Psychiatric Re-Evaluation of Patients with 22q11.2 Deletion Syndrome Presenting with Psychotic Symptoms, with Special Reference to Autism Spectrum Disorder

Research Article

Austin Med Sci. 2016; 1(3): 1013.

Psychiatric Re-Evaluation of Patients with 22q11.2 Deletion Syndrome Presenting with Psychotic Symptoms, with Special Reference to Autism Spectrum Disorder

Kawano M*, Oshimo T, Kawano M, Nishimura K and Ishigooka J

Department of Psychiatry, Tokyo Women’s Medical University, Japan

*Corresponding author: Miho Kawano, Department of Psychiatry, Tokyo Women’s Medical University 8-1 Kawada-cho Shinjuku-ku Tokyo 162-8666, Japan

Received: November 29, 2016; Accepted: December 19, 2016; Published: December 21, 2016


Background: Patients with 22q11.2 deletion syndrome (22q11.2DS) presenting with psychotic symptoms tend to be diagnosed with schizophrenia. However, it has recently been argued that these individuals may have Autism Spectrum Disorder (ASD). There is much controversy over this diagnosis and whether these symptoms may precede schizophrenia.

Methods: We studied the psychosis phenotypes of 11 patients with 22q11.2DS presenting with psychosis symptoms and of 11 non-syndromic patients with schizophrenia, matched by age and gender, using the Revised Autism Diagnostic Interview (ADI-R) and the Positive and Negative Syndrome Scale (PANSS). We compared these scores between groups using chi-square tests, Mann–Whitney U tests, and multiple regression analysis.

Results: The ADI-R scores indicated that the psychotic patients with 22q11.2DS had childhood and current autistic scores that were significantly more severe than those of the participants with schizophrenia. The PANSS positive symptom, general psychopathology, and total symptom scores did not differ significantly between the two groups. In contrast, the PANSS negative symptom scores were significantly lower in psychotic patients with 22q11.2DS. Current autistic features, apart from social interaction, and the PANSS symptoms were not associated with age, and no gender differences were observed between any of the variables.

Conclusions: The limited size of our case study does not reflect the overall epidemiological picture of psychotic patients with 22q11.2DS; however, all 11 psychotic patients with 22q11.2DS could be diagnosed as having ASD, which could preliminarily lead to a better social life. Children with 22q11.2DS usually require long-term treatment for systemic comorbidities. Earlier referral to a specialty clinic and psychiatric consultation as well as periodic psychiatric re-evaluation over a long-term follow-up period are therefore essential for the clinical management and proper support of the psychotic patients and their families.

Keywords: Velocardiofacial syndrome; Schizophrenia; Autism spectrum disorders; ADI-R; PANSS


Chromosome 22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome or DiGeorge syndrome, is a disorder caused by the deletion of a small region in the middle of chromosome 22 at a location designated as q11.2. The deletion affects an estimated one in 4000 live births and is the most common microdeletion syndrome known in humans [1]. It is either inherited as an autosomal dominant condition or arises de novo by deletion or translocation, without gender or racial differences [2]. This deletion or translocation results in the loss of the T-box1 gene (TBX1), which is considered to be responsible for many of the characteristic features of 22q11.2DS, including heart defects, cleft palate, distinctive facial features, hearing loss, and low calcium levels [3]. Many other genes in the region [e.g. catechol-O-methyltransferase (COMT) gene, proline dehydrogenase (PRODH) gene, among others] also might influence the clinical phenotype of patients with 22q11DS. Multi-system care is therefore necessary for individuals with 22q11.2 deletion syndrome, so that they can be evaluated for their various health needs and carefully monitored. Children with 22q11.2DS receive ongoing support, medical care, and information regarding major comorbidities from a team of health care workers. As a result, psychiatric referrals can often be delayed, due to serious comorbidities.

Many children with 22q11.2DS experience developmental delays, including delayed growth [4], poor speech development [5], and learning disabilities [6]. Later in life, these individuals are at an increased risk of developing mental illnesses such as schizophrenia, depression, anxiety, attention disorders, and bipolar disorder [7]. In particular, the affected children are more likely to develop attentiondeficit hyperactivity disorder [8] and autism spectrum disorders (ASDs) that can affect communication and social interactions [9].

There is a particularly high rate of psychotic disorders (29%) among individuals with 22q11.2DS, with most of these individuals (22%) meeting the diagnostic criteria for schizophrenia [10,11]. Overall, the prevalence of schizophrenia is reported to be 9%-38% among patients with 22q11.2DS, a rate that is greater than that in the general population [12-17]. The largest study on psychiatric morbidity in 22q11.2DS assessed 1402 patients with the condition (age range in years: 6-68) and found 22q11.2DS to be an important risk factor for psychosis [18]. In that study, ASDs were prevalent in all age groups (13%-27%) but they were shown to peak during adolescence. The prevalence of schizophrenia spectrum disorders was also high, ranging from 23.5% in young adults (18-25 years) to 41% in patients aged >25 years. The study authors, however, noted some limitations in diagnostic reliability [18] but might disagree that the diagnosis of schizophrenia spectrum disorder is not always reliable in 22q11.2DS.

Vorstman and colleagues (2006) [19] reported a high prevalence of ASDs in individuals with 22q11.2DS. However, this report was criticized by Eliez (2007) [20], who argued that the greater incidence rates of specific language delays (i.e., verbal reasoning skills, which are typically stronger than nonverbal intellectual profiles) and social deficits (ranging from “active but odd” to “overly withdrawn”) could make the diagnosis of ASD less justified. ASD and schizophrenia were considered distinct nosologic entities; however, emerging evidence has contributed to the blurring of symptomatic and genetic boundaries between these conditions. The phenotypical overlap between ASD and schizophrenia may indicate that both conditions can emerge from related neurodevelopment vulnerabilities or shared pathogenic mechanisms based on genotypic overlap [21]. Childhoodonset schizophrenia is preceded by an ASD diagnosis in 30%-50% of cases [22].

