Language Profiles of School-Aged Children with 22q11.2 Copy Number Variants.

Although it is known that copy number variants (CNVs) on chromosome 22, such as 22q11.2 deletion (22q11.2DS) and 22q11.2 duplication (22q11.2Dup) syndromes, are associated with higher risk for neurodevelopmental issues, few studies have examined the language skills across 22q11.2Dup nor compared them with the 22q11.2DS. The current study aims to characterize language abilities in school-aged children with 22q11.2Dup (n = 29), compared to age-matched children with 22q11.2DS (n = 29). Standardized language tests were administered, assessing receptive and expressive language skills across different language domains. Results indicate that children with 22q11.2Dup demonstrate significantly more language problems compared to the general population. Mean language skills were not significantly different among children with 22q11.2 CNVs in this cohort. While children with 22q11.2DS demonstrated language difficulties starting at the word level, the most common language problems in children with 22q11.2Dup started at the sentence level. Importantly, both expressive and receptive language as well as lexico-semantic and morphosyntactic domains were impaired in children with 22q11.2 CNVs. Early identification, therapeutic intervention, and follow-up of language impairments in children with 22q11.2Dup are recommended to support language development and to reduce longitudinal impact of language and communicative deficits.

Speech Outcomes Following Operative Management of Velopharyngeal Dysfunction (VPD) in Non-Syndromic Post-Palatoplasty Cleft Palate Patients.

OBJECTIVE: Approximately 30% of patients with a history of repaired cleft palate (CP) go on to suffer from velopharyngeal dysfunction (VPD). This study discusses the operative management of VPD and postoperative speech outcomes in a cohort of CP patients. SETTING: An academic tertiary pediatric care center. METHODS: Retrospective cohort study. PATIENTS: Patients with history of repaired CP (Veau I-IV) who underwent operative management of VPD between January 1st, 2010 and December 31st, 2020. Operative modalities were posterior pharyngeal flap (PPF), sphincter pharyngoplasty (SPP), Furlow palate re-repair, and buccal myomucosal flap palate lengthening (PL). OUTCOME MEASURES: The primary outcome measure is postoperative speech improvement evaluated by the Pittsburgh Weighted Speech Scale (PWSS). RESULTS: 97 patients met inclusion criteria. 38 patients with previous straight-line primary palatoplasty underwent Furlow re-repair; these patients were significantly younger (7.62 vs 11.14, P < .001) and were more likely to have severe VPD per PWSS (OR 4.28, P < .01, 95% CI 1.46-12.56) when compared to VPD patients with previous Furlow repair. 21.1% of these patients required an additional non-revisional VPD procedure. The remaining patients underwent a non-revision procedure (26 PPF, 22 SPP, 11 PL); all experienced significant (P < .001 on paired t-test) reductions in PWSS total and subgroup VPD severity scores without difference in improvement between operation types. SPP was statistically associated with all-cause complication (OR 2.79, 95% CI 1.03-7.59, P < .05) and hyponasality (OR 3.27, 95% CI 1.112-9.630, P < .05). CONCLUSION: Furlow re-repair reduced need for additional VPD operations. Speech outcomes between non-revisional operations are comparable, but increased complications were seen in SPP.

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

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

Early language measures associated with later psychosis features in 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11DS) is associated with impaired cognitive functions and increased risk for schizophrenia spectrum disorders. Speech and language deficits are prominent, with evidence of decline anteceding emergence of psychosis. There is paucity of data examining language function in children with 22q11DS with follow-up assessment of psychosis spectrum (PS) symptoms. We examined the association between early language measures, obtained clinically, and PS status, obtained on average 10.1 years later, in 166 youths with 22q11DS, with repeated language testing in 48. Participants were administered the Preschool Language Scale (receptive/expressive), and/or, for school aged children, the Clinical Evaluation of Language Fundamentals (receptive/expressive), and age appropriate IQ tests. The structured interview for prodromal syndromes (SIPS) assessed PS symptoms. We found that performance on all preschool measures showed age associated decline, and males performed more poorly on core composite (receptive/expressive) and receptive language measures. For language assessment later in childhood, poorer performance was consistently associated with subsequent PS status. Furthermore, steeper age-related decline was seen in the PS group across language measures and marginally for full-scale IQ. These findings suggest that while preschool language testing is useful in characterizing performance decline in individuals with 22q11DS, it does not robustly differentiate those with subsequent PS from those without. However, language testing in the school age population can help identify individuals with 22q11DS who are at risk for psychosis. Such data are needed for elucidating a lifespan trajectory for affected individuals and may help understand pathways to psychosis applicable to the general population.

