Neural Crest.

This chapter discusses the role of cardiac neural crest cells in the formation of the septum that divides the cardiac arterial pole into separate systemic and pulmonary arteries. Further, cardiac neural crest cells directly support the normal development and patterning of derivatives of the caudal pharyngeal arches, including the great arteries, thymus, thyroid, and parathyroids. Recently, cardiac neural crest cells have also been shown to indirectly influence the development of the secondary heart field, another derivative of the caudal pharynx, by modulating signaling in the pharynx. The contribution and function of the cardiac neural crest cells has been learned in avian models; most of the genes associated with cardiac neural crest function have been identified using mouse models. Together these studies show that the neural crest cells may not only critical for normal cardiovascular development but also may be involved secondarily because they represent a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Cardiac neural crest cells span from the caudal pharynx into the outflow tract, and therefore may be susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations resulting from genetic and/or environmental insults necessarily requires better understanding the role of cardiac neural crest cells in cardiac development.

Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare single nucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common single nucleotide polymorphisms associated with the risk for TOF.

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Human Genetics of Ventricular Septal Defect.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

Outcomes of primary repair of cleft palate using sommerled intravelar veloplasty associated with velocardiofacial syndrome.

OBJECTIVES: Velocardiofacial syndrome, a prevalent microdeletion syndrome occurring in 1 in 2000-4000 live births, is marked by speech and language disorders, notably velopharyngeal dysfunction. This study investigates speech outcomes, nasometric and videofluoroscopic results before and after primary repair of cleft palate using the Sommerlad intravelar veloplasty (SIVV) technique within the Isfahan cleft care team for patients with velocardiofacial syndrome. METHODS: Employing a quasi-experimental design, 19 participants with velocardiofacial syndrome, who underwent primary cleft palate repair by the Isfahan cleft care team, were included through convenience sampling. Perceptual and instrumental outcomes were assessed pre-and post-operatively. Statistical analysis encompassed paired t-tests and the non-parametric Wilcoxon signed-rank test (p < 0.05). RESULTS: The study identified no statistically significant differences between pre-and post-surgical speech outcome parameters and nasalance scores. Nonetheless, a significant distinction emerged in the velopharyngeal closure ratio based on fluoroscopic evaluation (p = 0.038). CONCLUSION: The efficacy of the SIVV technique in treating velopharyngeal dysfunction in velocardiofacial syndrome patients is inconclusive, demanding further research. Post-surgical speech outcomes are influenced by surgical technique, hypotonia, apraxia of speech, and surgery timing. Notably, an elevated velopharyngeal valve closure ratio, though anatomically indicative, does not exclusively predict surgical success.

A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens.

Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TBX1, implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TBX1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TBX1 expression levels compared to the ancestral allele. Tbx1-knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TBX1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TBX1 contributes to the formation of skull base and vertebral structures found in Homo sapiens.

The effectiveness and tolerability of pharmacotherapy for psychosis in 22q11.2 Deletion Syndrome: A systematic review.

OBJECTIVE: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans with over 180 phenotypic expressions. Approximately 30-40% of affected individuals will develop psychosis and 25% meet the criteria for schizophrenia. Despite this, pharmacotherapy for managing psychosis in 22q11.2DS is poorly understood and 22q11.2DS psychosis is frequently labelled as treatment resistant. The objectives of this paper are to evaluate the effectiveness and tolerability of pharmacotherapy for 22q11.2DS psychosis and evaluate the evidence for treatment resistance. METHOD: A systematic search was performed using CINAHL, The Cochrane Library (Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials and Cochrane Clinical Answers), EMBASE, PsycINFO, PubMed, Scopus and Web of Science Core Collection from inception to December 2022. It yielded 39 case reports, 6 case series and 1 retrospective study which met the inclusion criteria. RESULTS: Based on the current literature, individuals with 22q11.2DS psychosis experience a greater rate of medical co-morbidities such as cardiac arrhythmias, seizures and movement disorders, which complicate pharmacotherapy. Poor tolerability rather than poor clinical response motivates the switching of antipsychotics, which may explain the labelling of treatment resistance in the literature. CONCLUSION: There are insufficient data to recommend a single antipsychotic for 22q11.2DS psychosis. Nonetheless, with proactive management of co-morbidities, antipsychotic medication in 22q11.2DS psychosis is an effective treatment commonly resulting in improvement in quality of life.

