotype in 22q11.2 DS, the different developmental trajectories across life span, and the implications for clinical practice and management.

Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review.

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a risk-of-bias tool, a best-evidence synthesis was performed and the prevalence data was extracted. Sixty-nine published manuscripts described 58 orthopaedic manifestations in a total of 6,055 patients. The prevalence of at least one cervical or occipital anomaly is 90.5-100% (strong evidence). Fourteen studies (n = 2,264) revealed moderate evidence for a wide scoliosis prevalence of 0.6-60%. Two studies demonstrated that 5-6.4% of all 22q11.2DS patients required surgical scoliosis correction. Fifteen studies (n = 2,115) reported a 1.1-13.3% prevalence of clubfoot with moderate evidence. Other reported orthopaedic manifestations are patellar dislocation (10-20%), juvenile rheumatic arthritis (3.75%), impaired growth and skeletal anomalies like polydactyly (1.0-3.7%), syndactyly (11-11.8%), butterfly vertebrae (11.1%) and 13 ribs (2-19%). Orthopaedic findings are important manifestations of the 22q11.2DS, both in bringing patients to diagnostic attention and in requiring surveillance and appropriate intervention. Data on these manifestations are scattered and incomprehensive. Routinely screening for cervical anomalies, scoliosis, and upper and lower limb malformations is recommended in this vulnerable group of patients.