"Velocardiofacial Syndrome Associated with Adolescent Psychosis," Halifax, Nova Scotia, Canada; October 4, 2006 Psychiatry Clinical Case Conference at IWK Health Centre *Learn clinical features of velocardiofacial syndrome (VCFS) *Learn association of VCFS with psychosis and other psychiatric disorders *Learn genetic and biochemical abnormalities leading to psychosis in VCFS *Discuss case report of metyrosine in psychosis associated with VCFS *Discuss case reports of VCFS in childhood-onset schizophrenia

1. Velocardiofacial Syndrome
associated with Adolescent
Psychosis
Carlo G. Carandang, MD
Mood Disorders Group
IWK Health Centre

2. Objectives
Learn clinical features of velocardiofacial
syndrome (VCFS)
Learn association of VCFS with psychosis and
other psychiatric disorders
Learn genetic and biochemical abnormalities
leading to psychosis in VCFS
Discuss case report of metyrosine in psychosis
associated with VCFS
Discuss case reports of VCFS in childhood-onset
schizophrenia

3. Case Report
Carandang C and Scholten M (in press),
Metyrosine in Psychosis Associated with
22q11.2 Deletion Syndrome: A Case
Report. Journal of Child and Adolescent
Psychopharmacology.

4. Velocardiofacial Syndrome
(VCFS)
First described by Robert Shprintzen in 1978
From Latin words
Velum = palate
Cardia = heart
Facies = face
Recent literature uses nomenclature denoting genetic
deletion: 22q11.2 Deletion Syndrome (22q11.2 DS)
VCFS also known as:
Shprintzen Syndrome, DiGeorge Syndrome, Craniofacial
Syndrome, or Conotruncal Anomaly Unusual Face Syndrome

5. Velocardiofacial Syndrome
(VCFS)
Not uncommon
Prevalence 1 in every 4,000 newborns
8% of all cleft palate patients

6. VCFS Clinical Features
Clinical Features
Cleft palate
Heart defects
Characteristic facies
Hypernasal speech
Learning disabilities

7. Velocardiofacial Syndrome
(VCFS)
Facial Findings:
• Elongated face
• Almond-shaped eyes
• Wide nose
• Small ears
Pictures From: Shprintzen RJ: Velocardiofacial Syndrome. Otolaryngol Clin North Am 33(6), 2000.

9. VCFS Is a Risk Factor for
Schizophrenia
Among youth and adult patients with VCFS,
prevalence of schizophrenia is 10% to 30%
(Shprintzen et al. 1992, Pulver et al. 1994, Murphy et al. 1999, Vorstman et al.
2006)
Amongst youth with childhood-onset
schizophrenia, prevalence of VCFS is 3% to 6%
(Yan et al. 1998, Usiskin et al. 1999)
COS may be risk factor for VCFS…needs replication
Amongst adults with schizophrenia, prevalence of
VCFS ranges from 1% to 2% (Horowitz et al. 2005, Murphy
2002, Karayiorgou et al. 1995)

10. VCFS and Autistic Spectrum
Disorders
In youth with VCFS, prevalence of Autistic
Spectrum Disorders is 50% (Vorstman et al.
2006)
Other studies did not use structured
interviews for Autism (ADI, ADOS), and
therefore did not pick-up on Autistic
Spectrum Disorders

11. VCFS and OCD, ADHD
Up to 33% prevalence of OCD in VCFS
cohort (Gothelf et al. 2004)
Up to 46% prevalence of ADHD in youth
with VCFS (Feinstein et al. 2002)

12. VCFS and Mood Disorders
20% prevalence of Depression and 20%
prevalence of Dysthymic Disorder in youth
with VCFS (Arnold et al. 2001)
No bipolar disorder in Arnold cohort, utilized
KSADS for diagnosis
Up to 64% prevalence of bipolar disorder in
VCFS cohort (Papolos et al. 1996)
This outcome is questionable…

13. VCFS and Mental Illness in
Youth
In youth with VCFS, 67% prevalence of any
DSM-IV psychiatric disorder (Vorstman et al.
2006)
Most common is ASD and psychosis
Best study to date in youth, as it utilizes comprehensive
assessment battery (KSADS, ADI)
If Vorstman study is replicated with adequate
control group, then would recommend psychiatric
evaluations of all youth with VCFS