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.

Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.

Distinct neurocognitive profiles and clinical phenotypes associated with copy number variation at the 22q11.2 locus.

Rare genetic variants that confer large effects on neurodevelopment and behavioral phenotypes can reveal novel gene-brain-behavior relationships relevant to autism. Copy number variation at the 22q11.2 locus offer one compelling example, as both the 22q11.2 deletion (22qDel) and duplication (22qDup) confer increased likelihood of autism spectrum disorders (ASD) and cognitive deficits, but only 22qDel confers increased psychosis risk. Here, we used the Penn Computerized Neurocognitive Battery (Penn-CNB) to characterized neurocognitive profiles of 126 individuals: 55 22qDel carriers (MAge = 19.2 years, 49.1% male), 30 22qDup carriers (MAge = 17.3 years, 53.3% male), and 41 typically developing (TD) subjects (MAge = 17.3 years, 39.0% male). We performed linear mixed models to assess group differences in overall neurocognitive profiles, domain scores, and individual test scores. We found all three groups exhibited distinct overall neurocognitive profiles. 22qDel and 22qDup carriers showed significant accuracy deficits across all domains relative to controls (episodic memory, executive function, complex cognition, social cognition, and sensorimotor speed), with 22qDel carriers exhibiting more severe accuracy deficits, particularly in episodic memory. However, 22qDup carriers generally showed greater slowing than 22qDel carriers. Notably, slower social cognition speed was uniquely associated with increased global psychopathology and poorer psychosocial functioning in 22qDup. Compared to TD, 22q11.2 copy number variants (CNV) carriers failed to show age-associated improvements in multiple cognitive domains. Exploratory analyses revealed 22q11.2 CNV carriers with ASD exhibited differential neurocognitive profiles, based on 22q11.2 copy number. These results suggest that there are distinct neurocognitive profiles associated with either a loss or gain of genomic material at the 22q11.2 locus.

Sleep in 22q11.2 Deletion Syndrome: Current Findings, Challenges, and Future Directions.

PURPOSE OF REVIEW: To summarize current literature available on sleep in 22q11.2 Deletion Syndrome (22q11.2DS; Velocardiofacial or DiGeorge Syndrome), a neurogenetic disorder caused by a hemizygous deletion in a genomic region critical for neurodevelopment. Due to the greatly increased risk of developmental psychiatric disorders (e.g., autism and schizophrenia) in 22q11.2DS, this review focuses on clinical correlates of sleep disturbances and potential neurobiological underpinnings of these relationships. RECENT FINDINGS: Sleep disturbances are widely prevalent in 22q11.2DS and are associated with worse behavioral, psychiatric, and physical health outcomes. There are reports of sleep architecture and sleep neurophysiology differences, but the literature is limited by logistical challenges posed by objective sleep measures, resulting in small study samples to date. Sleep disturbances in 22q11.2DS are prevalent and have a substantial impact on well-being. Further investigation of sleep in 22q11.2DS utilizing multimodal sleep assessments has the potential to provide new insight into neurobiological mechanisms and a potential trans-diagnostic treatment target in 22q11.2DS.

Description of Neuropsychological Profile in Patients with 22q11 Syndrome.

BACKGROUND: 22q11 deletion syndrome (SD22Q11) is a neurogenetic condition that is associated with a high risk of neurodevelopmental disorders and intellectual disability. People with SD22Q11, both children and adults, often experience significant difficulties in social interactions, as well as neurocognitive deficits, and have elevated rates of autism spectrum disorder (ASD). Despite this, the relationship between basic cognitive processes and cognitive ability in this population has not been well investigated. METHODS: the main objective of the present research is to describe the neurocognitive profile of people with SD22Q11 using standardized neuropsychological assessment instruments. For this purpose, a sample of 10 participants aged between 7 and 15 years was administered an assessment battery with the following tests: WISC-V, CELF-5, NEPSY-II, CSAT-R, CARAS-R, TP, MABC-2, BRIEF-2, SENA, DABAS, ABAS-II, SCQ, and ADOS-2. RESULTS: the results showed IQ scores in the borderline normal range, as well as difficulties in language functions, social skills, motor skills, and executive functions. CONCLUSIONS: an individualized assessment taking into account the globality of its expression, and a therapeutic approach adapted to the specific needs of children with this syndrome is essential.

