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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.

The human chromosome 22q11.2 region is susceptible to rearrangements during meiosis leading to velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome (22q11DS) characterized by conotruncal heart defects (CTDs) and other congenital anomalies. The majority of individuals have a 3 Mb deletion whose proximal region contains the presumed disease-associated gene TBX1 (T-box 1). Although a small subset have proximal nested deletions including TBX1, individuals with distal deletions that exclude TBX1 have also been identified. The deletions are flanked by low-copy repeats (LCR22A, B, C, D). We describe cardiac phenotypes in 25 individuals with atypical distal nested deletions within the 3 Mb region that do not include TBX1 including 20 with LCR22B to LCR22D deletions and 5 with nested LCR22C to LCR22D deletions. Together with previous reports, 12 of 37 (32%) with LCR22B-D deletions and 5 of 34 (15%) individuals with LCR22C-D deletions had CTDs including tetralogy of Fallot. In the absence of TBX1, we hypothesized that CRKL (Crk-like), mapping to the LCR22C-D region, might contribute to the cardiac phenotype in these individuals. We created an allelic series in mice of Crkl, including a hypomorphic allele, to test for gene expression effects on phenotype. We found that the spectrum of heart defects depends on Crkl expression, occurring with analogous malformations to that in human individuals, suggesting that haploinsufficiency of CRKL could be responsible for the etiology of CTDs in individuals with nested distal deletions and might act as a genetic modifier of individuals with the typical 3 Mb deletion., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated., Methods and Results: In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A (p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family., Conclusions: Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: The 22q11.2 deletion syndrome is a common genetic microdeletion syndrome that results in cognitive delays and an increased risk of several psychiatric disorders, particularly schizophrenia. The current study investigates the prevalence of incidental neuroradiologic findings within this population and their relationships with psychiatric conditions., Materials and Methods: Brain MR imaging from 58 individuals with 22q11.2 deletion syndrome was reviewed by board-certified radiologists by using standard clinical procedures. Intracranial incidental findings were classified into 8 categories and compared with a large typically developing cohort., Results: The rate of incidental findings was significantly higher (P < .0001) in 22q11.2 deletion syndrome compared with typically developing individuals, driven by a high prevalence of cavum septum pellucidum (19.0%) and white matter abnormalities (10.3%). Both of these findings were associated with psychosis in 22q11.2 deletion syndrome., Conclusions: Cavum septum pellucidum and white matter hyperintensities are significantly more prevalent in patients with the 22q11.2 deletion syndrome and may represent biomarkers for psychosis., (© 2014 by American Journal of Neuroradiology.)

The 22q11.2 deletion syndrome (22q11DS) presents with medical and neuropsychiatric manifestations including neurocognitive deficits. Quantitative neurobehavioral measures linked to brain circuitry can help elucidate genetic mechanisms contributing to deficits. To establish the neurocognitive profile and neurocognitive 'growth charts', we compared cross-sectionally 137 individuals with 22q11DS ages 8-21 to 439 demographically matched non-deleted individuals with developmental delay (DD) and medical comorbidities and 443 typically developing (TD) participants. We administered a computerized neurocognitive battery that measures performance accuracy and speed in executive, episodic memory, complex cognition, social cognition and sensorimotor domains. The accuracy performance profile of 22q11DS showed greater impairment than DD, who were impaired relative to TD. Deficits in 22q11DS were most pronounced for face memory and social cognition, followed by complex cognition. Performance speed was similar for 22q11DS and DD, but 22q11DS individuals were differentially slower in face memory and emotion identification. The growth chart, comparing neurocognitive age based on performance relative to chronological age, indicated that 22q11DS participants lagged behind both groups from the earliest age assessed. The lag ranged from less than 1 year to over 3 years depending on chronological age and neurocognitive domain. The greatest developmental lag across the age range was for social cognition and complex cognition, with the smallest for episodic memory and sensorimotor speed, where lags were similar to DD. The results suggest that 22q11.2 microdeletion confers specific vulnerability that may underlie brain circuitry associated with deficits in several neuropsychiatric disorders, and therefore help identify potential targets and developmental epochs optimal for intervention.

Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present., (© 2014 Wiley Periodicals, Inc.)

