Psychosomatics 44:348-350, August 2003
© 2003 The Academy of Psychosomatic Medicine
Psychosis, Electrolyte Imbalance, and Velocardiofacial Syndrome
Zinia S. Thomas, M.D., Newark, N.J.
TO THE EDITOR: This report describes velocardiofacial syndrome and its genetic link to schizophrenia. Velocardiofacial syndrome and certain deletions on chromosome 22 may be considered a medical model for elucidating etiological pathways leading to the development of schizophrenia.
Case Report
Mr. A was a 23-year-old man with mild mental retardation. Upon presentation to a psychiatric emergency department, he was admitted for medical and psychiatric treatment after a recent change in behavior in which he was confused and psychotic. Mr. A had no previous psychiatric history. He had congenital hydrocephalus, which was drained after birth, and a transient seizure disorder in childhood. His major developmental milestones were delayed. He did not use tobacco, alcohol, or any illicit drugs and was not regularly taking any medication. His family history was significant for a maternal grandmother with a history of thyroid disorder and a questionable psychotic illness, details of which were unknown. He held a job working as a ticket collector in a movie theater after high school graduation at age 19 up until the day before he came to the hospital.
At his evaluation in the emergency room, his vital signs were normal, and he appeared as a tall, thin man with a broad nose, an elongated face, and low-set ears. He exhibited waxy flexibility as he imitated the crucifixion of Jesus for a half hour. His speech was rapid and clear, and he had a nasal voice. His affect was constricted and incongruent with his happy mood and delusions of grandeur. He appeared to be responding to internal stimuli and reported having auditory hallucinations about God. He described bizarre delusions and believed that his cat was Jesus and his dog was the devil, as well as grandiose delusions that he was God. He was religiously preoccupied but reported no suicidal or homicidal ideations. Mr. A was tangential and oriented only to self, stating that the hospital was heaven and the time was April (an error of 4 months). He was able to follow simple commands, but his overall concentration was impaired, and his higher cortical functioning could not be tested. The rest of his physical examination was unremarkable.
The results of a urine toxicology screen were negative; his CBC was within normal limits. The results of a serum chemistry showed a low calcium level (6.1 mg/dl), a low potassium level (3.2 mg/dl), a low magnesium level (1.4 mg/dl), and a slightly high phosphorus level (4.6 mg/dl). Mr. A's ECG had a shortened P-R interval and a prolonged QTc interval (570 msec). His CSF pressure and the results of chemistries from a lumbar puncture were normal. A computerized tomography scan of his head showed mild to moderate volume loss with enlarged ventricles and cisterns; also noted were calcifications in the basal ganglia. He received intravenous calcium and fluids. Various diagnoses, such as renal insufficiency, thyroid disorder, autoimmune process, HIV, and syphilis, were ruled out. His parathyroid hormone level was found to be low (an intact parathyroid hormone level of 9 pg/dl). With replacement, his electrolyte status levels approached the normal range (calcium: 8.2 mg/dl, potassium: 4.0 mg/dl, magnesium 1.5 mg/dl, phosphate: 5.5 mg/dl), and his cardiac conduction abnormalities disappeared; however, he continued to be psychotic. If hypocalcemia had been the cause of his psychosis, some improvement in his psychotic symptoms would be expected with correction of his abnormal calcium level.
Mr. A was given risperidone, titrated to 2 mg b.i.d.. Within a week, his mental status began to change; he began eating on his own, was able to answer simple questions, and was oriented to person and place. He still appeared to be responding to internal stimuli. He exhibited slight psychomotor retardation with a flat affect; he reported no auditory or visual hallucinations and no suicidal or homicidal ideations. He was sent home while receiving risperidone and calcium supplementation. Although his acute psychosis resolved, according to his mother, Mr. A was "not the same" as he had been before becoming ill.
Discussion
With our patient's multiple symptoms and slightly dysmorphic features, a syndrome capable of explaining all of these findings was sought. Consultation with endocrinologic and genetic services and a review of the literature pointed to velocardiofacial syndrome. Shprintzen et al.1 first described velocardiofacial syndrome in 1978 as a multiple malformation syndrome, congenital in nature, that may be suspected in patients with hypocalcemia, learning difficulties, psychiatric disorders, characteristic facial features, a hypernasal voice (due to palate abnormalities), and cardiac abnormalities. Chromosomal analysis with fluorescent in situ hybridization was performed, and results showed a deletion on chromosome 22, matching the chromosomal abnormality found in velocardiofacial syndrome.