Increased Central Auditory Gain and Decreased Parvalbumin-Positive Cortical Interneuron Density in the Df1/+ Mouse Model of Schizophrenia Correlate With Hearing Impairment.

Background: Hearing impairment is a risk factor for schizophrenia. Patients with 22q11.2 deletion syndrome have a 25% to 30% risk of schizophrenia, and up to 60% also have varying degrees of hearing impairment, primarily from middle-ear inflammation. The Df1/+ mouse model of 22q11.2 deletion syndrome recapitulates many features of the human syndrome, including schizophrenia-relevant brain abnormalities and high interindividual variation in hearing ability. However, the relationship between brain abnormalities and hearing impairment in Df1/+ mice has not been examined. Methods: We measured auditory brainstem responses, cortical auditory evoked potentials, and/or cortical parvalbumin-positive (PV+) interneuron density in over 70 adult mice (32 Df1/+, 39 wild-type). We also performed longitudinal auditory brainstem response measurements in an additional 20 animals (13 Df1/+, 7 wild-type) from 3 weeks of age. Results: Electrophysiological markers of central auditory excitability were elevated in Df1/+ mice. PV+ interneurons, which are implicated in schizophrenia pathology, were reduced in density in the auditory cortex but not the secondary motor cortex. Both auditory brain abnormalities correlated with hearing impairment, which affected approximately 60% of adult Df1/+ mice and typically emerged before 6 weeks of age. Conclusions: In the Df1/+ mouse model of 22q11.2 deletion syndrome, abnormalities in central auditory excitability and auditory cortical PV+ immunoreactivity correlate with hearing impairment. This is the first demonstration of cortical PV+ interneuron abnormalities correlating with hearing impairment in a mouse model of either schizophrenia or middle-ear inflammation.

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.

Distinct Neurocognitive Profiles and Clinical Phenotypes Associated with Copy Number Variation at the 22q11.2 Locus.

Rare genetic variants that confer large effects on neurodevelopment and behavioral phenotypes can reveal novel gene-brain-behavior relationships relevant to autism. Copy number variation at the 22q11.2 locus offer one compelling example, as both the 22q11.2 deletion (22qDel) and duplication (22qDup) confer increased likelihood of autism spectrum disorders (ASD) and cognitive deficits, but only 22qDel confers increased psychosis risk. Here, we used the Penn Computerized Neurocognitive Battery (Penn-CNB) to characterized neurocognitive profiles of 126 individuals: 55 22qDel carriers (MAge=19.2 years, 49.1% male), 30 22qDup carriers (MAge=17.3 years, 53.3 % male), and 41 typically developing (TD) subjects (MAge=17.3 years, 39.0 % male). We performed linear mixed models to assess group differences in overall neurocognitive profiles, domain scores, and individual test scores. We found all three groups exhibited distinct overall neurocognitive profiles. 22qDel and 22qDup carriers showed significant accuracy deficits across all domains relative to controls (Episodic Memory, Executive Function, Complex Cognition, Social Cognition, and Sensorimotor Speed), with 22qDel carriers exhibiting more severe accuracy deficits, particularly in Episodic Memory. However, 22qDup carriers generally showed greater slowing than 22qDel carriers. Notably, slower social cognition speed was uniquely associated with increased global psychopathology and poorer psychosocial functioning in 22qDup. Compared to TD, 22q11.2 CNV carriers failed to show age-associated improvements in multiple cognitive domains. Exploratory analyses revealed 22q11.2 CNV carriers with ASD exhibited differential neurocognitive profiles, based on 22q11.2 copy number. These results suggest that there are distinct neurocognitive profiles associated with either a loss or gain of genomic material at the 22q11.2 locus.

Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Clinical Approach.

The 22q11.2 deletion syndrome is a multisystemic disorder characterized by a marked variability of phenotypic features, making the diagnosis challenging for clinicians. The wide spectrum of clinical manifestations includes congenital heart defects-most frequently conotruncal cardiac anomalies-thymic hypoplasia and predominating cellular immune deficiency, laryngeal developmental defects, midline anomalies with cleft palate and velar insufficiency, structural airway defects, facial dysmorphism, parathyroid and thyroid gland hormonal dysfunctions, speech delay, developmental delay, and neurocognitive and psychiatric disorders. Significant progress has been made in understanding the complex molecular genetic etiology of 22q11.2 deletion syndrome underpinning the heterogeneity of clinical manifestations. The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers and environmental factors, as well as the impact of hemizygosity on the remaining allele, contribute to the intricate genotype-phenotype relationships. This comprehensive review has been aimed at highlighting the molecular genetic background of 22q11.2 deletion syndrome in correlation with a clinical multidisciplinary approach.

Executive functioning in preschoolers with 22q11.2 deletion syndrome and the impact of congenital heart defects.

BACKGROUND: Executive functioning (EF) is an umbrella term for various cognitive functions that play a role in monitoring and planning to effectuate goal-directed behavior. The 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome, is associated with a multitude of both somatic and cognitive symptoms, including EF impairments in school-age and adolescence. However, results vary across different EF domains and studies with preschool children are scarce. As EF is critically associated with later psychopathology and adaptive functioning, our first aim was to study EF in preschool children with 22q11DS. Our second aim was to explore the effect of a congenital heart defects (CHD) on EF abilities, as CHD are common in 22q11DS and have been implicated in EF impairment in individuals with CHD without a syndromic origin. METHODS: All children with 22q11DS (n = 44) and typically developing (TD) children (n = 81) were 3.0 to 6.5 years old and participated in a larger prospective study. We administered tasks measuring visual selective attention, visual working memory, and a task gauging broad EF abilities. The presence of CHD was determined by a pediatric cardiologist based on medical records. RESULTS: Analyses showed that children with 22q11DS were outperformed by TD peers on the selective attention task and the working memory task. As many children were unable to complete the broad EF task, we did not run statistical analyses, but provide a qualitative description of the results. There were no differences in EF abilities between children with 22q11DS with and without CHDs. CONCLUSION: To our knowledge, this is the first study measuring EF in a relatively large sample of young children with 22q11DS. Our results show that EF impairments are already present in early childhood in children with 22q11DS. In line with previous studies with older children with 22q11DS, CHDs do not appear to have an effect on EF performance. These findings might have important implications for early intervention and support the improvement of prognostic accuracy.

Childhood manifestations of 22q11.2 deletion syndrome: A Finnish nationwide register-based cohort study.

AIM: The aim of the study was to describe the clinical manifestations of 22q11.2 deletion syndrome patients in the Finnish paediatric population. METHODS: Nationwide registry data including all diagnoses and procedures of every public hospital in Finland between 2004 and 2018 along with mortality and cancer registry data were retrieved. Patients born during the study period and with an ICD-10 code of D82.1 or Q87.06 were included as having 22q11.2 deletion syndrome. A control group was formed with patients born during the study period and with benign cardiac murmur diagnosed under the age of 1 year. RESULTS: We identified 100 pediatric patients with 22q11.2 deletion syndrome (54% males, median age at diagnosis <1 year, median follow-up 9 years). Cumulative mortality was 7.1%. Among patients with 22q11.2 deletion syndrome, 73.8% had congenital heart defects, 21.8% had cleft palate, 13.6% had hypocalcaemia, and 7.2% had immunodeficiencies. Furthermore, 29.6% were diagnosed with autoimmune diseases, 92.9% had infections, and 93.2% had neuropsychiatric and developmental issues during follow-up. Malignancy was found in 2.1% of the patients. CONCLUSION: The 22q11.2 deletion syndrome is associated with increased mortality and substantial multimorbidity in children. A structured multidisciplinary approach is necessary for managing patients with 22q11.2 deletion syndrome.