Objective: Chromosome 22q11.2 deletion syndrome (22q11DS) confers 25% risk for psychosis and is an invaluable window for understanding the neurobiological substrate of psychosis risk. The Structured Interview for Prodromal Syndromes (SIPS) is well validated in nondeleted populations for detecting clinical risk but has only recently been applied to 22q11DS. We assessed the largest 22q11DS cohort to date and report on SIPS implementation and symptoms elicited., Method: The SIPS, including its 19 subscales, was administered to 157 individuals with 22q11DS aged 8 to 25 years. Youth and caregiver interviews were conducted and rated separately, then compared for agreement. Implementation of the SIPS in 22q11DS was challenging because of the prevalence of developmental delay and comorbid conditions. However, by explaining questions and eliciting examples, we were able to help youths and caregivers understand and respond appropriately. Consensus ratings were formulated and analyzed with itemwise and factor analysis., Results: Subthreshold symptoms were common, with 85% of individuals endorsing 1 or more. The most commonly rated items were ideational richness (47%) and trouble with focus and attention (44%). Factor analysis revealed a 3-factor solution with positive, negative, and disorganized components. Youth-caregiver comparisons suggested that youths report greater symptoms of perceptual abnormalities, suspiciousness, trouble with emotional expression, and bizarre thinking. Caregivers reported more impaired tolerance to normal stress, poor hygiene, and inattention., Conclusion: The SIPS was adapted for 22q11DS through comprehensive and semi-structured administration methods, yielding a high prevalence of subthreshold psychotic symptoms. The significance and predictive validity of these symptoms require future longitudinal analysis., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Survival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children., Methods: This is an analysis of a cohort of nonsyndromic congenital heart disease patients who underwent cardiac surgery with cardiopulmonary bypass before 6 months of age (n=422). Six single nucleotide polymorphisms (SNPs) in six genes involved in oxidative stress and vascular response pathways, identified through a priori literature search, were tested for effects on transplant-free survival. Survival curves, adjusting for confounding covariates, were calculated using the Cox proportional hazard models., Results: Long-term survival was strongly associated with vascular endothelial growth factor A gene SNP rs833069 (p=7.03×10(-4)) and superoxide dismutase 2 gene SNP rs2758331 (p=0.019). To test for joint effects of the two SNPs on transplant-free survival, the genotypes were grouped to form a risk score reflecting the cumulative number of risk alleles (0 to 4 alleles per patient). A higher risk score based on the VEGFA and SOD2 SNP genotypes was associated with worse transplant-free survival (p=3.02×10(-4)) after confounder adjustment. The total burden of risk alleles was additive; subjects with the highest risk score of 4 (n=59 subjects, 14.2% of the cohort) had a total covariate-adjusted hazard ratio of 15.64 for worse transplant-free survival., Conclusions: After cardiac surgery, infants who are homozygous for the high-risk alleles for both the VEGFA and SOD2 SNPs have an approximately 16-fold increased risk of death or heart transplant, suggesting that genetic variants are important modifiers of survival after surgery for congenital heart disease., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants., Method: The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years., Results: Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills., Conclusions: To the authors’ knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

Objectives: The study objectives were to compare the neurodevelopmental outcomes of preschool survivors of the Fontan procedure with those of children with congenital heart disease undergoing biventricular repair and to investigate predictors of neurodevelopmental outcome for those with single ventricle congenital heart disease, including hypoplastic left heart syndrome., Methods: Neurodevelopmental outcomes were assessed at 4 years of age, including cognition, visual-motor integration, behavior, social skills, and academic achievement. Unadjusted outcomes were compared between patients with biventricular circulation and patients with single ventricles. Predictors of neurodevelopmental outcome were assessed in the patients with single ventricles. Multiple covariate models were evaluated using patient-related, operative, and postoperative covariates., Results: Neurodevelopmental evaluation was performed in 365 children, 112 after the Fontan procedure (hypoplastic left heart syndrome, n = 91; other single ventricle, n = 21) and 253 after biventricular repair. Compared with patients with biventricular circulation, patients with single ventricles performed worse in terms of processing speed, inattention, and impulsivity. Otherwise, there were no significant differences between the groups for any domain. There was a trend toward lower performance for patients with single ventricles on visual motor integration. Outcomes for patients with hypoplastic left heart syndrome were not worse than for other forms of functional single ventricle. Patient factors were more important predictors of neurodevelopmental outcomes than were operative management variables., Conclusions: In this cohort, unadjusted neurodevelopmental outcomes for preschool survivors of the Fontan procedure are similar to those for children with congenital heart disease undergoing biventricular repair for most domains. Among the patients undergoing the Fontan procedure, hypoplastic left heart syndrome was not associated with worse outcomes compared with other forms of single ventricle., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Chromosome 22q11.2 deletion syndrome (22q11DS) is a common genetic disorder with high rates of psychosis and other psychopathologies, but few studies discuss treatment. Our aim was to characterize the prevalence and treatment of major psychiatric illnesses in a well-characterized sample of individuals with 22q11DS., Method: This was a cross-sectional study of 112 individuals aged 8 to 45 years with a confirmed diagnosis of 22q11DS. Each participant was administered a modified Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) and the Structured Interview for Prodromal Syndromes (SIPS). Phenotypes assessed were threshold and subthreshold psychosis, depression, mania, generalized and separation anxiety, obsessions/compulsions, inattention/hyperactivity and substance use. Histories of mental health care and current psychotropic treatment were obtained., Results: Psychopathology was common, with 79% of individuals meeting diagnostic criteria for a disorder at the time of assessment. Diagnoses of psychosis were made in 11% of cases, attenuated positive symptom syndrome (APS) in 21%, and 47% experienced significant subthreshold symptoms. Peak occurrence of psychosis risk was during adolescence (62% of those aged 12-17 years). Criteria for a mood disorder were met by 14%, for anxiety disorder 34% and for attention deficit hyperactivity disorder (ADHD) 31%. Mental health care had been received by 63% of individuals in their lifetime, but only 40% continued therapy and 39% used psychotropics. Antipsychotics were used by 42% of participants with psychosis and none of the participants with APS. Half of those at risk for psychosis were receiving no mental health care., Conclusions: Psychopathology is common in 22q11DS but is not adequately treated or clinically followed. Particular attention should be paid to subthreshold psychotic symptoms, especially in adolescents.

