Psychosomatics 2013:]:]]]–]]] & 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved

Case Reports

Number Variant Analysis in a Hospitalized Patient withPsychosis

Sipra Laddha, M.D., Ann C. Schwartz, M.D.

Wepresent the case of a 23-year-old woman whopresented with psychotic symptoms and was

subsequently diagnosed with velocardiofacial syn-drome (VCFS) or 22q11 deletion syndrome (DS) bycopy number variant analysis. This case highlights theimportance of suspicion of genetic disorders in youngindividuals presenting with psychotic disorders andsyndromic features. In addition, it raises an issue ofclassification of these disorders in patients with anunderlying chromosomal abnormality.

Received June 13, 2013; revised July 5, 2013; accepted July 8, 2013.From Department of Psychiatry and Behavioral Sciences, EmoryUniversity School of Medicine, Atlanta, GA. Send correspondenceand reprint requests to Ann C. Schwartz, M.D., Department ofPsychiatry and Behavioral Sciences, Emory University School ofMedicine, 80 Jesse Hill Jr Dr, P.O. Box 26238, Atlanta, GA 30303;e-mail: aschwa2@emory.edu

& 2013TheAcademy of PsychosomaticMedicine. Published byElsevier Inc. All rights reserved

Case Report

“Ms. B”, a 23-year-oldAfricanAmericanwomanwitha reported history of schizophrenia, was brought to themedical emergency room by her father owing toworsening in his daughter's behavior. Her fatherrevealed over the last 3–4 months, Ms. B was eatingonly intermittently and having worsening outbursts ofanger. She had become increasingly more isolative athome, and on the day before presentation, she hadbecome completely nonverbal andwould not come outof her bedroom. He also stated that she had a previousreported diagnosis of schizophrenia and had discon-tinued her medications 3 months prior for unclearreasons.

On initial examination in the emergency room,Ms. B was curled up in a chair in the corner of theroom. She was nonverbal during the interview.Ms. B'svital signs were within normal limits and her physicalexamination was significant for an incomplete cleftpalate. Laboratory results showed a normal sodiumlevel, blood urea nitrogen, and creatinine. Her calciumlevel was slightly low at 8.7 mg/dL, and magnesium

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and phosphate were within normal limits. Her bloodchemistry was normal and urine drug screen werenegative.

The psychiatric consultation service was con-tacted to evaluate Ms. B given her reported historyof schizophrenia and the recent changes in herbehavior. On the examination by the psychiatryservice, Ms. B was noted to be tall and thin withslightly low-set ears. She was dressed casually, but herclothes were dirty and she was disheveled and mal-odorous. She actively huddled in the corner of theroom and demonstrated very poor eye contact. Heraffect was constricted. She was nonverbal and par-ticipated minimally in the interview. She occasionallywould nod her head in response to questions asked, buther answers were not consistent. Shewas able to followsimple commands, but her overall concentration wasimpaired. She exhibited waxy flexibility, and as perstaff report, held the same position for approximatelyan hour. Although she shook her head “no” whenasked about auditory hallucinations, she appeared tobe responding to internal stimuli.

Ms. B was admitted to the psychiatric servicebecause of concerns that she was unable to take care ofherself as exhibited by her poor oral intake, lack ofgrooming, and nonverbal behavior. On the inpatientunit, Ms. B remained unable to provide a history.

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Case Reports

Collateral history from her father confirmed that Ms.B had a diagnosis of schizophrenia and had oneprevious admission to a county hospital 5 years earlierat the age of 18 years for agitation and aggression atschool. She was started on an unknown medicationand was receiving psychiatric treatment in the com-munity. Her father stated that he had taken her off allher medications 3–4 months ago because he felt thatthey made her more agitated and aggressive, but wasunable to elaborate. Her father also reported that Ms.B was placed in special education classes beginning inthe seventh grade. She dropped out of school aftercompleting the tenth grade. Her father stated that hefelt school was not a good environment for her as hefelt that she was a target of bullying from classmates.Ms. B has never been employed.

