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.

Social skills in neurodevelopmental disorders: a study using role-plays to assess adolescents and young adults with 22q11.2 deletion syndrome and autism spectrum disorders.

BACKGROUNDS: Social skills are frequently impaired in neurodevelopmental disorders and genetic conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). Although often assessed with questionnaires, direct assessment provides a more valid estimate of the constructs. Role-plays (i.e., simulates situational settings) therefore appear to be an appropriate indicator of social skills in daily life. METHODS: This co-registered study involved 53 individuals with 22q11DS, 34 individuals with ASD, and 64 typically developing (TD) peers aged 12-30 years. All participants were assessed with role-plays as well as parent-reported questionnaires and clinical interviews focusing on social skills, functioning and anxiety. RESULTS: Both clinical groups showed impaired social skills compared to TD, but distinct social profiles emerged between the groups. Individuals with 22q11DS displayed higher social appropriateness and clarity of speech but weaker general argumentation and negotiation skills, with the opposite pattern observed in participants with ASD. No association was found between social skills measured by direct observation and caregiver reports. Social anxiety, although higher in clinical groups than in TD, was not associated with role-plays. CONCLUSIONS: This study highlights the need to train social skills through tailored interventions to target the specific difficulties of each clinical population. It also highlights the importance of combining measures as they do not necessarily provide the same outcome.

Congenital cytomegalovirus infection in a preterm infant with 22q11.2 deletion syndrome and immunological abnormalities.

The 22q11.2 deletion syndrome has many complications; one of them is immunodeficiency. However, the time of onset and the degree of immunodeficiency can vary. We report a case of a preterm infant with congenital cytomegalovirus infection complicated with 22q11.2 deletion syndrome and immunological abnormalities. Ultrasonography revealed pulmonary atresia, ventricular septal defect, major aortopulmonary collateral artery, and thymic hypoplasia. His serum chemistry tests on admission revealed immunoglobulin G, A, and M levels of 1,547 mg/dL, 70 mg/dL, and 274 mg/dL, respectively. A surface antigen analysis of the peripheral lymphocytes using flow cytometry revealed the following: relatively low CD4-positive T-cell levels (18.1%; 1,767/µL), very high CD8-positive T-cell levels (58.9%; 5,751/µL), and CD4/CD8 ratio of 0.31. The level of T-cell receptor excision circles was relatively low at 17.5 copies/µL. After birth, the CD8-positive T-cell level began to gradually decrease, whereas the CD4/CD8 ratio began to increase. Thrombocytopenia, neutropenia, and skin petechiae were observed on admission. However, the condition improved. Treatment for congenital cytomegalovirus infection was not provided due to the absence of viremia. Unfortunately, the patient died suddenly on the 158th day of life, and the cause of death was unknown. To the best of our knowledge, no association between 22q11 deletion syndrome and cCMV has been described in the recent medical literature. According to the calculation, around one newborn infant who have both 22q11 deletion syndrome and cCMV infection will be born each year in Japan. Healthcare providers should pay more attention to this medical situation in the future.

Untargeted metabolomic, and proteomic analysis identifies metabolic biomarkers and pathway alterations in individuals with 22q11.2 deletion syndrome.

INTRODUCTION: The chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles. OBJECTIVES: Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time. METHODS: In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression. RESULTS: We observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P < 0.05) in 22q11.2DS as compared to TD, including those involved in 70 pathways such as gene expression, the PI3K-Akt signaling pathway and the complement system. Within participants with 22q11.2DS, no significant changes in those with and without medical or psychiatric conditions were observed. CONCLUSION: To our knowledge, this is the first report on plasma metabolic and proteomic profiling and on the identification of unique biomarkers in 22q11.2DS. These findings may suggest the potential role of the identified metabolites and proteins as biomarkers for the onset of comorbid conditions in 22q11.2DS. Ultimately, the altered protein pathways in 22q11.2DS may provide insights of the biological mechanisms underlying the neurodevelopmental phenotype and may provide missing molecular outcome measures in future clinical trials to assess early-diagnosis treatment and the efficacy of response to targeted treatment.

Evaluation of the effect of palatoplasty on the quality of life and speech outcomes in patients with velocardiofacial syndrome.

BACKGROUND: Children diagnosed with velocardiofacial syndrome (VCFS) suffer from various disabilities. Palatal abnormalities, as well as speech and language impairment, adversely affect a child's quality of life (QoL) and are some of the most distressing aspects for the parents of these children. OBJECTIVES: The present study aimed to explore the effect of palatoplasty on the health-related quality of life (HRQoL) and speech outcomes in children with VCFS. MATERIAL AND METHODS: The study recruited 20 patients (N = 20) with VCFS and connected speech, aged 3 years or older, having either undiagnosed submucous cleft palate (SMCP) or velopharyngeal insufficiency (VPI), and requiring primary cleft palate surgery or revision surgery. Speech assessment was conducted prior to palatoplasty and 6 months after the surgery. Intelligibility and hypernasality were evaluated using the Cleft Audit Protocol for Speech - Augmented (CAPS-A). The parent proxy-report form of the Pediatric Quality of Life Inventory (PedsQL™) was used to evaluate and compare the HRQoL of the VCFS patients before and after palatoplasty. RESULTS: Significant improvement in the HRQoL scores was achieved after the surgery across all domains (physical, emotional, social, and school functioning), especially in the emotional and social dimensions (p < 0.000). The post-operative speech assessment based on CAPS-A demonstrated improvement in speech intelligibility and hypernasality in the majority of patients. CONCLUSIONS: Given that children with VCFS face various medical and social problems, suitable palatal interventions are beneficial, improving both the speech ability and QoL of these children.