Children with 22q11.2 deletion syndrome (22q11DS) present with congenital heart disease (CHD) and high prevalence of psychiatric disorders and neurocognitive deficits. Although CHD has been implicated in neurodevelopment, its role in the neuropsychiatric outcome in 22q11DS is poorly understood. We investigated whether CHD contributes to the high prevalence of psychiatric disorders and neurocognitive impairments in 22q11DS. Fifty-four children ages 8-14 years with 22q11DS and 16 age-matched non-deleted children with CHD participated. They were assessed using semi-structured interviews and a Computerized Neurocognitive Battery. CHD status was assessed using available medical records. Prevalence of psychiatric disorders and cognitive profiles were compared among the groups. There were no significant differences between the prevalence of psychiatric disorders in the 22q11DS with and without CHD. In 22q11DS with CHD, the prevalence rates were 41% anxiety disorders, 37% ADHD and 71% psychosis spectrum. In 22q11DS without CHD, the rates were 33% anxiety disorders, 41% ADHD and 64% psychosis spectrum. In comparison, the non-deleted CHD group had lower rates of psychopathology (25% anxiety disorders, 6% ADHD, and 13% psychosis spectrum). Similarly, the 22q11DS groups, regardless of CHD status, had significantly greater neurocognitive deficits across multiple domains, compared to the CHD-only group. We conclude that CHD in this sample of children with 22q11.2DS does not have a major impact on the prevalence of psychiatric disorders and is not associated with increased neurocognitive deficits. These findings suggest that the 22q11.2 deletion status itself may confer significant neuropsychiatric vulnerability in this population., (© 2013 Wiley Periodicals, Inc.)

Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations., (© 2013 Wiley Periodicals, Inc.)

Objective: Asymmetric crying facies (ACF) is congenital hypoplasia of the depressor anguli oris muscle characterized by asymmetry of lower lip depression during crying. This has an overall incidence of 0.6%. This study determines the incidence of ACF in a large population of patients with 22q11.2 deletion., Patients and Methods: A retrospective review of medical records on patients with a confirmed 22q11.2 deletion was undertaken., Results: A total of 836 records were reviewed. Of these, 117 (14%) were noted to have ACF on physical examination. Within this latter group, palatal anomalies were common (77%), as was congenital heart disease (78%); however, these numbers did not differ significantly from their known prevalence in the 22q11.2 population., Conclusions: We report a 14% incidence of ACF in patients with a 22q11.2 deletion, significantly higher than in the general population. We suggest, therefore, that newborns with ACF be referred for further screening for the 22q11.2 deletion syndrome.

Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders., (© 2013 Wiley Periodicals, Inc.)

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype., Methods: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals., Results and Conclusions: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS 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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Growth faltering occurs frequently in infancy in the 22q11 Deletion syndrome (22q11 DS). The subsequent course of growth in childhood and outcome for final adult height lacks consensus. We analyzed 5,149 growth data points from 812 Caucasian subjects with 22q11 DS, from neonates to 37 years old. Charts were constructed for height, weight, body mass index, and head circumference (OFC) using the LMS Chart Maker program. These charts were compared with the WHO birth to 4 years growth standard and US CDC 2000 growth reference between 5 and 20 years. Starting from the 50th centile at birth, by 6-9 months of age boys mean height and weight had fallen to the 9th centile, as did girls height but their weight fell less markedly, to the 25th centile. Feeding difficulties were non-contributory. In children under 2 years old with congenital heart disease (CHD) mean weight was -0.5 SD lighter than no CHD. Catch up growth occurred, more rapid in weight than height in boys. Up to 10 years old both sexes tracked between the 9th and 25th centiles. In adolescence, the trend was to overweight rather than obesity. At 19 years mean height was -0.72 SD for boys, -0.89 SD girls. OFC was significantly smaller than the WHO standard in infancy, between the 9th and 25th centile, rising to the 25th centile by 5 years old. Thereafter the mean was close to the 9th centile of the OFC UK growth reference, more prolonged and marked than in previous studies., (Copyright © 2012 Wiley Periodicals, Inc.)