Medical records from Ms. B's previous psychiatrichospitalization were obtained and reviewed. Therecords reported that Ms. B had exhibited delusionsregarding her teacher and themurders of other students,andwas convinced that her teacherwas going to kill heras well. The records indicated that she experiencedauditory and visual hallucinations, and was found to beintermittently agitated and withdrawn. Ms. B wasstarted on risperidone and later switched to quetiapineowing to inadequate control of her symptoms. Aftercontinuing to have outbursts where she was verballyand physically aggressive, valproic acid was added andwas titrated up to a dose of 1000 mg at night. Ms. B'squetiapine was titrated to 400 mg twice daily. Themedical records indicated that she continued tohave outbursts but they had decreased in frequency,andMs. Bwas discharged after approximately 6 weeks.The treating psychiatrist during this hospitaliza-tion listed schizophrenia as the primary dischargediagnosis.

On the current admission, Ms. B was initiallystarted on lorazepam 1 mg every 4 hours orally orintramuscularly for her symptoms of catatonia, includ-ing mutism, posturing, waxy flexibility, withdrawal,and negativism. Ms. B was observed holding positionsfor many hours and staring off into space for longperiods. Additional laboratory tests were obtained, andher thyroid panel was normal, and HIV and rapidplasma reagin were negative. Ms. B's parathyroidhormone level was found to be low at 12 pg/mL.

Five milligrams of olanzapine was administeredevery night, as it appeared that Ms. B was havingvisual hallucinations and seemed internally

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preoccupied. Initially, Ms. B was uncooperative withstaff regarding medication compliance and requiredextensive coaching to take her medication. She alsowas uncooperative with her daily hygiene and eating.She would take multiple showers daily, sometimesfully clothed. She allowed the bathroom to floodseveral times. She also exhibited bizarre behavior,including frequently rearranging the furniture in herroom into a corner of the room or into the bathroom.Olanzapine was titrated up to 20 mg every night withgood effect, and lorazepam was discontinued becauseher catatonic symptoms had diminished.

Ms. B remained nonverbal for the first 4 days ofthe admission, though she communicated preferencesthrough nodding. During the multidisciplinary treat-ment team, she was given pen and paper to commu-nicate, as she seemed unwilling to do so verbally. Shecommunicated in this manner, but her messages wereoften tangential, with written clang associations, suchas “I love Justin Timberlake, lake for the sake ofbaboons, Beiber is great.” She wrote several 1–2-pagemessages to the treatment team, which exhibitedtangential thinking and included themes of angels,kittens, and going to heaven. The content demon-strated a good vocabulary.

Although she continued to have auditory andvisual hallucinations, she spontaneously started tocommunicate verbally on the sixth day of admission.Her voice was hypernasal when she began communi-cating. GivenMs. B's subtly dysmorphic features (low-set ears) and incomplete cleft, genetic testing wascompleted via chromosomal analysis with microarrayanalysis. Results yielded a deletion on chromosome22q11.2 consistent with VCFS. She continued to betangential and expressed little understanding orinsight regarding her diagnosis of VCFS or psychoticdisorder. A family meeting was held to discuss Ms. B'sdiagnosis. Ms. B was continued on 20 mg of olanza-pine every night and she was discharged to her father'scare with close psychiatric follow-up in the commun-ity. Her diagnosis upon discharge was psychoticdisorder in the setting of 22q11 DS.

Discussion

VCFS, also referred to as DiGeorge Syndrome or22q11 DS, is the result of a microdeletion from thelong arm of chromosome 22 at the q11.2 band with

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Laddha and Schwartz

an autosomal dominant pattern of inheritance. Thedeletion usually occurs as a spontaneous mutationand in the absence of a family history of psychoticillness. Estimates of the frequency of VCFS areapproximately 1:2000 in surviving newborns.1

VCFS was first described in 1978 by Shprintzenas a multiple malformation syndrome with character-istic facial features, a hypernasal voice (due to palateabnormalities), and cardiac abnormalities.2 Manyof the major findings are not evident or detectable atbirth or in infancy,3 and studies suggest that atleast one-third, if not nearly one-half of cases arenot diagnosed until later in life, and many cases goundetected.3