Clinically, any individual with ASD, with or without 22q11.2DS, requires careful assessment vis-à-vis their specific personal needs and strengths, to guide treatment [19]. We therefore investigated whether ASD could be identified in patients with 22q11.2DS who present with psychotic symptoms using age- and gender-matched controls without 22q11.2DS and who had already been diagnosed as having schizophrenia.



More than 225 patients have been genetically diagnosed as having 22q11.2DS and treated at various departments in Tokyo Women’s Medical University Hospital [23]. Diagnoses of 22q11.2DS were confirmed by the presence of a 22q11.2 hemizygous partial chromosome deletion using the fluorescence in situ hybridization method. From 2011 to 2013, approximately 40 of these patients with 22q11.2DS, (median age 17 years), were referred to the Department of Psychiatry for various neuropsychiatric problems, usually after their systemic comorbidities were well treated and had achieved stable status. Of these patients, those who had been treated over several years for psychotic symptoms were asked to participate in this study. The sample included seven men and four women with 22q11.2DS and psychotic symptoms (aged 17-40 years; mean age, 30.36 ± 7.89 years), with their parents approving participation. Patients (seven men and four women aged 18–39 years, with a mean age: 30.27 ± 7.06 years) with an established diagnosis of schizophrenia and without other systemic or psychiatric comorbidities were matched by age and gender and recruited as controls. The control patients were confirmed as having a schizophrenia diagnosis using the Japanese edition of Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association Text Revision (DSM-IV-TR), fourth ed. Igakushoin, Tokyo [24]. All participants and their parents provided written informed consent. This case-control study was approved by the Research Ethics Committee of Tokyo Women’s Medical University.


The participants and their parents were interviewed, and medical records were scrutinized for past medical histories and sociodemographic data. The patients were physically examined to assess their baseline condition. The ADI-R is a semi-structured interview administered to a patient’s parents to assess the presence of ASD. In this study, a well-trained and certified ADI examiner questioned the parents about the participant’s current and early childhood levels of functioning with respect to autistic features. The Positive and Negative Syndrome Scale (PANSS) was used to measure the severity of schizophrenia symptoms. This medical scale is used for measuring the severity of positive symptoms, where there is an excess or distortion of normal functions (e.g., hallucinations and delusions), and negative symptoms, where there is a diminution or loss of normal functions. Participants were evaluated using the ADI-R and the PANSS while they were clinically stable and without having changed medication during the previous 6 months (the stabilization phase).

Data analysis

Mann–Whitney U tests were used to compare the two clinical groups with regard to sociodemographic data, childhood autistic features, current autistic features, and current positive and negative schizophrenia symptoms. The frequency of positive ADI-R scores was tested between the two groups using the chi-square test. Multiple regression analyses were used to estimate the relationship between current ADI-R and PANSS domains (the dependent variables) and age, diagnosis, and gender (the independent variables). The variables analyzed included childhood autistic features, current autistic features, and current positive and negative schizophrenia symptoms. Specifically, the analysis included all three ADI-R childhood domains (qualitative abnormalities in reciprocal social interaction; qualitative abnormalities in communication; and restricted, repetitive, and stereotyped patterns of behavior), all three ADI-R current domains, a combination of all six ADI-R domains, and all four PANSS domains (positive symptoms, negative symptoms, general psychopathology symptoms, and total symptoms).


All of the participants studied were Japanese, including eleven 22q11.2DS patients with psychotic symptoms and eleven age- and gender-matched schizophrenia patients without 22q11.2DS. Their clinical and sociodemographic characteristics are presented in (Table 1). These ADI-R childhood autistic features of the 22q11.2DS group were greater than the cutoff value for the diagnosis of ASD, whereas those of the schizophrenia group were below the cutoff. All 11 22q11.2DS patients with psychotic symptoms were diagnosed with ASD. The ADI-R childhood autism scores of the 22q11.2DS participants were significantly more severe than those of the participants with schizophrenia, including scores for childhood social interaction (20:1, [the ratio of the median scores, 22q11.2DS group: schizophrenia group]), communication (15:1), and repetitive interests and behaviors (5:0) (all p < 0.001). The 22q11.2DS group also had more severe current ADI-R autism scores, including social interaction (10:0), communication (6:1), and repetitive interests and behaviors (3:0) (all p < 0.001). Multiple regression analysis confirmed that these childhood and current ADI-R features of the 22q11.2DS group were greater than those of the schizophrenia group (Table 2). The median PANSS positive symptom scores, general psychopathology scores, and total symptom scores did not differ between the groups (20:18, 30:30, and 67:68, respectively). The median PANSS negative symptom scores, however, were significantly lower in the 22q11.2DS group (17:19, p < 0.01) (Tables 1 & 2). Multiple regression analysis confirmed these PANSS features (Table 2). As a result, these patients received the behavioral and communication help appropriate for individuals with an ASD diagnosis. Preliminary narrative data suggest that they have gone on to lead uneventful, stable lives, with dose-reduced medication, better relationships with family members and/or coworkers, and improving social confidence.

Citation: Kawano M, Oshimo T, Kawano M, Nishimura K and Ishigooka J. Psychiatric Re-Evaluation of Patients with 22q11.2 Deletion Syndrome Presenting with Psychotic Symptoms, with Special Reference to Autism Spectrum Disorder. Austin Med Sci. 2016; 1(3): 1013.