14. VCFS
Results from hemizygous deletion of the
long arm of chromosome 22, spanning 22
well-characterized genes, including COMT
gene
Only 10% of cases are inherited
For other 90%, cause of deletion unknown
Diagnosis confirmed by fluorescence in situ
hybridization (FISH)

16. TBX-1 (T-box transcription factor)
CRKL
UFD1L (Ubiquitination degradation)
HIRA(transcription factor)
Centromere
DGCR6
IDD/DGCR2
TSK/DGS-G
ES2/DGS1
GSCL (Goosecoid-like homeobox gene)
CTP (Citrate transporter) CLTCL
TMVCF
CDCrel-1
GP1b (Platelet glycoprotein)
T10
COMT (Catechol-O-methyltransferase)
ARVCF
LZTR-1 (Transcriptionfactor)
ZNF74
CDC45L
RANBP1
Human Ch22q11.2
Heparin cofactor
90% 8%

17. Psychosis and VCFS
Hypothesized that psychosis associated with
22q11.2 deletion syndrome may be associated
with excess catecholamines from a functional
deficiency of catechol-O-methyltransferase
(COMT)
Deficiency of COMT could result from either or
both:
Half-dose expression (only one copy of allele)
Presence of low-activity COMT variant on the non-
deleted allele

18. Catecholamine Biosynthesis
A key step in the biosynthesis of dopamine,
epinephrine, and norepinephrine involves the
conversion of tyrosine to dihydroxyphenylalanine
(DOPA)
This rate-limiting step is catalyzed by the enzyme
tyrosine hydroxylase
The catalytic conversion is blocked by the
competitive inhibitor, α-methyltyrosine
(metyrosine)

19. Metyrosine (Demser®)
Metyrosine competitively inhibits the enzyme
tyrosine hydroxylase
Inhibition of tyrosine hydroxylase leads to
decrease of dopamine levels and reduction of
psychotic symptoms
also decreases epinephrine and norepinephrine
Psychosis associated VCFS are relatively
unresponsive to currently used antipsychotics
(Graf et al. 2001, Gothelf et al. 1999)

21. Metyrosine (Demser®)
Indicated for pheochromocytoma, a
condition where excessive norepinephrine
and epinephrine are produced
Half-life: about 4 hours after single dose
Dosing: initiate at 250mg QID, titrating to
maximum of 4grams/day
Sedation, tremor, diarrhea most common
AEs

22. Intervention Studies of VCFS
Psychosis
Graf et al. 2001, case series, N=5
Metyrosine was effective in reducing
neuropsychiatric symptoms in 4 patients
Carandang and Scholten (in press)
Case report
Metyrosine effective in treating VCFS
psychosis resistant to antipsychotics

23. Case Report
15 year-old male presents for 1st
psych
hospitalization
Diagnosed VCFS in early childhood
RFA: Aggression towards mother
Multiple mood symptoms lasting months
Mood lability, tearfulness, hypersomnia, social
withdrawal, apathy, and declining school
performance

24. Case Report
While in NYC, ran away for 2 days on the
subway
After NYC trip, convinced he will be
miserable if he lives with his parents in the
countryside, and would be happy if he lived
in a big city
Threatened mother with knife, as she was a
barrier to his moving to the big city

25. Case Report
Early childhood: speech and motor delays
Age 4, problems with attention: a trial of
methylphenidate led to a negative reaction
Elementary school: problems processing
multi-step directions
Recent testing: verbal IQ 85, performance
IQ 83

26. Case Report
Premorbid functioning otherwise normal
average student, friendly and affectionate person
VCFS confirmed by FISH age 12
Hypernasal speech, typical facies, learning deficits
No other medical problems
2 paternal first cousins and a maternal aunt had
mood disorders

27. Case Report
Additional Symptoms:
Poor hygiene, poor eye contact, dysarthria,
non-spontaneous/telegraphic speech, affect
blunted, guarded, and exhibited significant
mood lability. Thought processes were
concrete. No loosening of associations were
noted. He perseverated on moving to the big
city
DDx: prodromal schizophrenia vs. mood
disorder

28. Case Report
Psychosis Clinic: Structured Interview for
Prodromal Syndromes (SIPS)
Scoring of the SIPS was in the psychotic range
with regards to the unusual thought content
While his belief about “moving to the big city to be
happy” was not the bizarre or typical beliefs associated
with psychosis, the patient held this belief with
unwavering conviction and had acted on this belief in
aggressive and risky ways.
His pervasive thoughts also affected his academic,
social, and family functioning.
Patient had minimal insight into the seriousness of his
dangerous behaviors.

