Answers

Short answers

1 Patients with schizophrenic symptoms with a history of delayed motor development, early onset of the disorder, history of learning disability, history of cleft palate, or hypernasal speech should be screened for the velocardiofacial syndrome (VCFS) deletion.

2 With a variable clinical presentation, genetic testing (with patient consent) would be the most appropriate step. This can be made more challenging by the degree of learning disability the patient may have.

3 As with many other genetic conditions a holistic approach with the smooth coordination of different specialties would help the patient best. Counselling is important.

Long answers
1 Possible diagnosis
Patients with schizophrenic symptoms who have a history of delayed motor development, early onset of the disorder, a history of learning disability, a history of cleft palate, or hypernasal speech should be screened for the velocardiofacial syndrome deletion. Although guidelines for screening have not been agreed, a few authors say that screening should be considered, particularly if a congenital cardiac abnormality is detected.^{1 2}

Velocardiofacial syndrome is a genetic disorder associated with hemizygous interstitial deletions of chromosome 22q11.2.³ The clinical expression ranges from mildly affected patients to severe DiGeorge syndrome.⁴ Paediatricians are more likely to come across patients with more severe presentations of the illness. The estimated prevalence of the syndrome is 1/4000,⁵ and 10-28% of cases are transmitted as an autosomal dominant trait; the remainder are spontaneous mutations.^{4 6}

The faces of these patients are characterised by narrow palpebral fissures, broad nasal root and squared-off tip, malar flatness, retrognatia, small mouth and minor ear anomalies. In addition, cleft palate, hypernasal speech, conotruncal cardiac anomalies, slender hands, and thymic hypoplasia causing lymphopenia and hypocalcaemia are common manifestations.^{4 6} The pattern of anomalies suggests abnormal movement of neural crest cells that migrated into the embryonic pharyngeal arches.¹

Mental retardation and learning disabilities, including impairments in development of reading, language, spelling, and numerical skills, are additional common manifestations of the syndrome.^{6 7} One study found higher verbal IQs than performance IQs, and these were probably related to deficits in visuospatial-perceptual functioning.⁸ Patients with velocardiofacial syndrome also tend to have a high rate of psychiatric morbidity, most commonly schizophrenia and bipolar affective disorder. The overall rate of psychopathology varies widely, from 10.8% to 96%,^{4 5} probably because of screening different populations (from 5 years to adults), polymorphic symptom profiles (from anxiety to frank psychosis), and variations in the screening instruments. Also, substance misuse in this group of patients could lead medical staff to ascribe psychotic symptoms to the use of illicit drugs rather than to a primary psychotic disorder.

2 Confirming the diagnosis
With such variable presentation, genetic testing is the best way to confirm the diagnosis. Fluorescence in situ hybridisation (FISH) is available in many cytogenetics laboratories. Fluorescently labelled pieces of DNA permit the identification of tiny deletions not visible on Giemsa banded metaphase chromosome spreads, making it easier to diagnose conditions involving microdeletions, such as velocardiofacial syndrome.⁹

Most patients with velocardiofacial syndrome have a 3 Mb hemizygous deletion of 22q11.2. Others have smaller deletions within this region. A few patients have rare deletions that show no overlap with the typically deleted region.¹⁰ As the deletion may be inherited, both parents should also be screened.

3 Management
As with many genetic conditions a holistic approach with smooth coordination of different specialties would help the patient best. With the patient’s consent, clinicians should consider consulting local cytogenetics services for a clinical diagnosis and to establish the need for specific genetic testing.

Establishing a diagnosis can help patients get a better understanding of their condition as well as informing healthcare professionals involved in care. In this case, understanding the influence of genetic factors may help remove the mistaken belief that all his psychotic symptoms stem from his use of illicit substances.

Medical challenges for patients with velocardiofacial syndrome range from haematological disorders to surgical pitfalls. Some aspects of the illness, such as hypocalcaemia, may resolve with time.^{5 6}

Managing the severe and chronic course of psychotic symptoms in patients with velocardiofacial syndrome can also prove challenging. In this case the treatment of psychotic symptoms was particularly difficult because he was not forthcoming in expressing his symptoms and his psychosis was untreated for a long time. Whether this is a common pattern among patients with velocardiofacial syndrome is unclear.

Patients with prominent symptoms like delusions and hallucinations are usually given atypical antipsychotics. Patients with velocardiofacial syndrome seem to respond poorly to treatment with neuroleptics and are more likely to develop side effects.^{11 12}

Cite this as: BMJ 2008;337:a2706