VCFShas an expansive phenotypewithmore than180 clinical features described, both physical andbehavioral.4 In addition to the physical symptomsthat have been identified, a variety of cognitive andneurobehavioral features have been associated withthe condition, including learning disabilities and mildmental retardation (see Table).1,567 Studies suggestthat identifying adults with 22q11 deletions shouldinvolve careful examination for the presence of 2 ormore clinical features from 5 main areas: centralnervous system abnormalities (cognitive or psychiatricor both), palatal or speech anomalies or both, cranio-facial dysmorphisms, anomalies of the heart or majorvessels or both, and miscellaneous anomalies.1 The

TABLE. Common Clinical Features of Velocardiofacial Syndrome2,6,7

CNSabnormalities

Palatal/speech anomalies Craniofacialdysmorphisms

Learningdisabilities

Cleft palate (submucosal,occult submucous, andovert)

Long face

Mild mentalretardation

Hypernasal speech Narrow palpebralfissures

Attention-deficithyperactivitydisorder

High-pitched voice Retrognathia(retruded lower jaw)

Mood disorders Feeding problems ininfancy

Asymmetric face

Psychoticdisorders

Palatal and pharyngealasymmetry

Bulbous nasal tip withprominent nasalbridge

Anxiety disorders Articulation impairment Flattened malarregion

OCD Speech delays Low-set earsOverfolded helix

CNS ¼ central nervous system; OCD ¼ obsessive-compulsive disor

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more common findings of the disorder are summarizedin the Table. In the case of Ms. B, palatal abnormal-ities, psychiatric symptoms, learning difficulties, aswell as subtle craniofacial dysmorphisms (low-set ears)were evident. In addition, she had mild hypocalcemiaand hypoparathyroidism, both of which have beenreported as features of the disorder.3

Serious psychiatric illnesses have been identifiedwith the identification of a deleted region from chro-mosome 22,3,8,9 and individuals with 22q11 DS repre-sent a particularly high-risk group as it is estimated thatpsychosis develops in 25% or more of individuals.1

Deletions at 22q11 are associated with an increased riskfor psychosis andVCFS presents an excellentmodel forunderstanding psychiatric disorders, as these findingsthus far represents one of the strongest links to datebetween vulnerability to psychotic disorders and aknown congenital abnormality.10–13 Associations withpsychosis have also been found for large deletions onchromosome 15q13.3 and 1q21.1.

There have been several recent studies examiningrisk factors for the development of psychosis in patientswith genomic disorders.14–16 A two-hit hypothesis inVCFS regarding the increased risk for psychotic symp-toms has been proposed.14,16 In a number of patientswithVCFS and psychosis, the 22q11.2 deletion gives riseto the VCFS phenotype, and a further secondary copynumber variant gives rise to the psychosis phenotype, or

Anomalies of heart/majorvessels

Miscellaneous

Tetralogy of Fallot Small stature

Disrupted aortic arch Immune disorders (respiratoryinfections, sinusitis, and middle eareffusions)

Septal defects Emesis

Truncus arteriosus Hypotonia

Vascular anomalies ofpharynx, neck, and brainvessels

Endocrine disorders (hypocalcemia,hypothyroidism, andhypoparathyroidism)Seizures

der.

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the two-hit hypothesis.14 Although this hypothesis maybe relevant to VCFS patients with psychosis, furtherstudies are warranted. Consistent with this theory is therecent findings of increased rates of disease-related copynumber variant in patients with childhood-onset schiz-ophrenia.15 In addition, evidence suggests that atypicalfunctional is a risk factor for the development ofpsychosis.17

Ms. B was previously diagnosed with schizophre-nia; however, there is some debate about whether thepsychiatric symptoms associated with VCFS shouldbe classified with typical schizophrenia, or whetherthis is a distinct entity and an inherent part of thedevelopmental abnormality. Bassett et al. investi-gated the schizophrenia phenotype in subjects with22q11DS to determine the similarities and differencesof the schizophrenia subtype with 22q11 DS fromother more typical groups of patients with schizo-phrenia.1 The study found that there were no signifi-cant differences in age at onset, lifetime or cross-sectional core positive and negative schizophrenicsymptoms, or global functioning between the 2 groupsof patients with schizophrenia. The findings indicatethat the core clinical schizophrenia phenotype wouldnot distinguish individuals with the 22q11DS subtypefrom those who did not have the 22q11 DS subtype.1

In addition, there is at least one case report ofcatatonic symptoms in a patient with VCFS, andthe presenting symptoms were difficult to distinguishfrom symptoms of schizophrenia.18 In summary, theschizophrenia phenotype of a 22q11 DS etiologicsubtype of the illness was largely indistinguishablefrom other forms of schizophrenia,1 and any differ-ences appeared to be in auxiliary features of the illnessrather than the major phenotypic features of schizo-phrenia, such as onset, course, and core symptoms.