Orofacial Manifestations of Stickler Syndrome: An Analysis of Speech Outcome and Facial Growth After Cleft Palate Repair.

PURPOSE: The purpose of this study was to characterize airway problems, speech outcomes, and facial growth in patients with Stickler syndrome undergoing cleft palate repair. METHODS: A retrospective, longitudinal study was performed at the Children's Hospital of Philadelphia on 25 patients with Stickler syndrome and 53 nonsyndromic patients with clefts of the secondary palate repaired between 1977 and 2000. Airway problems were characterized by the incidence of Pierre Robin Sequence (PRS) and the necessity for surgical airway management. Speech was analyzed using the Pittsburgh weighted values for speech symptoms associated with velopharyngeal incompetence (VPI). Longitudinal anthropometric measurements represented up to 12 years of longitudinal cephalofacial growth. RESULTS: Seventy-two percent of patients with Stickler syndrome were diagnosed with PRS, 55.6% of whom required surgical airway management. Conversely, 20.8% of nonsyndromic patients were diagnosed with PRS (P < 0.0001), 18% of whom required surgical intervention (P < 0.05). Speech outcomes were poorer in patients with Stickler syndrome with 40% demonstrating borderline VPI and 13.3% demonstrating VPI, compared with 21.8% and 9.1%, respectively, in the nonsyndromic group. Both groups exhibited significantly shallower upper and mid facial depths and wider upper facial breadths when compared with normal standards of facial growth. Although there was a tendency toward decreased facial depths in patients with Stickler syndrome relative to nonsyndromic patients, the differences were nonsignificant. CONCLUSIONS: Patients with Stickler syndrome show significant potential for early airway compromise and a poorer prognosis for speech outcome after cleft palate repair. Their cephalofacial growth does not differ significantly from that of nonsyndromic cleft palate patients.

Speech-Language Disorders in 22q11.2 Deletion Syndrome: Best Practices for Diagnosis and Management.

Purpose Speech and language disorders are hallmark features of 22q11.2 deletion syndrome (22qDS). Learning disabilities, cognitive deficits, palate abnormalities, velopharyngeal dysfunction, behavioral differences, and various medical and psychiatric conditions are also major features of this syndrome. The goal of this document is to summarize the state of the art of current clinical and scientific knowledge regarding 22qDS for speech-language pathologists (SLPs) and provide recommendations for clinical management. Method Best practices for management of individuals with 22qDS were developed by consensus of an expert international group of SLPs and researchers with expertise in 22qDS. These care recommendations are based on the authors' research, clinical experience, and literature review. Results This document describes the features of 22qDS as well as evaluation procedures, treatment protocols, and associated management recommendations for SLPs for the often complex communication disorders present in this population. Conclusion Early diagnosis and appropriate management of speech-language disorders in 22qDS is essential to optimize outcomes and to minimize the long-term effects of communication impairments. Knowledge of this diagnosis also allows anticipatory care and guidance regarding associated features for families, health care, and educational professionals.

What is new with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia.

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.

Hearing Loss after Cardiac Surgery in Infancy: An Unintended Consequence of Life-Saving Care.