Ablepharon-Macrostomia syndrome (AMS) is a rare collection of findings characterized by absent or hypoplastic eyelids, fusion defects of the mouth with unfused lateral commissures, abnormal ears, ambiguous genitalia, skin differences including dry and coarse skin or redundant folds of skin, and developmental delay. Fewer than 20 patients have been reported to date. These include a parent and two children and a recent report of a father and daughter, therefore suggesting autosomal dominant inheritance. Here we present one additional sporadic case with an expanded phenotype. This patient has more significant hand and foot anomalies than previously reported., (Copyright © 2011 Wiley Periodicals, Inc.)

Prior to the advent of cardiac bypass, most children with congenital cardiac anomalies and chromosome 22q11.2 deletion syndrome died. With improved technology, there is now a wave of young adults with chromosome 22q11.2 deletion syndrome requiring clinical care. Fifteen young children and 20 adults with chromosome 22q11.2 deletion had flow cytometry, functional T cell analyses, and functional B cell analyses to characterize their immune system. Subjects were vaccinated with the annual inactivated influenza vaccine, and responses were evaluated by hemagglutination inhibition titer assessment. The pattern of T cell subset abnormalities was markedly different between pediatric and adult patients. In spite of the cellular deficits observed in adults, titers produced after influenza vaccine administration were largely intact. We conclude that disruption to T cell production appears to have secondary consequences for T cell differentiation and B cell function although the clinical impact remains to be determined.

We report on the novel association of trigonocephaly and polysyndactyly in two unrelated patients due to mutations within the last third (exon 14) and first third (exon 6) of the GLI3 gene, respectively. GLI3 acts as a downstream mediator of the Sonic hedgehog signal-transduction pathway which is essential for early development; and plays a role in cell growth, specialization, and patterning of structures such as the brain and limbs. GLI3 mutations have been identified in patients with Pallister-Hall, Grieg cephalopolysyndactyly syndrome (GCPS), postaxial polydactyly type A1, preaxial polydactyly type IV, and in one patient with acrocallosal syndrome (ACLS). Furthermore, deletions including the GLI3 gene have been reported in patients with features of GCPS and ACLS. To date, trigonocephaly has not been associated with abnormalities of GLI3 and craniosynostosis is not a feature of GCPS. However, Hootnick and Holmes reported on a father with polysyndactyly and son with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum, considered GCPS thereafter. Guzzetta et al. subsequently described a patient with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum postulating a diagnosis of GCPS, later considered ACLS. In retrospect, these two patients, evaluated prior to mutational analysis, and our patients, with confirmed mutations, likely fall within the GLI3 morphopathy spectrum and may provide a bridge to better understanding those patients with overlapping features of GCPS and ACLS. Based on this observation, we suggest GLI3 studies in patients presenting with this constellation of findings, specifically metopic craniosynostosis with polysyndactyly, in order to provide appropriate medical management and genetic counseling., ((c) 2010 Wiley-Liss, Inc.)

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

We report here on a normal-appearing male with pervasive developmental disorder who was found to have a de novo, apparently balanced complex rearrangement involving chromosomes 6, 10, and 21: 46,XY,ins(21;10)(q11.2;p11.2p13)t(6;21)(p23;q11.2). Further analysis by high-density oligonucleotide microarray was performed, showing an 8.8-Mb heterozygous deletion at 21q21.1-q21.3. Interestingly, the deletion is distal to the translocation breakpoint on chromosome 21. The deletion involves 19 genes, including NCAM2 and GRIK1, both of which are associated with normal brain development and function, and have been considered as possible candidate genes in autism and other neurobehavioral disorders. This case underscores the utility of genomewide microarray analysis for the detection of copy number alterations in patients with apparently balanced complex rearrangements and abnormal phenotypes.

Background: 22q11.2 Deletion Syndrome (22qDS) is a common chromosome deletion syndrome that has been associated with severe psychopathology, including bipolar disorder and schizophrenia, in adults. Assessment of psychiatric diagnoses in children and adolescents with 22qDS is in the early stages of investigation., Methods: 24 children and adolescents with 22qDS established by chromosomal analysis were randomly selected from a 22qDS clinic. Children and their parents were interviewed by trained psychometricians with a standardized structured diagnostic interview. A diagnosis was considered present if DSM-IV diagnostic criteria were met on either the parent or the child interview., Results: 24 22qDS subjects (mean age 9.7+/-3.3 years) had a mean of two DSM-IV psychiatric disorders. 79% met criteria for at least one DSM-IV psychiatric disorder and over one third had three or more diagnoses. 12.5% met criteria for major depression but none had bipolar disorder. Anxiety disorders (54%), attention-deficit/hyperactivity disorder (38%), and oppositional defiant disorder (38%) were common. Although 29% reported at least one psychotic-like symptom, none met criteria for a psychotic disorder., Limitations: Small sample size may have obscured significant associations. Other limitations included non-blinded interviewers and lack of a simultaneously studied control group., Conclusion: Affective, anxiety, attentional, and behavioral disorders were relatively common in this randomly selected group of children and adolescents with 22qDS. No child met criteria for bipolar disorder or schizophrenia. Prospective, longitudinal study is needed to determine whether early psychiatric symptomatology in children with 22qDS predicts continuing or more severe psychopathology later in life. Early psychiatric screening and monitoring appears warranted in 22qDS patients.