29. Case Report
However, the clinicians and in the psychosis clinic
had difficulty giving a diagnosis of psychosis
(despite the scoring on the SIPS), as this was an
atypical presentation for psychosis.
Nonetheless, the working diagnosis was Psychotic
Disorder NOS, with the differential including
prodromal psychosis and Delusional Disorder.

30. Case Report
In the ensuing months, patient endured
multiple psychiatric hospitalizations
2nd
psych hosp was for suicide attempt
Aripiprazole (Abilify®) was started and
titrated to 10mg daily. The patient initially
responded, as he was less labile, less
withdrawn, and more animated.
Discharged on aripiprazole

31. Case Report
Readmitted the next month for his third
hospitalization for self-harm behaviors, and
eventually discharged.
1 month later, behaviors again worsened. He had
been making excessive attempts to communicate
with his friend, which prompted a call from the
friend’s parents to the patient’s parents.
Precipitated a rapid decompensation, where the
patient barricaded himself in his room and cut
both his forearms.

32. Case Report
Police were summoned to escort the patient to the
hospital (4th hospitalization)
When police arrived, the patient attempted to stab
the officer with a knife, who blocked the attempt
and disarmed the patient.
Parents had never seen this level of aggression
with their son, and opined that the treatment with
aripiprazole worsened his symptoms.

33. Case Report
Inpatient attending consulted with an expert on
VCFS. The expert recommended a trial of
metyrosine (Demser®), as many patients with
VCFS have a COMT deficiency.
Aripiprazole was discontinued and metyrosine
was titrated to 1750mg daily. The patient had
significant response to metyrosine, as he exhibited
less mood lability and was less perseverative on
his belief of moving to the big city to be happy.
He was discharged on a maintenance dose of
metyrosine 1000mg daily, and exhibited
significant functional improvement.

34. Case Report
While on metyrosine, the patient was able to avoid
hospitalization, attend school, and engage in
relationships with family and friends.
Patient reported improved moods, less irritability,
and denied fixed ideations. In addition, he no
longer believed that it was absolutely necessary
for him to live in the big city to be happy.
Continued to function on metyrosine for over 1
year, at which time he was transferred to another
psychiatrist.

35. (Carandang and Scholten, in press)
Innovative
“The treatment of metyrosine for VCFS psychosis
represents a first in psychiatry, where a known
biochemical abnormality in a psychiatric disorder
was corrected by a treatment that targets the
biochemical pathway, leading to reduction of
psychiatric symptoms.”
“Treatment of a specific biochemical consequence
of a genetic variation is important not only for the
treatment of a specific group of patients, but as a
model for elucidating the genetic correlates of
psychiatric disorders.”

36. Childhood-Onset Schizophrenia
may be a risk factor for VCFS
Rate of VCFS in youth with COS: 3% to
6%
Rate of VCFS in adult-onset schizophrenia,
1% to 2%
Rate of VCFS in general population:
0.025%

37. (Usiskin et al. 1999)

38. (Usiskin et al. 1999)

39. (Usiskin et al. 1999)

40. Summary
Rule-out VCFS in youth with psychosis,
especially if the patient has two or more features
of the syndrome and does not respond to
antipsychotic medication.
Definitive diagnosis obtained with FISH.
Consider Metyrosine for VCFS psychosis not
responsive to antipsychotics.
Consider psychiatric evaluation of VCFS patients.
Preliminary data: up to 67% will have mental illness
ASD and psychosis most prevalent in youth VCFS
cohort…study needs replication with adequate controls
(Vorstman et al. 2006)