Palatal evaluation and treatment in 22q11.2 deletion syndrome.

Palatal involvement occurs commonly in patients with 22q11.2 Deletion Syndrome (22qDS), and includes palatal clefting and velopharyngeal dysfunction in the absence of overt or submucous clefts. The reported incidence and distribution of palatal abnormalities vary in the literature. The aim of this article is to revisit the incidence and presenting features of palatal abnormalities in a large cohort of patients with 22qDS, summarize the surgical treatments performed in this cohort, and provide an overview of surgical treatment protocols and management guidelines for palatal abnormalities in this syndrome. Charts of 1,121 patients seen through the 22q and You Center at the Children's Hospital of Philadelphia were reviewed for palatal status, demographic factors, deletion size, and corrective surgical procedures. Statistical analysis was performed using Pearson's chi-squared test to identify differences between gender, deletion size, and palatal abnormality. Of the patients with complete evaluations, 67% were found to have a palatal abnormality. The most common finding was velopharyngeal dysfunction in 55.2% of patients, and in 33.3% of patients, this occurred in the absence of palatal clefting. There was no significant difference in the incidence of palatal abnormalities by gender; however, a difference was noted among race (p < 0.01) and deletion sizes (p < 0.01). For example, Caucasian and Asian patients presented with a much higher prevalence of palatal abnormalities, and conversely those with nested deletions presented with a much lower rate of palatal defects. Overall, 26.9% of patients underwent palatal surgery, and the most common indication was velopharyngeal dysfunction. Palatal abnormalities are a hallmark feature of 22q11.2 Deletion Syndrome; understanding the incidence, presenting features, and treatment protocols are essential for practitioners counseling and treating families affected with this disorder.

22q11.2 deletion syndrome in diverse populations.

22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P < 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.

Velocardiofacial syndrome in Mexican patients: Unusually high prevalence of congenital heart disease.

INTRODUCTION: Velocardiofacial syndrome (VCFS) is the most common microdeletion syndrome with an incidence of 1:4000 live births. Its phenotype is highly variable with facial, velopharyngeal, cardiac, endocrine, immunologic and psychiatric abnormalities. It is caused by a microdeletion in chromosome 22q11.2. OBJECTIVES: We present 7 years of experience evaluating patients with VCFS regarding their main clinical characteristics. MATERIAL AND METHODS: The patients included were multidisciplinary evaluated and had a positive FISH analysis for del22q11.2. RESULTS: A total of 62 patients were assessed, a 34 female/28 male ratio was observed with ages ranging from 9 days to 16 years, all but one patient had typical facial features. A diagnosis of congenital heart disease was established in 97% of the patients; other clinical characteristics were identified with different percentages such as cleft palate, and hypocalcaemia. Three cases had a familial presentation. DISCUSSION: While the clinical findings of this study were in general terms in keeping with the literature, it is interesting the unexpectedly high percentage of congenital heart disease identified in Mexican children with VCFS that also was the main cause for clinical referral.

Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: implications in transitional care.

22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Under-diagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects.

Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome.

BACKGROUND: The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion. METHODS: Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher's exact test was used to evaluate the association between the cardiac phenotype and each potential modifier. RESULTS: The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype. CONCLUSIONS: Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region.

High specificity PCR screening for 22q11.2 microdeletion in three different ethnic groups

Congenital heart defects are the most common of all human birth defects. Numerous studies have shown that a deletion within chromosome 22q11 is associated with DiGeorge syndrome and certain forms of sporadic congenital cardiovascular disease. We have determined the value of a PCR assay using markers D22S941, D22S944 and D22S264 designed for the screening of 22q11.2 deletion through consecutive homozygosity in an ethnically admixed urban population. The study population comprised 149 unrelated men and women from three different ethnic groups (white, mulatto and black). Test specificity for the overall population was estimated at 98.3 percent. We found no significant difference when comparing heterozygosity indices and ethnicity (P value = 0.43 (D22S944), 0.22 (D22S264), and 0.58 (D22S941)). There was no significant difference regarding assay specificity between the three different ethnic groups studied. This assay could constitute a cost-effective way to screen a large number of patients at increased risk, since PCR techniques are easily available, are fast, can be automatized, and are significantly less expensive than fluorescence in situ hybridization

High specificity PCR screening for 22q11.2 microdeletion in three different ethnic groups.

Congenital heart defects are the most common of all human birth defects. Numerous studies have shown that a deletion within chromosome 22q11 is associated with DiGeorge syndrome and certain forms of sporadic congenital cardiovascular disease. We have determined the value of a PCR assay using markers D22S941, D22S944 and D22S264 designed for the screening of 22q11.2 deletion through consecutive homozygosity in an ethnically admixed urban population. The study population comprised 149 unrelated men and women from three different ethnic groups (white, mulatto and black). Test specificity for the overall population was estimated at 98.3%. We found no significant difference when comparing heterozygosity indices and ethnicity (P value = 0.43 (D22S944), 0.22 (D22S264), and 0.58 (D22S941)). There was no significant difference regarding assay specificity between the three different ethnic groups studied. This assay could constitute a cost-effective way to screen a large number of patients at increased risk, since PCR techniques are easily available, are fast, can be automatized, and are significantly less expensive than fluorescence in situ hybridization.