Background: Patients with Saethre-Chotzen syndrome have a heterogeneous phenotype. The purpose of this study was to use the genotypic diagnosis of the authors' series of patients with TWIST1-confirmed Saethre-Chotzen syndrome to describe their natural history and long-term surgical outcomes., Methods: A retrospective chart review was performed on patients treated at The Children's Hospital of Philadelphia with TWIST1-confirmed Saethre-Chotzen syndrome (n = 22) over 23 years (1985 to 2008). Their phenotype, need for primary cranial vault remodeling surgery, and subsequent need for reoperation were recorded. Genetic records were reviewed to identify each patient's TWIST1 mutation., Results: There were nine female patients and 13 male patients. Ten had bicoronal (45 percent), six had unicoronal (27 percent), and four had multisuture (18 percent) craniosynostosis. One had metopic and another had sagittal craniosynostosis. Average follow-up was 7.6 years (range, birth to 19.6 years). Seventeen (77 percent) underwent initial cranial vault remodeling and 10 (59 percent) required repeat intracranial vault remodeling (Whitaker class IV). One patient required major reoperation with bone grafting (Whitaker class III). Three patients needed minor revision procedures (Whitaker class II). Three patients needed no further intervention (Whitaker class I). The locations of the TWIST1 gene mutations in this study did not correlate to a specific surgical outcome., Conclusions: TWIST1-confirmed Saethre-Chotzen syndrome is heterogeneous and manifests as either mild or severe craniofacial deformities. Our patients with TWIST1-confirmed Saethre-Chotzen syndrome had a reoperation rate of 65 percent for Whitaker class III and IV surgical outcome, and 59 percent required a secondary intracranial procedure for recurrent supraorbital retrusion.

We report on three unrelated patients with the 22q11.2 microdeletion syndrome (del22q11) who have phenotypic anomalies compatible with oculo-auriculo-vertebral spectrum (OAVS). Hemifacial microsomia, unilateral microtia, hearing loss, congenital heart/aortic arch arteries defects, and feeding difficulties were present in all three patients. Additional anomalies occasionally diagnosed included coloboma of the upper eyelid, microphthalmia, cerebral malformation, palatal anomalies, neonatal hypocalcemia, developmental delay, and laryngomalacia. Several clinical features characteristic of OAVS have been described in patients with del22q11 from the literature, including ear anomalies, hearing loss, cervical vertebral malformations, conotruncal cardiac defects, renal malformations, feeding and respiratory difficulties. Atretic ear with facial asymmetry has been previously described in one patient. Thus, clinical expression of hemifacial microsomia and microtia resembling OAVS should now be included within the wide phenotypic expression of del22q11. The occurrence of this manifestation in del22q11 is currently low. Nevertheless, patients with hemifacial microsomia and microtia associated with clinical features typically associated with del22q11 should now have for specific cytogenetic testing.

We report a 3.1-Mb de novo deletion of 3p21.31 in a 3.5-year-old female with cortical blindness, cleft lip, CNS abnormalities, and gross developmental delays. Examination of the region showed approximately 80 genes to be involved in the deletion. Functional analysis of the deleted genes suggests that several of them may be important in normal neuronal maturation and function. Thus, haploinsufficiency of one or more of these genes could potentially contribute to the observed phenotype. Our patient does not have clinical features that overlap completely with either proximal or distal 3p deletions, suggesting that the deletion seen in our patient leads to a distinct clinical phenotype not described previously.

Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates., Objective: To characterise genetic and clinical findings in patients with SIX3 mutations., Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish., Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%., Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

The 22q11.2 deletion syndrome is characterized by a highly variable phenotype including a range of cardiac malformations. The most common cardiovascular features include a subset of conotruncal defects, perimembranous ventricular septal defects and aortic arch anomalies. This report describes a series of patients with 22q11.2 deletion syndrome with the novel cardiac finding of mild aortic root dilation. A chart review was performed on 93 patients with documented 22q11.2 deletion without significant congenital heart disease to determine the number of patients with aortic root dilation. Patients ranged in age from 1 to 13 years of age. Of these 93 patients, 10 patients were found to have aortic root dilation on a screening echocardiogram. Seven of these patients did not have any additional risk factors while three patients had a bicuspid aortic valve (BAV). Four of 10 patients had additional minor cardiac anomalies including repaired ventricular septal defect (1), patent ductus arteriosus(1), arch anomalies (1), and left pulmonary artery stenosis (1). Three patients had isolated cases of aortic root dilation. Interestingly, several of these patients did not have aortic root dilation on their initial echocardiograms. The purpose of this study is to draw attention to a novel cardiac finding in patients with 22q11.2 deletion that may be of clinical importance. Further long-term study is warranted to assess the need for echocardiographic screening in the 22q11.2 deleted population for aortic root dilation into adolescence and adulthood.