Although the positive symptoms may be largelyindistinguishable between subjects with 22qDS andthe subjects with an idiopathic or unique schizophre-nia, this does not take into account potential differ-ences in the trajectory of level of functioning, orthe B criterion for schizophrenia in the Diagnosticand Statistical Manual, Fifth Edition.19 Those withthe idiopathic or unique schizophrenia with an onsetin late adolescence or early adulthood typicallyexperience a change in their course where there is aloss of, or decline in, functioning in one or moremajor areas, such as work, interpersonal relations, orself-care.19 However, patients with chromosomal

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disorders may have lower levels of overall function-ing at baseline, and often do not experience thedecline seen in patients with the more typical casesof schizophrenia. These differences highlight classi-fication issues and whether the psychotic symptomsassociated with VCFS in Ms. B's case are bestcharacterized as schizophrenia or an inherent partof her chromosomal abnormality.

Genetic risk factors are important in the causa-tion of all major psychiatric disorders, and newergenetic testing techniques provide us with tools todiagnose VCSF and other chromosomal disorders.20

Copy number variant analysis, such as fluorescencein situ hybridization (FISH) studies, developed in theearly 1980s, can identify the underlying chromosomedefect in VCFS. At this time, FISH is a commonlyused and easily accessible diagnostic procedure thatuses DNA probes to determine if a specific region ofthe genome (e.g., 22q11.2 region) in 2 copies in achromosome preparation obtained from a peripheralblood sample.3 This is an extremely accurate test thatallows for themost rapid detection of themost commonchromosomeDS. One limitation of FISH analysis withlocus-specific probes or chromosome-specific DNAlibraries is that it is restricted to the targeted chromo-some or chromosomal subregion. Therefore, thistargeted testing may be used to confirm a diagnosisof VCFS or to test parents of children with VCFS.21

Results can typically be reported in 24–48 hours fromthe time of receipt. The cost averages around $500 andis covered by most insurance policies.

Newer advances in genetic testing, includingcomparative genomic hybridization (CGH), alsoreferred to as chromosomal microarray analysis,and array CGH, may identify small deletions andduplications, and shared cause can be examined at amolecular level. Array CGH can detect cytogeneticanomalies at a resolution undetectable by conven-tional techniques. Array CGH has the advantage ofbeing highly comprehensive, amenable to high resolu-tion, sensitive, and fast. This newer technique eli-minates the need for targeted FISH experiments (i.e.,need toknowwhere toFISH).21Testing is approximately$1500 and is covered by most insurance companies.The turnaround time for results is 5–7 days.

Consultation with genetic professionals is anessential component of the comprehensive assessmentand management of patients with 22q11 DS andother genetic syndromes. Genetic professionals can be

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Laddha and Schwartz

helpful in providing guidance on the recommendedworkup and testing if a genetic disorder is suspected,including the necessary documentation to supportthe testing for insurance reimbursement purposesif required. If a patient is diagnosed with 22q11 DS,genetic professionals can be helpful in providinginformation on the syndrome, its variable expression,and discussing the full implications of a geneticdiagnosis to the patient and family members. Forexample, testing of the parents of patients with 22q11DS may be recommended as in 10% of the cases, thedeletionmay be inherited from a parent, who often hasa milder presentation of the syndrome.22

It is important to identify adults with 22q11 DSas they likely present a high-risk population forthe development of treatable psychiatric and medicalillnesses. As many of the features are not evidentin infancy, many cases could go undetected, andlikely many individuals remain to be detected. Physi-cians need to maintain a degree of suspicion forsyndromic features, and if present in young individualswith primary psychotic disorders, genetic testing for22q11 deletion and other genetic conditions should beconsidered. Adults identified in psychiatric popula-tions with this syndrome require follow-up for theassociated physical conditions, and genetic counselingshould be offered to them and their families.8

