Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk

Abstract

Background: Velocardiofacial syndrome (VCFS), a genetic deletion condition with numerous cognitive sequelae, is associated with a high rate of psychiatric disorders in childhood. More recently, VCFS has been identified as a high-risk factor for developing adult onset schizophrenia. However, it has never been demonstrated that the childhood psychiatric disorders found in children with VCFS differ from those found in children with a similar degree of cognitive impairment. Identification of a specific behavioral (psychiatric) phenotype in childhood VCFS offers the potential for elucidating the symptomatic precursors of adult onset schizophrenia.

Methods: Twenty-eight children with VCFS and 29 age- and cognitively matched control subjects received a standardized assesment of childhood psychiatric disorders and behaviors measured by the Child Behavior Checklist (CBCL). Findings from the two groups were compared.

Results: The rates and types of psychiatric disorder and behavior problems in VCFS and cognitively matched control subjects were very high, but showed no significant differences.

Conclusions: Psychopathology in children with VCFS may not differ from that found in cognitively matched control subjects. Another explanation is that subtle phenotypic differences in behavior found in VCFS can not be observed using standard symptom inventories. The high rate of psychopathology in children with VCFS is not a useful phenotypic indicator of high risk for adult onset schizophrenia.

Introduction

Velocardiofacial syndrome (VCFS) is one of the most common of the genetically based developmental disorders and is manifested by a complex of several medical abnormalities, a reduction in intelligence, learning disabilities, and psychiatric disorder Bassett and Chow 1999, Cohen et al 1999, Feinstein and Eliez 2000, Moss et al 1999, Murphy et al 1999, Ryan et al 1997, Shaikh et al 2000, Swillen et al 1999. It is estimated to occur in at least 1 per 2000 to 4500 live births (Tezenas Du Montcel et al 1996). In most affected individuals, a de novo 3 Mb deletion at chromosome 22q11.2 is responsible for the syndrome Carlson et al 1997, Driscoll et al 1993, Lindsay et al 1995, Scambler et al 1992, Shaikh et al 2000.

Recently, investigators utilizing both psychiatric assessments of subjects known to have VCFS and genetic testing of patients with schizophrenia have demonstrated a strong association between VCFS and schizophrenia in adulthood. Shprintzen and coworkers (Shprintzen et al 1992) reported that 20–30% of his cohort of VCFS patients 16 years or older developed schizophrenia or schizoaffective disorder. Murphy and coworkers found 30% of 50 adult patients with VCFS to be psychotic (24% schizophrenia, 2% schizoaffective, 2% psychosis not otherwise specified, and 2% rapid-cycling bipolar disorder) (Murphy et al 1999).

In 1995, Karayiorgou and colleagues identified by genetic testing two patients with VCFS in a random sample of 100 schizophrenic patients (Karayiorgou et al 1995). Gothelf et al (1997) identified three individuals with VCFS by genetic testing of 20 hospitalized schizophrenic patients who had medical anomalies suggestive of VCFS. Bassett and coworkers applied a screening procedure based on five types of medical or developmental anomalies characteristic of VCFS to identify VCFS in a schizophrenic sample. Ten of 15 schizophrenic patients who had at least two of these were found to have VCFS by genetic testing Bassett and Chow 1999, Bassett et al 1998. These patients had intelligence quotients (IQs) ranging from borderline to mild mental retardation. In addition to symptoms and signs diagnostic of schizophrenia, most of these patients had a cluster of behavioral features that included impulsivity, frequent aggressive or temper outbursts, mood lability, anxiety, and compulsions. Usiskin and colleagues have recently reported that 6.4% of a cohort of youngsters with childhood-onset schizophrenia had VCFS (Usiskin et al 1999).

Because VCFS can be diagnosed reliably early in life, it should be possible to determine if there is a characteristic pattern of childhood behavior problems associated with this genetic disorder that arises prior to the high-risk period for the onset of schizophrenia. Such a behavior profile could possibly represent a phenotypic indicator of later-onset schizophrenia that might be of general use in identifying children at high risk. Perhaps more salient from a humane perspective, it appears that clinical neuroscience has advanced to the unsettling point where the families of children with VCFS know that a significant subgroup of their children will develop schizophrenia, a severely impairing lifelong psychiatric disorder. Yet, we cannot help families with VCFS predict the future for any specific child. We do not know if VCFS is simply a powerful general risk factor for schizophrenia or whether some yet-undetected aspect of the genetic deficit is specifically responsible for a child’s developing schizophrenia from VCFS. Furthermore, our ability to formulate a preventive intervention strategy is greatly hampered by our inability to determine which children will develop the disorder.

Velocardiofacial syndrome has been associated with a high rate of psychiatric disorder in both children and adults (Feinstein and Eliez 2000). Studies of VCFS children have documented problems with social interaction, mood lability, disinhibition, and shyness Golding-Kushner et al 1985, Swillen et al 1999. Papolos and colleagues reported that children with VCFS commonly suffer from attention-deficit/hyperactivity disorder, separation anxiety disorder, and obsessive-compulsive disorder, and that 64% of their cohort met criteria for bipolar spectrum disorders in adolescence (Papolos et al 1996). Gerdes et al (1999) found that 75% of preschool children with VCFS in their sample were overactive, impulsive, highly emotional, and disorganized. Swillen and colleagues, utilizing behavior checklist data, found significant behavioral difficulties, such as “social problems,” “attention problems,” “thought problems,” “withdrawn behaviors,” and anxiety Swillen et al 1997, Swillen et al 1999.

Even though we have ample evidence of a high rate of psychiatric disorder and behavior problems in children with VCFS, the relationship between these childhood psychiatric conditions and the later onset of schizophrenia is unknown. The psychiatric problems of children with VCFS could also be explained as simply deriving from their developmental delays and cognitive deficits, rather than having any specific relationship to increased risk for schizophrenia. In fact, it is well documented that the rate of childhood psychiatric disorder is generally elevated in children with developmental disabilities, developmental language disorders, and learning disabilities Beitchman et al 1986, Beitchman and Young 1997, Cantwell and Baker 1991, Einfeld and Tonge 1996, Feinstein and Reiss 1996, all problems consistently found in children with VCFS. We are not aware of any published reports comparing psychiatric disorders and behavior problems in VCFS children with those found in other groups of developmentally disabled children. This raises the question of whether the psychiatric disorders found in children with VCFS are phenotypic indicators of later-onset schizophrenia, or simply a nonspecific outcome of brain dysfunction due to VCFS.

This article approaches the issues raised above by comparing the psychiatric diagnoses and behavioral profiles found in a sample of children and adolescents with VCFS with those found in a matched control group of youngsters with mental retardation and learning disabilities. The main research question is whether there is a unique profile of childhood psychiatric disorders or behavioral profiles in VCFS that can be distinguished from the behaviors of a group of comparably disabled children without VCFS. The identification of a unique psychiatric profile for VCFS would strengthen the hypothesis that the behavioral problems that children with VCFS experience are a phenotypic indicator of vulnerability to schizophrenia.