This study included 145 children and adolescents with 22q11.2DS who presented at the Asan Medical Center Children's Hospital between 1996 and 2013. The diagnosis of 22q11.2DS was confirmed in all participants using fluorescence in situ hybridization or multiplex ligation-dependent probe amplification. Data on sex, age, ages at presentation and diagnosis, family history, birth-related history (gestational age and birthweight), initial manifestations, growth profiles, and other characteristic phenotypes associated with 22q11.2DS were obtained by a retrospective review of the medical records. The initial manifestations and presenting phenotypes associated with 22q11.2DS involved facial dysmorphisms, growth retardation, congenital heart defects, velopharyngeal abnormalities, parathyroid dysfunction, immune deficiency, microcephaly, and CNS manifestations including epilepsy, developmental delay, and psychiatric illness. Epilepsy was classified etiologically according to the 2010 International League Against Epilepsy classification.17 Epilepsy without a distinct structural or metabolic condition was defined as genetic epilepsy in the present 22q11.2DS patients, where the epilepsy is understood to directly result from a known or presumed genetic defect. Structural epilepsy in 22q11.2DS was defined when there were distinct structural abnormalities associated with a substantial risk of developing epilepsy. Developmental delay was defined as a failure to reach appropriate developmental age-related milestones in motor skills and cognitive function. Psychiatric disorders were clinically diagnosed by a pediatric psychiatrist (H.W. Kim) based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. In patients with reported epilepsy and other NP symptoms, detailed neurological examinations, electroencephalogram (EEG) recording, brain imaging studies (ultrasonography, computed tomography, or magnetic resonance imaging), and psychological examinations were performed according to their symptoms. Clinical variables were also reviewed, including age at the onset of seizures, seizure type, antiepileptic drugs used, comorbidities of other NP manifestations, and laboratory data. The overall and individual prevalence rates of the various NP phenotypes were analyzed, and the patients with epilepsy were categorized into two groups based on etiology and described in detail. To investigate the possible associations between epilepsy and other clinical factors, the clinical factors were compared between 22q11.2DS patients with and without epilepsy.

This study was approved by the Institutional Review Board of the Asan Medical Center, University of Ulsan College of Medicine, Korea. Informed consent was provided by the parents or guardians of the study subjects.

Clinical variables were compared across 22q11.2DS patients with and without epilepsy using independent t-tests for the continuous variables and χ² and Fisher's exact tests for the categorical variables. All statistical analyses were performed using SPSS statistical software (version 18.0, SPSS, Chicago, IL, USA). A p value of <0.05 was considered indicative of statistical significance.

One hundred and forty-five patients (72 males and 73 females) with a diagnosis of 22q11.2DS were included. The median patient age at enrollment was 6.6 years [interquartile range (IQR)=2.5-12.1 years], and the median duration of follow-up was 3.9 years (IQR=0.8-9.1 years). The median age at diagnosis was 10.3 months (IQR=1-47 months), and a prenatal diagnosis was made in one case. The most common initial manifestation at diagnosis was CHD (n=105, 72.4%), followed by NP symptoms of developmental delay (n=13, 9.0%) and epileptic seizures (n=2, 1.4%). Fig. 1A describes the presenting phenotypes and their frequency at the time of study enrollment. NP disorders (n=66, 45.5%) were the third most common manifestation (Fig. 1A), and 25 (37.9%) among those 66 patients showed at least two coexisting NP symptoms (Fig. 1B). The most common NP manifestation of 22q11.2DS was developmental delay or intellectual disability (n=58). Other common psychiatric disorders were attention-deficit/hyperactivity disorder (ADHD) (n=9) and mood disorders (n=4) (Fig. 1B).

Twenty-two of the patients (15.2%) presented with epileptic seizures. The median age at seizure onset was 8 months (IQR=4-33), and 16 patients experienced their first seizures when they were younger than 2 years. The most common type of seizure was generalized tonic-clonic seizure (n=16, status epilepticus in one) followed by focal clonic seizure (n=4) and myoclonic seizure (n=2). Among the 22 patients with epileptic seizures, 12 patients (8.3%; 5 males and 7 females) were diagnosed as having genetic epilepsy (Table 1). The types of seizures in the genetic epilepsy cases were mostly generalized seizures: the exceptions were one patient with focal clonic seizures and a second with subtle seizures with desaturation. EEGs were obtained in the 12 patients with genetic epilepsy (Table 1), of which 6 (50.0%) had a developmental delay or intellectual disability and 2 (16.7%) had psychiatric disorders: 1 with ADHD and mood disorder and 1 with a mood disorder.

Epilepsy with a structural etiology was diagnosed in 10 patients (Table 2). The type of seizures and EEG findings are described in Table 2. Among these 10 patients with structural epilepsy, 9 patients (90.0%) had developmental delay or intellectual disability and 3 (33.3%) had comorbid psychiatric disorders, comprising autism spectrum disorder (ASD), ADHD, and mood disorder. Developmental delay was significantly more common in the 22q11.2DS patients with epilepsy than in those without epilepsy (p=0.003) (Table 3). The risk of epilepsy increased significantly when a 22q11.2DS patient showed a developmental delay, with an odds ratio of 3.98 (95% confidence interval=1.5-10.5; p=0.005). A psychiatric disorder was also more frequent in patients with an epilepsy phenotype (5/22, 22.7%) than in those without epilepsy (11/123, 8.9%), but there was no statistical significance (p=0.057). In comparing the etiologies of epilepsy, developmental delay was found to be significantly associated with structural epilepsy (p=0.045), whereas a psychiatric manifestation did not show this relationship.

There were abnormal findings in 18 of the 53 patients (34.0%) who underwent brain imaging studies, which revealed congenital CNS abnormalities in six patients. Malformations of cortical development, including diffuse polymicrogyria (n=3) (Fig. 2A) or focal cortical dysplasia and subependymal heterotopia (n=1) (Fig. 2B), were demonstrated in four patients, and Chiari malformation was present in one patient (Fig. 2C) and hypoplasia of the intracranial artery in another patient. Various acquired CNS abnormalities were observed, including a cerebral infarction (n=4), diffuse or focal atrophy (n=3), cerebral hemorrhage (n=2), calcification (n=2), and multifocal white-matter changes (n=1).

We examined the possibility that other clinical variables affected the occurrence of the epilepsy phenotype in the current patient series (Supplementary Table 1 in the online-only Data Supplement). Comparing sex, age at diagnosis, microcephaly, facial dysmorphism, hypocalcemia, severity of CHD, and birth-related factors between 22q11.2DS patients with and without epilepsy revealed that none of these variables was associated with the development of the epilepsy phenotype in this genetic syndrome.