Otorhinologic Disorders in 22q11.2 Deletion Syndrome.

OBJECTIVE: Investigate incidence and natural history of otologic and sinonasal disease associated with 22q11.2 deletion syndrome. STUDY DESIGN: Case series. SETTING: Tertiary care children's hospital. METHODS: Charts from consecutive children born 2000 to 2018 with a diagnosis of 22q11.2 deletion, DiGeorge, or velocardiofacial syndrome based on the International Classification of Diseases (ICD)-9 and ICD-10 codes were reviewed. Otologic and rhinologic diagnoses and surgeries and immune and microbiologic laboratory findings were collected from the medical record. RESULTS: After the exclusion of patients with no 22q11.2 deletion (n = 101), otologic care at an outside hospital (n = 59), and loss to follow-up prior to 3 years of age (n = 22), 128 were included. Males comprised 80 (62.5%) patients, 115 (89.8%) were white, and the median age at genetic confirmation of 22q11.2 deletion was 119 days (range 0 days to 14.6 years). Recurrent acute otitis media (RAOM), chronic otitis media with effusion, chronic rhinosinusitis, and recurrent acute sinusitis were diagnosed in 54 (42.2%), 37 (28.9%), 10 (7.8%), and 8 (6.3%), respectively. Tympanostomy tubes were placed in 49 (38.3%). Adenoidectomy and sinus surgery were performed in 38 (29.7%) and 4 (3.1%), respectively. Neither immunoglobulin nor cluster of differentiation deficiency increased the odds of RAOM diagnosis, tympanostomy tube placement, or chronic/recurrent sinusitis. Methicillin-resistant Staphylococcus aureus was the most common organism in sinus cultures (4/13, 30.8%). Streptococcus pneumonia dominated otorrhea cultures (11/21, 52.4%). CONCLUSION: Approximately half of children with 22q11.2 deletion may experience otologic disease that often requires surgical management. Future studies will utilize a larger cohort to examine the role of immunodeficiency in otologic and rhinologic disease in this population.

Association of Ear Anomalies and Hearing Loss Among Children With 22q11.2 Deletion Syndrome.

OBJECTIVE: To identify inner and middle ear anomalies in children with 22q11.2 deletion syndrome (22q11DS) and determine associations with hearing thresholds. STUDY DESIGN: Retrospective study. SETTING: Two tertiary care academic centers. METHODS: Children presenting with 22q11DS between 2010 and 2020 were included. Temporal bone imaging with computed tomography or magnetic resonance imaging was reviewed by 2 neuroradiologists. RESULTS: Twenty-two patients (12 female, 10 male) were identified. Forty-four ears were evaluated on imaging. There were 15 (34%) ears with abnormal semicircular canals, 14 (32%) with abnormal vestibules, 8 (18%) with abnormal ossicles, 6 (14%) with enlarged vestibular aqueducts, 4 (9.1%) with abnormal facial nerve canals, and 4 (9.1%) with cochlear anomalies. There were 25 ears with imaging and audiometric data. The median pure tone average (PTA) for ears with any structural abnormality was 41.0 dB, as compared with 28.5 dB for ears without any structural abnormality (P = .21). Of 23 ears with normal imaging, 6 (26%) had hearing loss in comparison with 13 (62%) of 21 ears with abnormalities (P = .02). Total number of anomalies per ear was positively correlated with PTA (Pearson correlation coefficient, R = 0.479, P = .01). PTA was significantly higher in patients with facial nerve canal anomalies (P = .002), vestibular aqueduct anomalies (P = .05), and vestibule anomalies (P = .02). CONCLUSIONS: Semicircular canal, ossicular, vestibular aqueduct, and vestibular anomalies were detected in children with 22q11DS, especially in the setting of hearing loss. Careful evaluation of anatomic anomalies is needed prior to surgical intervention in these patients.

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

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