OBJECTIVES: To investigate the prevalence of hearing loss after cardiac surgery in infancy, patient and operative factors associated with hearing loss, and the relationship of hearing loss to neurodevelopmental outcomes. STUDY DESIGN: Audiologic and neurodevelopmental evaluations were conducted on 348 children who underwent repair of congenital heart disease at the Children's Hospital of Philadelphia as part of a prospective study evaluating neurodevelopmental outcomes at 4 years of age. A prevalence estimate was calculated based on presence and type of hearing loss. Potential risk factors and the impact of hearing loss on neurodevelopmental outcomes were evaluated. RESULTS: The prevalence of hearing loss was 21.6% (95% CI, 17.2-25.9). The prevalence of conductive hearing loss, sensorineural hearing loss, and indeterminate hearing loss were 12.4% (95% CI, 8.8-16.0), 6.9% (95% CI, 4.1-9.7), and 2.3% (95% CI, 0.6-4.0), respectively. Only 18 of 348 subjects (5.2%) had screened positive for hearing loss before this study and 10 used a hearing aid. After adjusting for patient and operative covariates, younger gestational age, longer postoperative duration of stay, and a confirmed genetic anomaly were associated with hearing loss (all P < .01). The presence of hearing loss was associated with worse language, cognition and attention (P <.01). CONCLUSIONS: These findings suggest that the prevalence of hearing loss in preschool children after heart surgery in infancy may be 20-fold higher than in the 1% prevalence seen in the general population. Younger gestational age, presence of a genetic anomaly, and longer postoperative duration of stay were associated with hearing loss. Hearing loss was associated with worse neurodevelopmental outcomes.

Rates of autism and potential risk factors in children with congenital heart defects.

OBJECTIVE: Atypical development, behavioral difficulties, and academic underachievement are common morbidities in children with a history of congenital heart defects and impact quality of life. Language and social-cognitive deficits have been described, which are associated with autism spectrum disorders. The current study aimed to assess the rates of autism spectrum disorders in a large sample of children with a history of congenital heart defects and to assess medical, behavioral, and individual factors that may be associated with the risk of autism spectrum disorders. DESIGN: Participants included 195 children with a history of congenital heart defects, who are followed in a large-scale longitudinal study. Measures included behavioral data from 4-year-old neurodevelopmental evaluations and parent-report data from a later annual follow-up. RESULTS: Using established cutoffs on an autism spectrum disorder screener, children with congenital heart defects showed higher rates of "possible" autism spectrum disorders than national rates, (Chi-square Test of Equal Proportions), all Ps < .05. A stepwise variable selection method was used to create a "best prediction model" and multivariable logistic regression was used to identify variables predicting diagnostic status. Factors associated with diagnostic risk included medical (delayed sternal closure, prematurity, positive genetic findings), behavioral (cognitive, language, attention issues), and individual (socioeconomic, cultural/racial) variables. ROC analyses identified a cutoff of 7 to maximize sensitivity/specificity based on parent-reported diagnosis. CONCLUSIONS: Risk of autism spectrum disorder screening status in children with congenital heart defects was higher than expected from population rates. Findings highlight the need for referral to a specialist to assess the presence and severity of social-communication issues and congenital heart defects population-specific screening thresholds for children with concern for autism spectrum disorders.

International Adoptees With Cleft Lip and/or Palate: Lessons Learned From a Growing Population.