Velocardiofacial syndrome is a genetic syndrome characterized by a deletion of band 11 on the long arm (q) of chromosome 22.2 Most cases are caused by a de novo 3-Mb microdeletion. However, this deletion may also be inherited in an autosomal-dominant manner.3 The 22q11.2 deletion is estimated to occur in 1 per 2,000–4,500 live births.4 At least 30 genes are encoded in the deleted segment, some of which are essential for normal brain development.5 Because of the disparity in size of the deleted segment and, thus, the genes involved, there is a great variability in the phenotypic manifestations of this syndrome. More than 40 congenital medical conditions or physical anomalies are associated with velocardiofacial syndrome. The most common clinical signs are clefting of the secondary palate, long facies, prominent noses, malar flattening, cardiac anomalies, hypoparathyroidism, small stature, slender hands and digits, learning disabilities or mental retardation, and behavioral disturbances.3,6 Approximately 40% of these patients have mild to moderate mental retardation.3 Individuals with velocardiofacial syndrome are described as having little facial expression, blunted affect, and poor social skills.
According to work by Feinstein and Eliez,3 approximately 30% of people with velocardiofacial syndrome develop schizophrenia, thus establishing velocardiofacial syndrome as the first diagnosable genetic cause of schizophrenia. Murphy et al.7 conducted a study and found that 30% of patients with velocardiofacial syndrome had a psychotic disorder, with 24% fulfilling DSM-IV criteria for schizophrenia. Karayiorgou et al.8 examined the genetic overlap between schizophrenia and velocardiofacial syndrome; their results translated into a prevalence of 22%, which is much higher than the 1% prevalence of schizophrenia in the general population. As stated by Eliez et al.,9 velocardiofacial syndrome is the highest known risk factor identified to date for the development of schizophrenia and supports the notion of velocardiofacial syndrome as a potential genetic-developmental model for schizophrenia.
As mentioned, at least 30 genes are encoded in the area of the deletion on chromosome 22. Of particular interest is the COMT gene. The COMT gene produces an enzyme, catechol O-methyltransferase (COMT), that is responsible for the degradation of dopamine, norepinephrine, and epinephrine. Disturbances in dopamine neurotransmission have been presumed to contribute to the etiology of psychotic disorders, particularly schizophrenia. Dunham et al.10 have hypothesized that individuals with a defective COMT gene have a higher dopamine level in the brain and are therefore predisposed to the development of psychosis. However, according to the study by Murphy et al.,7 they and others have found no evidence for an association between the COMT genotype and schizophrenia. They also found no association between the low-activity COMT allele and schizophrenia in their study of individuals with velocardiofacial syndrome. Thus, the putative role of COMT in the pathogenesis of psychiatric disorders remains unclear.3
Our review of the literature illuminated the strong association between the 22q11.2 chromosomal deletion in velocardiofacial syndrome and schizophrenia. With further genetic advances, the entire chromosome 22 will be mapped and the genes identified. Tracing the effects of each gene in the deleted segment will provide greater insight into brain development, cognition, and behavior. As eloquently stated by Feinstein and Eliez,3 the determination of the precise gene responsible for greatly increasing the vulnerability to schizophrenia of people with this genetic disorder may help elucidate the pathogenesis of a mental illness that has been a major scourge to mankind.3
REFERENCES
- Shprintzen RJ, Goldberg RB, Lewin ML, Sidoti EJ, Berkman MD, Argamaso RV, Young D: A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J 1978; 15:56-62[Medline]
- Thomas JA, Graham JM: Chromosome 22q11 deletion syndrome: an update and review for the primary pediatrician. Clin Pediatr 1997; 36:253-266[Abstract/Free Full Text]
- Feinstein C, Eliez S: The velocardiofacial syndrome in psychiatry. Curr Opin Psychiatry 2000; 13:485-490[CrossRef]
- du Montcel ST, Mendizabal H, Ayme S, Levy A, Philip N: Prevalence of 22q11 microdeletion (letter). J Med Genet 1996; 33:719[Free Full Text]
- Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G, Goldberg R, Kucherlapati R, Papolos DF: Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 1996; 67:468-472[CrossRef][Medline]
- Pike AC, Super M: Velocardiofacial syndrome. Postgrad Med J 1997; 73:771-775[Abstract/Free Full Text]
- Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56:940-945[Abstract/Free Full Text]
- Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, et al: Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 1995; 92:7612-7616[Abstract/Free Full Text]
- Eliez S, Antonarakis SE, Morris MA, Dahoun SP, Reiss AL: Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome: a preliminary study. Arch Gen Psychiatry 2001; 58:64-68[Abstract/Free Full Text]
- Dunham I, Collins J, Wadey R, Scambler P: Possible role for COMT in psychosis associated with velo-cardio-facial syndrome (letter). Lancet 1992; 340:1361-1362
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