Remote assessment of the Penn computerised neurocognitive battery in individuals with 22q11.2 deletion syndrome.

BACKGROUND: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome. The current study compares in-person and remote assessments of the Penn computerised neurocognitive battery (CNB). METHODS: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in-person at a laboratory (n = 222) or remotely (n = 162). RESULTS: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. CONCLUSIONS: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains.

Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

Atypical cortical networks in children at high-genetic risk of psychiatric and neurodevelopmental disorders.

Although many genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Resting-state oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, neurodevelopmental symptoms and IQ. Children with 22q11.2DS had altered network activity and connectivity in high and low frequency bands, reflecting modified local and long-range cortical circuitry. Alpha and theta band connectivity were negatively associated with ASD symptoms while frontal high frequency (gamma band) activity was positively associated with ASD symptoms. Alpha band activity was positively associated with cognitive ability. These findings suggest that haploinsufficiency at the 22q11.2 locus impacts short and long-range cortical circuits, which could be a mechanism underlying neurodevelopmental and psychiatric vulnerability in this high-risk group.

Assessing Complication Risk of Pressure Equalizing Tube Placement in Children With Velocardiofacial Syndrome (22q11.2 Deletion Syndrome/DiGeorge Syndrome).

INTRODUCTION: Persistent tympanic membrane perforation is a known complication of pressure-equalizing (PE) tube insertion. Conductive hearing loss and otorrhea can necessitate surgical repair of these perforations. Long-term tympanostomy tube placement can increase the risk of these complications. Patients with velocardiofacial syndrome (VCFS) typically require prolonged PE tube placement and are thought to have higher risk of requiring additional otologic interventions after PE tube placement. To date, no work has established rates of post-PE tube complications requiring myringoplasty or tympanoplasty in patients with VCFS. METHODS: A retrospective case review including all patients with VCFS at a single large children's hospital between the years 2000 and 2020 was performed. Number of PE tube insertions required and additional otologic interventions performed were the primary endpoints assessed. RESULTS: Of 212 total patients with VCFS, 66 (31%) underwent PE tube placement. Of these children, 46 (70%) required 2 or more sets of PE tubes. A total of 53 patients (80.3%) required no otologic interventions apart from PE tube insertions. Of the 13 patients (19.7%) requiring additional otologic surgery, 6 (9.5%) underwent myringoplasty, and 9 patients (13.6%) required tympanoplasty. There was no significant difference in tympanoplasty (P > 1), myringoplasty (P > 1), or other surgical intervention rates (P = .7464) between VCFS patients with any type of cleft palate versus those with anatomically normal palates. CONCLUSION: This work suggests that most VCFS patients that require tubes, require at least 2 sets of PE tubes, and that the rate of post-PE tube complications requiring further otologic surgery is an order of magnitude higher than the rate established at this institution. Counseling for PE tube placement in VCFS patients may require specific dialogue regarding the substantially increased risk of complications and effort to build appropriate expectations for surgical outcomes regardless of palatal status.

A case-control study of bleeding risk in children with 22q11.2 deletion syndrome undergoing cardiac surgery.

Previous research suggests that individuals with 22q11.2 deletion syndrome (DS) have an increased risk of bleeding following cardiac surgery. However, current guidelines for management of patients with 22q11.2DS do not provide specific recommendations for perioperative management. This study sought to identify specific risk factors for bleeding in this patient population. Examine the factors determining bleeding and transfusion requirements in patients with 22q11.2DS undergoing cardiac surgery. This was a single center review of patients who underwent cardiac surgery at the Children's Hospital of Philadelphia from 2000 to 2016. Data was extracted from the medical record. Frequency of bleeding events, laboratory values, and transfusion requirements were compared. We included 226 patients with 22q11.2DS and 506 controls. Bleeding events were identified in 13 patients with 22q11.2DS (5.8%) and 27 controls (5.3%). Platelet counts were lower among patients with 22q11.2DS than in control patients, but not statistically different comparing bleeding to not bleeding. Patients with 22q11.2DS received more transfusions (regardless of bleeding status). However, multivariate analysis showed only procedure type was associated with increased risk of bleeding (p = .012). The overall risk of bleeding when undergoing cardiac surgery is not different in patients with 22q11.2DS compared to non-deleted patients. Though platelet counts were lower in patients with 22q11.2DS, only procedure type was significantly associated with an increased risk of bleeding.

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.

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.

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.

Self-reported eye contact sensitivity and face processing in chromosome 22q11.2 deletion syndrome.