BACKGROUND: International adoptees with cleft lip and palate (CLP) are a growing population in the United States. They represent a clinical challenge, presenting at various ages and stages of cleft repair. METHODS: A retrospective review of patients seen at the CLP Program at the Children's Hospital of Philadelphia (CHOP) between 1998 and 2012 with a history of international adoption was performed. Demographics, surgical histories, and long-term speech outcomes were reviewed. RESULTS: Seventy-four female and 77 male patients were evaluated. Patients were adopted at an average age of 2.3 years (range, 0.4-8.6 years); 80.8% (n = 122) of patients were adopted from China. The rate of international cleft adoption increased by approximately 1.5 patients per year (r = 0.7739, P < 0.001); 13.2% (n = 19) of all subjects with cleft palates had oronasal fistulas (ONFs) that required repair. The ONF rates for primary palatoplasties at CHOP were significantly lower compared to both preadoption repairs (P = 0.002) and postadoption repairs at outside hospitals (P = 0.01); 14.8% (n = 21) of all patients had secondary surgeries for velopharyngeal incompetence (VPI). Rates of secondary surgery for VPI were also significantly lower for primary palatoplasties at CHOP compared to both preadoption repairs (P = 0.0018) and postadoption repairs at outside hospitals (P = 0.0033). CONCLUSIONS: International adoptees with CLP are a growing population and are clinically challenging with high ONF rates and high secondary surgery rates for VPI. We recommend expedited repair of unoperated cleft palates in adoptees older than 18 months. Adopted patients with CLP should be rigorously evaluated for the need for speech therapy and secondary surgeries to correct for VPI.

Perioperative risk factors in patients with 22q11.2 deletion syndrome requiring surgery for velopharyngeal dysfunction.

Objective : To determine the prevalence of cardiac, cervical spine, and carotid artery abnormalities in patients with 22q11.2 deletion syndrome (22q11.2DS) undergoing surgery for velopharyngeal dysfunction (VPD), associations between the presence of these abnormalities, and whether these abnormalities caused changes in surgical management or perioperative complications. Design : Retrospective review. Setting : Tertiary pediatric hospital. Patients : Seventy patients with 22q11.2DS with complete preoperative cervical vascular and spine imaging and cardiac evaluation between 1998 and 2011. Main Outcome Measures : Incidence of cardiac, cervical spine, and vascular abnormalities; related perioperative complications; and resulting changes in surgical, anesthetic, or perioperative management plan. Results : Cardiac abnormalities occurred in 45 patients (64.3%), and 8 patients required cardiac anesthesia. Thirty-eight patients (54.3%) had at least one vascular abnormality of the neck, and 14% had medial deviation of the internal carotid artery. Surgery was not performed in one patient, and the surgical plan was altered in three patients because of carotid anomalies. Cervical spine abnormalities were found in 24 patients (34.3%); 8 patients demonstrated radiographic evidence of cervical instability and were treated with spinal precautions during surgery. The presence of one anomaly was not predictive of any other finding, and there were no complications related to the heart, cervical spine, or carotid arteries. Conclusions : Anomalies of the heart, cervical spine, and cervical vasculature occur frequently in 22q11.2DS, vary drastically in severity, and are impossible to predict based on other features of the syndrome. Preoperative diagnosis of these comorbidities with routine imaging can minimize the risk of avoidable surgical complications.

Long term speech outcomes following late cleft palate repair using the modified Furlow technique.

OBJECTIVES: Published reports and previous studies from our institution have reported worse overall speech results, including significantly higher rates of persistent articulation errors, in patients undergoing palatoplasty at age >18 months. This study further investigates the effects of late repair on long term speech outcomes. METHODS: A retrospective review was performed of non-syndromic patients undergoing primary palatoplasty at age >18 months between 1980 and 2006 at our institution. Longitudinal speech results were compared based on reason for late repair and age at repair. RESULTS: Forty-one patients were greater than 18 months of age at the time of palatoplasty, and 24 fit criteria for longitudinal data analysis. There was a statistically significant improvement in nasality scores at Time Point 1 for international adoptees compared to the non-adopted population (p=0.04). Patients with submucosal clefts were found to have significantly less severe nasal emission scores at Time Point 1 compared to those with overt clefts (p=0.04), but not at Time Point 2. There were no significant differences between scores if repair was performed between 18 and 36 months or >36 months, nor any difference in incidence of articulation errors between subgroups of patients with late repair at either Time Point. CONCLUSION: Our experience demonstrates that cleft palate repair after 18 months of age is associated with a significantly increased incidence of articulation errors associated with VPI, irrespective of reason for late repair, highlighting the persistence of learned compensatory behaviors in speech and the importance of proceeding with early repair.