Cardiovascular abnormalities, especially structural congenital heart defects, commonly occur in malformation syndromes and genetic disorders. Individuals with syndromes comprise a significant proportion of those affected with selected congenital heart defects such as complete atrioventricular canal, interrupted arch type B, supravalvar aortic stenosis, and pulmonary stenosis. As these individuals age, they contribute to the growing population of adults with special health care needs. Although most will require longterm cardiology follow-up, primary care providers, geneticists, and other specialists should be aware of (1) the type and frequency of cardiovascular abnormalities, (2) the range of clinical outcomes, and (3) guidelines for prospective management and treatment of potential complications. This article reviews fundamental genetic, cardiac, medical, and reproductive issues associated with common genetic syndromes that are frequently associated with a cardiovascular abnormality. New data are also provided about the cardiac status of adults with a 22q11.2 deletion and with Down syndrome.

Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal-anomaly-face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbe's line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)-confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral., (Copyright 2008 Wiley-Liss, Inc.)

Background: Muenke-type craniosynostosis is defined as fibroblast growth factor receptor 3 (FGFR3)-associated coronal craniosynostosis with or without mental retardation. With complementary genetic information, more precise diagnosis and long-term functional outcome of cranial vault remodeling in affected patients can be studied, and additional distinct features of Muenke syndrome can now be investigated. This study was undertaken to assess craniofacial growth and long-term functional outcome in patients with Muenke-type craniosynostosis., Methods: A chart review of all FGFR3 patients at The Children's Hospital of Philadelphia who had undergone cranial vault remodeling for unicoronal or bicoronal synostosis (n = 16) was performed. Need for reoperation, midface surgery, and functional corrections were assessed. Audiology and orthodontic records were reviewed., Results: All patients underwent cranial remodeling during infancy. Repeated intracranial surgery was performed or is currently scheduled for aesthetic reasons only (n = 7). Sexual dimorphism with male preponderance in FGFR3 unicoronal synostosis was detected. Despite dental crowding amenable to palatal expansion in patients with bicoronal synostosis, significant midface hypoplasia was not observed. Sensorineural hearing loss with a distinctive pattern was present in all patients who had undergone audiology testing., Conclusions: Patients with FGFR3-associated craniosynostosis demonstrate a sexual dimorphism, with a male preponderance for unicoronal synostosis. A secondary major intracranial procedure is required for recurrent supraorbital retrusion in at least 43 percent of patients. A secondary or tertiary extracranial forehead contouring procedure should be anticipated in nearly all patients. No patient required any midface correctional procedure. These patients demonstrate characteristic bilateral, symmetric, low- to mid-frequency sensorineural hearing loss.

Objective: We hypothesized that most patients with 22q11.2 deletion and a history of hypocalcemia have inadequate parathyroid function, manifested by intact parathyroid hormone levels below normal. We aimed to evaluate intact parathyroid hormone levels both during normocalcemia and at hypocalcemia, in this population., Study Design: Retrospective chart review of 103 patients with 22q11.2 deletion born since 1997 and cared for at the Children's Hospital of Philadelphia. Calcium and intact parathyroid hormone drawn simultaneously were recorded, along with clinical presentation at hypocalcemia., Results: Forty-seven simultaneous Ca/intact parathyroid hormone values were available. Seventy-nine percent of calcium levels and 81% of parathyroid hormone levels were within normal range. There were 19 patients with a history of symptomatic hypocalcemia, for whom any available simultaneous Ca/parathyroid hormone levels, before, during, or after hypocalcemia were analyzed. In this subgroup, 59% of calcium and 76% of parathyroid hormone levels were normal. None had an intact parathyroid hormone of >39.2 pg/mL at hypocalcemia. Seventy-three percent of hypocalcemic events had a precipitating stressor., Conclusions: Hypoparathyroidism in 22q11.2 deletion is mild, manifesting as a phenomenon of decreased parathyroid hormone reserve. Subjects are normocalcemic most of the time, but are unable to mount elevated intact parathyroid hormone levels, and therefore unable to correct hypocalcemia, in response to stressors.

Children with one of two genetic disorders (chromosome 22q11.2 deletion syndrome and Turner syndrome) as well typically developing controls, participated in three cognitive processing experiments. Two experiments were designed to test cognitive processes involved in basic aspects numerical cognition. The third was a test of simple manual motor reaction time. Despite significant differences in global intellectual abilities, as measured by IQ tests, performance on the two numerical cognition tasks differed little between the two groups of children with genetic disorders. However, both performed significantly more poorly than did controls. The pattern of results are consistent with the hypothesis that impairments were not due to global intellectual ability but arose in specific cognitive functions required by different conditions within the tasks. The fact that no group differences were found in the reaction time task, despite significant differences in the standardized processing speed measure, further supports the interpretation that specific cognitive processing impairments and not global intellectual or processing speed impairments explain the pattern of results. The similarity in performance on these tasks of children with unrelated genetic disorders counters the view that numerical cognition is under any direct genetic control. Instead, our findings are consistent with the view that disturbances in foundational spatiotemporal cognitive functions contribute to the development of atypical representations and processes in the domains of basic magnitude comparison and simple numerical enumeration.