INTRODUCTION: 22q11.2 deletion syndrome (22qDS) has been associated with varying levels of social impairments, and with atypical visual scanning of faces. The present study explored whether self-reported sensitivity to eye contact might be related to these phenomena. METHOD: Individuals with confirmed 22qDS were interviewed about their experience and possible discomfort with eye contact. In cases where individuals expresesed discomfort, they were subsequently asked about coping mechanisms used to deal with this discomfort. In addition to self-reported eye contact discomfort, gaze to emotional faces was examined using eye tracking. RESULTS: In the subgroup of individuals who reported discomfort during eye contact, eye tracking results revealed a lower amount of gaze in the eyes of neutral faces, as well as the absence of the typical left visual field (LVF) bias, indicative of alterations in hemispheric lateralization. This subgroup also scored lower on a measure of everyday functioning. CONCLUSIONS: Our results show that, by simply asking individuals with this social and communicative disorder about eye gaze discomfort, we may better understand the specific challenges that they experience. Moreover, information gained from such first-person reports together with eye-tracking measures further informs about the integrity of their face processing system, as well as about the nature and degree of impairment in this population.

Abnormal developmental trajectory and vulnerability to cardiac arrhythmias in tetralogy of Fallot with DiGeorge syndrome.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Ventricular dysfunction and cardiac arrhythmias are well-documented complications in patients with repaired TOF. Whether intrinsic abnormalities exist in TOF cardiomyocytes is unknown. We establish human induced pluripotent stem cells (hiPSCs) from TOF patients with and without DiGeorge (DG) syndrome, the latter being the most commonly associated syndromal association of TOF. TOF-DG hiPSC-derived cardiomyocytes (hiPSC-CMs) show impaired ventricular specification, downregulated cardiac gene expression and upregulated neural gene expression. Transcriptomic profiling of the in vitro cardiac progenitors reveals early bifurcation, as marked by ectopic RGS13 expression, in the trajectory of TOF-DG-hiPSC cardiac differentiation. Functional assessments further reveal increased arrhythmogenicity in TOF-DG-hiPSC-CMs. These findings are found only in the TOF-DG but not TOF-with no DG (ND) patient-derived hiPSC-CMs and cardiac progenitors (CPs), which have implications on the worse clinical outcomes of TOF-DG patients.

Risk of thyroid neoplasms in patients with 22q11.2 deletion and DiGeorge-like syndromes: an insight for follow-up.

Introduction: The chromosome 22q11.2 deletion syndrome comprises phenotypically similar diseases characterized by abnormal development of the third and fourth branchial arches, resulting in variable combinations of congenital heart defects, dysmorphisms, hypocalcemia, palatal dysfunction, developmental or neuropsychiatric disorders, and impairment of the immune system due to thymic dysfunction. Other genetic syndromes, often called DiGeorge-like, share clinical and immunological features with 22q11.2 deletion syndrome. This syndrome has been rarely associated with malignancies, mainly hematological but also hepatic, renal, and cerebral. Rarely, malignancies in the head and neck region have been described, although no aggregate of data on the development of thyroid neoplasms in patients with this clinical phenotype has been conducted so far. Materials and methods: To characterize this possible association, a multicenter survey was made. Thus, we present a case series of five pediatric patients with 22q11.2 deletion syndrome or DiGeorge-like syndrome who were occasionally found with confirmed or highly suspected neoplasms of the thyroid gland during their follow-up. In three cases, malignancies were histologically confirmed, but their outcome was good due to an early recognition of suspicious nodules and precocious surgery. Conclusions: This study underlines for clinicians the higher risk of neoplasms in the head and neck district for patients affected by these syndromes. It also emphasizes the importance of a prolonged clinical and ultrasound follow-up for patients with this clinical and immunological phenotype.

Pharyngeal Flap Versus Sphincter Pharyngoplasty for the Treatment of Velopharyngeal Insufficiency in 22q11.2 Deletion Syndrome: Preliminary Findings From a Systematic Review.

The purpose of this study was to examine and compare surgical and speech outcomes of the posterior pharyngeal flap and sphincter pharyngoplasty following surgical management of velopharyngeal insufficiency in patients with 22q11.2 deletion syndrome (22q11.2DS). This systematic review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses checklist and guidelines. Selected studies were chosen using a 3-step screening process. The 2 primary outcomes of interest were speech improvement and surgical complications. Preliminary findings based on included studies suggest a slightly higher rate of postoperative complications with the posterior pharyngeal flap in patients with 22q11.2DS but a lower percentage of patients needing additional surgery compared with the sphincter pharyngoplasty group. The most reported postoperative complication was obstructive sleep apnea. Results from this study provide some insight into speech and surgical outcomes following pharyngeal flap and sphincter pharyngoplasty in patients with 22q11.2DS. However, these results should be interpreted with caution due to inconsistencies in speech methodology and lack of detail regarding surgical technique in the current literature. There is a significant need for standardization of speech assessments and outcomes to help optimize surgical management of velopharyngeal insufficiency in individuals with 22q11.2DS.