22q11.2 Deletion syndrome and obstructive sleep apnea.

UNLABELLED: Otolaryngologic problems are common in the 22q11.2 deletion syndrome (DS) population. Structural anomalies and retrognathia may predispose these patients to obstructive sleep apnea (OSA). The current association of OSA in this population is not defined. OBJECTIVE: (1) Define the frequency of OSA in 22q11.2 DS patients referred for polysomnography (PSG). (2) Determine if OSA is present before and/or after surgery to correct velopharyngeal insufficiency (VPI). (3) Determine effect of prior adenotonsillectomy on OSA following VPI surgery. METHODS: Retrospective review of children treated from 2006 to 2013 in a tertiary care setting identified by ICD-9 758.32 (velocardiofacial syndrome) and 279.11 (DiGeorge syndrome). Surgical history and PSG data were abstracted from the identified records. RESULTS: We identified 323 patients with 22q11.2 DS; 57 (18%) were screened at any point in care using PSG and 15 patients had PSG at multiple time points in care. In most cases, indication for PSG was sleep disordered breathing or pre-operative planning. Overall, 33 patients met criteria for OSA on PSG, accounting for 10.2% of our study population; however, the percentage of patients with OSA was significantly higher within the group of 57 patients (58%) who were screened with PSG. Twenty-one of the screened patients (54%) had PSG prior to any pharyngeal surgery and had mild to severe OSA (obstructive apnea/hypopnea index (AHI): median 5.1/h, range 1.9-25.6). Eighteen patients had PSG after adenotonsillectomy; 8 of these patients (44%) had mild to moderate OSA (median AHI 2.95/h, range 1.9-5.4). Seventeen patients had PSG after VPI surgery (palatopharyngeal flap (PPF) n=16, sphincteroplasty n=1). Nine of these patients (53%) had mild to severe OSA (median AHI 3/h, range 1.9-15). Patients who underwent adenotonsillectomy prior to VPI surgery had similar prevalence of OSA (50%, n=12) than those who did not (OSA: 60%, n=5, p=0.70). Most children had mild OSA. CONCLUSION: Prevalence of OSA in this population of 22q11.2 DS patients is higher than expected in the general population. OSA risk is highest after VPI surgery, and may be decreased by adenotonsillectomy. Providers should have awareness of increased prevalence of OSA in patients with 22q11.2 DS. Close monitoring for OSA is warranted given the likelihood of subsequent surgical intervention that can worsen OSA.

A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients.

OBJECTIVE: Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0. METHODS: Patients from Children's Hospital of Philadelphia, USA and Wilhelmina Children's Hospital Utrecht, The Netherlands were stratified based on palatal phenotype (overt cleft, submucosal cleft, bifid uvula). SNPs in 21 candidate genes for cleft palate were analyzed for genotype-phenotype association. In addition, TBX1 sequencing was carried out. Quality control and association analyses were conducted using the software package PLINK. RESULTS: Genotype and phenotype data of 101 unrelated patients (63 non-cleft subjects (62.4%), 38 cleft subjects (37.6%)) were analyzed. A Total of 39 SNPs on 10 genes demonstrated a p-value ≤0.05 prior to correction. The most significant SNPs were found on FGF10. However none of the SNPs remained significant after correcting for multiple testing. CONCLUSIONS: Although these results are promising, analysis of additional samples will be required to confirm that variants in these regions influence risk for cleft palate or palatal anomalies in 22q11.2DS patients.

Results of genome-wide analyses on neurodevelopmental phenotypes at four-year follow-up following cardiac surgery in infancy.

