Abstract
The apparent association between schizophrenia and velo-cardio-facial syndrome (VCFS)-22q11 deletion syndrome has received attention lately in light of recent findings in linkage studies implicating chromosomal region 22q12, which is telomeric to the VCFS region, as a candidate region associated with genetic susceptibility to schizophrenia [1]. Velocardio-facial syndrome was initially described by Shprintzen in 12 children with similar presentations of cleft palate, cardiac anomalies and typical facial appearance characterised by prominent nose, broad nasal root, narrow palpebral fissures and retrognathia. These features are caused by a hemizygous deletion at the chromosomal region 22q11. Thus, a new acronym CATCH 22 (cardiac anomaly, abnormal facies, thymic aplasia, cleft plate and hypocalcaemia) was coined to summarise the key diagnostic features seen in association with 22q11 deletion [2].
Case report
A 26-year-old woman, who had been working as a kindergarten teacher for 3 years, was referred for psychiatric assessment of a 2-months history of strange experiences, such as hearing voices and seeing shadows, in December 1992. On mental state examination, she was found to have various psychotic symptoms including third-person auditory hallucinations, auditory hallucinations in the form of a running commentary, persecutory delusions, and thought broadcasting. However, she did not have other symptoms of schizophrenia such as formal thought disorder, catatonia, grossly disorganised behaviour or negative symptoms. She was diagnosed as suffering from schizophrenia and was treated with haloperidol 3 mg per day, and has been regularly followed as an outpatient since 1992. She did not require any hospitalisation throughout the 6 years. In subsequent years, she continued to harbour residual symptoms of delusion of persecution, delusion of reference, thought broadcast and third-person auditory hallucinations. However, she was able to work as a delivery worker and receive a stable income. Although, she recognised that her psychotic experiences were abnormal, she did not attribute them to be related to mental illness. On the whole, her drug compliance was irregular. The lack of insight contributes to her irregular drug compliance.
The patient was the last of three siblings. Her birth and development was normal. She described her childhood as unremarkable. She did not report any conduct problem or emotional difficulties during her childhood and adolescence. She finished her school certificate examination with a pass in four subjects. There was no significant history of psychiatric or medical illness in her family.
The patient also had been suffering from idiopathic hypoparathyroidism since the age of 17. Initially, she presented with generalised convulsion associated with low serum ionised calcium at 1.10mol/L. Throughout all of these years, her serum calcium was maintained at the low normal range by oral calcium supplement. The psychotic symptoms persisted despite the correction of hypocalcaemic states. Primary hypoparathyroidism was confirmed with serum parathyroid hormone at 0.8 pmol/L. Physical examination did not reveal any abnormality suggestive of VCFS. Electroencephalogram showed episodes of focal spike waves over left parietal region. Computerised tomography scan of the brain, skeletal survey, results of testing of urea and other electrolytes including magnesium and liver function were all normal except for a raised alkaline phosphatase level. The presence of 22q11 deletion was confirmed by fluorescent in situ hybridisation (FISH) using a N25 cosmid probe [3].
Discussion
Psychiatric morbidity of velo-cardio-facial syndrome
Along-term follow-up revealed that more than 10% of these patients developed psychiatric disorders, especially schizophrenia, in their late adolescence and early adulthood [4]. Two out of 100 randomly selected schizophrenic patients were reported to harbour the 22q11 deletion [3]. The apparent association of schizophrenia and VCFS is also supported by the findings of four other groups [5–8]. However, both Papolos et al. [9] and Siegel-Barlett et al. [10] reported a wide range of psychiatric disorders associated with deletion of 22q11, including attention deficit hyperactivity disorder, schizotypal disorder, schizoaffective disorder and various affective disorders, especially bipolar affective disorder [9,10]. It is well recognised that intellectual disability and hypocalcaemia are often present in VCFS [11] and both are associated with a wide range of psychiatric morbidities. It is possible that VCFS may be secondarily associated with a variety of psychiatric symptoms including psychosis and mood disturbances with intellectual disability and hypocalcaemia serving as the mediating aetiologic factor.
Phenotypic variability of velo-cardio-facial syndrome
It is well recognised that the clinical diagnosis of VCFS in any affected individual may be difficult because the individual feature may be occult or may only manifest later in life. The severity of clefting may range from open cleft palate to submucous cleft palate and hypernasal speech may be the only recognisable abnormality. Cardiac anomalies may also be asymptomatic and identified only on detailed echocardiographic examination. Hypocalcaemia may only present transiently in the neonatal period. A complete absence of thymus is usually incompatible with life, while the lymphocyte count may be normal or slightly depressed in thymic hypoplasia. Facial dysmorphism is even more non-specific.
To date, FISH has become the gold standard for diagnosis of VCFS and has been used to delineate the phenotypic variability of the 22q11 deletion syndrome. It has been reported that different phenotypes occurred in the same families with members harbouring the same molecular lesion [12]. Similarly, discordant phenotypes in monozygotic twins concordant for 22q11 deletion were reported [13]. Lindsay et al. have found a striking consistency in the size of deletions (about 2 Mb) across different patients with highly variable phenotypes [14]. Therefore, the wide range of phenotypic variability among people with presumably identical deletions suggests that other factors may interact with the 22q11 deletion to give rise to the subsequent phenotype.
Hypocalcaemia in velo-cardio-facial syndrome
Lindsay et al. [14] reported combinations of hypocalcaemia with either facial anomalies or with severe heart disease were associated with a higher deletion frequency at 22q11 (66–70%) than the presence of palatal anomalies and nose anomalies with a milder heart defect or with no heart defect (13%). So, the presence of hypocalcaemia and 22q11 deletion in our patient also supports the initial findings of Lindsay et al. [14] that hypocalcaemia together with other VCFS features is highly predictive of 22q11 deletion.
Conclusions
The wide range of phenotypic variability of VCFS makes effective screening of 22q11 deletion in schizophrenia difficult. The use of FISH will delineate the clinical spectrum of VCFS and determine the specificity of individual VCFS features. The presentation of our patient seems to support that hypocalcaemia may be one of the VCFS features alerting the psychiatrist to screen for deletion 22q11.
Footnotes
Acknowledgements
This study was funded by the Direct Grant for Research and the Ho Sin Hang Education Endowment Fund of the Chinese University of Hong Kong.