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

The classic clinical features in the 22q11.2 deletion syndrome are congenital heart defects, hypocalcemia, immunodeficiency, learning, speech, and behavioral difficulties. The phenotype is highly variable and continues to expand. We present two cases of absent uterus and unilateral renal agenesis in females with the 22q11.2 deletion. Clinicians caring for these adolescents should be aware of the possibility of renal anomalies and Mullerian agenesis. The diagnosis of 22q11.2 deletion may be considered in a female with Mullerian agenesis, particularly, in association with a history of learning difficulties and speech delay., (Copyright 2007 Wiley-Liss, Inc.)

Hay-Wells/ankyloblepharon-ectodermal dysplasia-clefting syndrome is a rare autosomal dominant disorder characterized by ankyloblepharon, ectodermal dysplasia, and cleft lip and/or cleft palate. Mutations in the p63 gene recently have been shown to be etiologic in the majority of cases of ankyloblepharon-ectodermal dysplasia-clefting syndrome. To date, there have been no reports to document wound healing after cleft lip and/or palate repair in ankyloblepharon-ectodermal dysplasia-clefting patients. We describe two patients with ankyloblepharon-ectodermal dysplasia-clefting syndrome and provide a review of the literature. There have been no reported instances of wound healing complications in affected patients. Seventeen percent (3/18) of reported patients required revisions or repair of oronasal fistulae. Cleft lip and palate repair can be performed safely in patients with Hay-Wells syndrome.

Purpose: To identify the ocular features of the chromosome 22q11.2 deletion syndrome and to provide ophthalmologic examination recommendations for affected patients., Methods: Ocular abnormalities were evaluated prospectively in patients with 22q11.2 deletion at the Children's Hospital of Philadelphia between 1997 and 1999., Results: Ninety patients with confirmed 22q11.2 deletion were examined. Posterior embryotoxon was found in 49%, tortuous retinal vessels in 34%, eyelid hooding in 20%, strabismus in 18%, ptosis in 4%, amblyopia in 4%, and tilted optic nerves in 1%., Conclusions: The high incidence of ocular conditions that can potentially affect visual development suggest that children with 22q11.2 deletion should undergo a comprehensive eye examination upon diagnosis of the condition with follow-up as indicated by the findings in each case. In addition, knowledge of the ocular findings, in conjunction with certain cardiac, otolaryngologic, immunologic, and other systemic findings, may alert physicians to the possibility of a chromosome 22q11.2 deletion.

In this paper, novel methods were used to map the corpus callosum morphology of children with chromosome 22q11.2 deletion syndrome in order to further investigate changes to that structure and to examine their possible effects on cognitive function. The callosal profiles were extracted from the centermost MRI midsagittal slice by supervised thresholding and the structure's boundary and midline were computed automatically. Difference analysis was based on non-rigid registration, in which a template image is warped to conform to the shape of each corpus callosum in the sample. Boundaries and midlines were registered to a template and the results used to determine the average callosal shapes for children with the deletion and for controls. Pointwise registration also enabled the detailed evaluation of callosal curvature, width, area and length. Significant differences between the two groups were found in shape, size and bending angle. Results showed group differences that were concentrated in the anterior part of the structure, more specifically in the rostrum, which was larger and longer in the group with the syndrome. Correlation analyses showed that ventricular enlargement does not fully account for callosal morphology differences in children with the deletion. However, areal measurements did reveal important relationships between changes in callosal morphology and cognitive function. These novel findings reveal intricate relationships between genetic and disease-specific factors in the callosal anatomy and the potential impact of those changes on cognitive functions.

Background/purpose: Apert syndrome, a disorder of craniosynostosis, syndactyly, and other craniofacial malformations, is caused by point mutations (Ser252Trp or Pro253Arg) in the fibroblast growth factor receptor 2 gene. This study's goal was to determine ophthalmic phenotype/genotype correlations in patients with either mutation., Methods: A retrospective chart review of demographic and ophthalmologic data was performed for 18 children carrying either the S252W (11) or the P253R (7) mutation. Fisher exact tests were performed to determine significance of variable phenotypes between the two mutation groups., Results: In the P253R group, 85% had strabismus (14% required surgery), 71% had ptosis, 43% had amblyopia, 14% had nasolacrimal duct obstruction, 14% had myopia, 14% had hyperopia, and 14% had astigmatism. In the S252W group, 91% had strabismus (64% required surgery), 73% had ptosis, 73% had amblyopia, 100% had nasolacrimal duct obstruction, 36% had myopia, 9% had hyperopia, and 82% had astigmatism. Overall, S252W and P253R groups showed significantly different numbers of patients with strabismus requiring surgery (p = 0.039), superior rectus muscle underaction (p = 0.024), nasolacrimal duct obstruction (p = 0.0002), and astigmatism (p = 0.005)., Conclusions: Compared with patients with the P253R mutation, Apert syndrome patients with the S252W mutation may have more severe ocular phenotypes with a higher likelihood of developing strabismus, especially vertical deviation. They also are more likely to develop astigmatic refractive errors and tearing secondary to nasolacrimal system anomalies.

Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11., ((c) 2006 Wiley-Liss, Inc.)

Background/purpose: Despite the similar clinical phenotype of the Saethre-Chotzen and Muenke craniosynostoses, the 2 syndromes are now genotypically distinct. Patients with Saethre-Chotzen and Muenke syndromes carry mutations in the TWIST and fibroblast growth factor receptor (FGFR) 3 genes, respectively. We sought to assess possible ocular phenotypic differences in patients with mutations of either gene previously grouped according to phenotype only., Methods: A retrospective chart review was performed for 21 children with known mutations of the TWIST (n=10) or the FGFR3 (n=11) genes. Data gathered included patient sex, age, family craniofacial history, craniofacial and ophthalmic surgeries, type of strabismus, ptosis, cycloplegic refraction, visual acuity, the presence of amblyopia, nasolacrimal duct obstruction (NLDO), nystagmus, hypertelorism, epicanthal fold anomalies, and any ocular structural abnormalities., Results: In the TWIST group, ptosis was present in 90%, amblyopia in 70%, horizontal strabismus in 70%, vertical strabismus in 60%, NLDO in 60%, astigmatism in 50%, inferior oblique overaction (IOOA) in 40%, hyperopia in 40%, myopia in 30%, nystagmus in 30%, and optic nerve findings in 30%. In the FGFR3 group, ptosis was present in 36%, amblyopia in 18%, horizontal strabismus in 55%, vertical strabismus in 36%, NLDO in 0%, astigmatism in 9%, IOOA in 45%, hyperopia in 27%, myopia in 18%, nystagmus in 18%, and optic nerve findings in 27%., Conclusions: Patients with TWIST gene mutations may have more ophthalmic abnormalities, including more strabismus, ptosis, NLDO, astigmatism, vertical deviations, and amblyopia compared with patients with FGFR3 gene mutations.

Objective: The occurrence of a seizure after the arterial switch operation is associated with a worse long-term neurodevelopmental outcome. The significance of seizures after neonatal and infant repair of other congenital heart defects is not known., Methods: A recent study at our institution demonstrated seizures documented by 48-hour electroencephalographic monitoring in 20 (11%) of 178 neonates and infants after surgery for complex congenital heart defects, including hypoplastic left heart syndrome or variants. The developmental outcomes of this cohort were evaluated at 1 year of age by using the Bayley Scales of Infant Development II, which yields 2 scores: the Mental Developmental Index and the Psychomotor Developmental Index., Results: Developmental evaluations were performed in 114 (70%) of 164 survivors, including 36 with hypoplastic left heart syndrome. Postoperative electroencephalographic seizures had occurred in 15 (13%) of 114 of the entire group and in 8 (22%) of 36 of those with hypoplastic left heart syndrome. For the entire cohort, the Mental Developmental Index was 92.3 +/- 13.5, and the Psychomotor Developmental Index was 79.9 +/- 18.8 for patients without seizures, compared with 90.3 +/- 10.7 and 74.4 +/- 19.3 for those with seizures (both P > .5). For the hypoplastic left heart syndrome subgroup, the Mental Developmental Index was 92.3 +/- 14.9, and the Psychomotor Developmental Index was 74.8 +/- 19.3 for patients with seizures, compared with 91.9 +/- 12.4 and 73.9 +/- 18.3 for those without seizures (both P > .5). A frontal onset of seizures was predictive of a lower score on the Psychomotor Developmental Index, but not on the Mental Developmental Index., Conclusions: The occurrence of a seizure after cardiac operation is a marker of central nervous system injury. However, in this cohort of neonates and infants with complex congenital heart defects, the occurrence of a seizure was not predictive of a worse developmental outcome at 1 year of age as assessed by the Bayley Scales of Infant Development II.

This study demonstrates, in patients with 22q11.2 deletion, the wide variety of complex aortic arch anomalies that can be accurately defined by cardiac magnetic resonance imaging (MRI) compared with echocardiography. From May 1999 to August 2003, 17 of 68 patients (25%) with 22q11.2 deletion referred for cardiac evaluation required cardiac MRI, after echocardiography, to clarify aortic arch anatomy. Images of cardiac anatomy were obtained using steady-state free precession, half-Fourier acquired single turbo spin-echo dark blood sequences and gadolinium for 3-dimensional reconstruction. All MRI findings were abnormal, and in 16 of 17 cases, echocardiography was unable to define aortic arch anomalies correctly compared with MRI.