BACKGROUND: Adverse neurodevelopmental sequelae are reported among children who undergo early cardiac surgery to repair congenital heart defects (CHD). APOE genotype has previously been determined to contribute to the prediction of these outcomes. Understanding further genetic causes for the development of poor neurobehavioral outcomes should enhance patient risk stratification and improve both prevention and treatment strategies. METHODS: We performed a prospective observational study of children who underwent cardiac surgery before six months of age; this included a neurodevelopmental evaluation between their fourth and fifth birthdays. Attention and behavioral skills were assessed through parental report utilizing the Attention Deficit-Hyperactivity Disorder-IV scale preschool edition (ADHD-IV), and Child Behavior Checklist (CBCL/1.5-5), respectively. Of the seven investigated, three neurodevelopmental phenotypes met genomic quality control criteria. Linear regression was performed to determine the effect of genome-wide genetic variation on these three neurodevelopmental measures in 316 subjects. RESULTS: This genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with three neurobehavioral phenotypes in the postoperative children ADHD-IV Impulsivity/Hyperactivity, CBCL/1.5-5 PDPs, and CBCL/1.5-5 Total Problems. The most predictive SNPs for each phenotype were: a LGALS8 intronic SNP, rs4659682, associated with ADHD-IV Impulsivity (P=1.03 × 10(-6)); a PCSK5 intronic SNP, rs2261722, associated with CBCL/1.5-5 PDPs (P=1.11 × 10(-6)); and an intergenic SNP, rs11617488, 50 kb from FGF9, associated with CBCL/1.5-5 Total Problems (P=3.47 × 10(-7)). 10 SNPs (3 for ADHD-IV Impulsivity, 5 for CBCL/1.5-5 PDPs, and 2 for CBCL/1.5-5 Total Problems) had p<10(-5). CONCLUSIONS: No SNPs met genome-wide significance for our three neurobehavioral phenotypes; however, 10 SNPs reached a threshold for suggestive significance (p<10(-5)). Given the unique nature of this cohort, larger studies and/or replication are not possible. Studies to further investigate the mechanisms through which these newly identified genes may influence neurodevelopment dysfunction are warranted.

Is cardiac diagnosis a predictor of neurodevelopmental outcome after cardiac surgery in infancy?

OBJECTIVES: To determine whether a cardiac diagnosis is a predictor of neurodevelopmental outcomes after infant cardiac surgery. METHODS: Infants with ventricular septal defect (VSD), tetralogy of Fallot (TOF), transposition of the great arteries (TGA), and hypoplastic left heart syndrome (HLHS) in a study of apolipoprotein E (APOE) polymorphisms, and neurodevelopmental outcome underwent neurodevelopmental and genetic evaluation at 4 years of age. The domains tested included cognition, language, speech, memory, executive function, visual-motor, fine motor, and reading and math skills. RESULTS: Testing was completed in 178 patients with normal genetic evaluations: VSD (n = 26), TOF (n = 44), TGA (n = 41), and HLHS (n = 67). No differences were found in gestational age, ethnicity, APOE genotype, socioeconomic status, or maternal education among groups. Patient age at the first surgery was significantly lower for patients with TGA and HLHS compared with those with TOF and VSD. The postoperative length of stay was significantly longer for HLHS than all other groups and for TGA compared with TOF and VSD. HLHS correlated significantly with the use of deep hypothermic circulatory arrest and multiple operations. The mean scores for each domain were within normal limits for all groups. Compared with the other patients, those with HLHS had significantly lower scores for cognition, fine motor skills, executive function, and math skills. No significant differences were found among the TGA, TOF or VSD patients for any domain. Significant impairments in at least 1 domain were identified in 8% (2/25) of patients with VSD, 20% (8/41) with TOF, 17% (7/41) with TGA, and 18% (12/65) with HLHS. After correction for the demographic, preoperative, and operative variables, no significant differences were found among the groups for any domain. CONCLUSIONS: The mean scores for the neurodevelopmental outcomes domains tested were in the normal range for preschool children with no recognized genetic syndromes after surgery for VSD, TOF, TGA, and HLHS. In each diagnostic group, the number of children with impairments in at least 1 domain increased compared with the general population. Unadjusted neurodevelopmental outcomes for HLHS were lower for cognition, fine motor skills, executive function, and math skills compared with the other patients. After correction for the demographic, preoperative, and operative variables, no significant differences were found among the groups for any domain. The specific cardiac diagnosis determines a large portion of the variation in these covariates. Therefore, although HLHS did predict for poorer outcomes in some domains, it did not add predictive power to the other factors considered.

Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery.

OBJECTIVE: The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery. METHODS: A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. RESULTS: Parents of 380 children completed the neurobehavioral measures. Child Behavior Checklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE epsilon2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P = .009). In each case, the epsilon4 allele was associated with a better outcome. APOE epsilon2 carriers had impaired social skills, compared with epsilon4 carriers (P = .009). CONCLUSIONS: For preschool-aged children with congenital heart defects requiring surgery, parental rating scales showed an increased prevalence of restricted behavior patterns, inattention, and impaired social interactions. The APOE epsilon2 allele was associated with increased behavior problems, impaired social interactions, and restricted behavior patterns.

Velopharyngeal anatomy in 22q11.2 deletion syndrome: a three-dimensional cephalometric analysis.

OBJECTIVE: 22q11.2 deletion syndrome is the most common genetic cause of velopharyngeal dysfunction (VPD). Magnetic resonance imaging (MRI) is a promising method for noninvasive, three-dimensional (3D) assessment of velopharyngeal (VP) anatomy. The purpose of this study was to assess VP structure in patients with 22q11.2 deletion syndrome by using 3D MRI analysis. DESIGN: This was a retrospective analysis of magnetic resonance images obtained in patients with VPD associated with a 22q11.2 deletion compared with a normal control group. SETTING: This study was conducted at The Children's Hospital of Philadelphia, a pediatric tertiary care center. PATIENTS, PARTICIPANTS: The study group consisted of 5 children between the ages of 2.9 and 7.9 years, with 22q11.2 deletion syndrome confirmed by fluorescence in situ hybridization analysis. All had VPD confirmed by nasendoscopy or videofluoroscopy. The control population consisted of 123 unaffected patients who underwent MRI for reasons other than VP assessment. INTERVENTIONS: Axial and sagittal T1- and T2-weighted magnetic resonance images with 3-mm slice thickness were obtained from the orbit to the larynx in all patients by using a 1.5T Siemens Visions system. OUTCOME MEASURES: Linear, angular, and volumetric measurements of VP structures were obtained from the magnetic resonance images with VIDA image-processing software. RESULTS: The study group demonstrated greater anterior and posterior cranial base and atlanto-dental angles. They also demonstrated greater pharyngeal cavity volume and width and lesser tonsillar and adenoid volumes. CONCLUSION: Patients with a 22q11.2 deletion demonstrate significant alterations in VP anatomy that may contribute to VPD.

The Children's Hospital of Philadelphia modification of the Furlow double-opposing z-palatoplasty: long-term speech and growth results.

Of the 261 nonsyndromic patients we studied, over 90% had minimal or absent hypernasality, almost 86% had inconsistent or no nasal emission, and 95% had no articulation errors related to velar function. The patients with a Pittsburgh score indicating an incompetent velopharyngeal mechanism comprised only about 6% of the group. Ninety-four percent had a socially functional speech quality. Secondary surgery was done in 6.5% of patients and was done or was recommended in about 8% of patients. Patients with isolated cleft palate seemed to do less well, although their outcomes were not statistically different from those with complete unilateral and bilateral clefts. Relaxing incisions have kept our fistula rate to an acceptably low rate of 6.8%. No major soft palate dehiscences or hard palate flap losses have occurred. The speech outcomes we are achieving are improved over our historical results and compared with published reports using nondouble reversing z-palatoplasty techniques. Similar outcomes with the Furlow repair have been confirmed. Maxillary growth, occlusion, and the need for orthognathic surgery do not seem to be influenced by the CHOP modification of the Furlow double-opposing z-palatoplasty. These modifications facilitate a tension free-closure and a low fistula rate.