There are few studies looking at prognostic andtreatment implications of distinguishing the2 groups, those with and without VCFS. Case

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reports have reported treatment difficulties in treat-ing psychosis in patients with VCFS, including poortreatment response andmedication side effects.23–25

In addition, neurologic abnormalities have beenidentified in patients with 22q11 DS, includingrecurrent, apparently unprovoked seizures.26 Thereare reports of increased seizures and electroence-phalography abnormalities in patients with VCFSwhen given atypical antipsychotics, again high-lighting the importance in distinguishing thesepatients from patients with schizophrenia in thegeneral population.18

Advances in genetic testing provide the capacity toclearly and efficiently identify VCFS and other syn-dromal psychiatric disorders. We have previouslyrelied on only the clinical symptomatology to distin-guish these disorders. Currently, genetic testing, suchas microarray analysis, provides an additional tool foridentifying homogenous groups of people. Identifica-tion of the candidate genes provides an opportunity forsystematic longitudinal comparison between subjectswith syndromal disorders, such as 22q11 DS and theidiopathic or more typical cases of schizophrenia.Further research is needed to analyze investigatedifferences in response and treatment outcomesbetween these groups.

Disclosure: The authors disclosed no proprietary orcommercial interest in any product mentioned or con-cept discussed in this article.

References

1. BassettAS,ChowEWC,AbdelMalikP,GheorghiuM,HustedJ,WeksbergR: The schizophrenia phenotype in 22q11 deletionsyndrome. Am J Psychiatry 2003; 160:1580–1586

2. Shprintzen RJ, Goldberg RB, Lewin ML, et al: A newsyndrome involving cleft palate, cardiac anomalies, typicalfacies, and learning disabilities: velo-cardio-facial syn-drome. Cleft Palate J 1978; 15:56–62

3. Shprintzen RJ: Velo-cardio-facial syndrome: 30 years ofstudy. Dev Disabil Res Rev 2008; 14:3–10

4. RobinNH, ShprintzenRJ: Defining the clinical spectrum ofdeletion 22q11.2. J Pediatr 2005; 147:90–96

5. Lewandowski KE, Shashi V, Berry PM, Kwapil TR:Schizophrenic-like neurocognitive deficits in children andadolescents with 22q11 deletion syndrome. Am J MedGenet 2007; 144B:27–36

6. ShprintzenRJ: Velo-cardio-facial syndrome. InCassidy SB,Allanson J, (ed) Management of Genetic Syndromes.2nd ed. New York, NY: Wiley; 2004, pp. 615–632

7. Fomin A, Pastorino AC, Kim CA, Pereira AC, Carneiro-Sampaio M, Abe Jacob CM: DiGeorge syndrome: a not sorare disease. Clinics 2010; 65:865–869

8. Bassett AS, Hodgkinson K, Chow EWC, Correia S, ScuttLE: Weksberg: 22q11 deletion syndrome in adults withschizophrenia. Am J Med Genet 1998; 81:328–337

9. PapolosDF,FaeddaGL,Veit S,GoldbergR:Bipolar spectrumdisorders in patients diagnosed with velo-cardio-facial syn-drome: does a hemizygous deletion of chromosome 22q11result in bipolar affective disorder? Am J Psych 1996;153:1541–1547

10. Karayiorgou M, Simon TJ, Gogos JA: 22q11.2 micro-deletions: linking DNA structural variation to brain dys-function and schizophrenia. Nature 2010; 11:402–412

11. Yan W, Jacobsen LK, Kransnewich DM, et al: Chromo-some 22q11.2 interstitial deletions among childhood-onsetschizophrenics and multidimensionally impaired. Am JMed Genet 1998; 81:41–43

www.psychosomaticsjournal.org 5

Case Reports

12. Usiskin SI, Nicolson R, Krasnewich DM, et al: Veloc-ardialfacial syndrome in childhood-onset schizophrenia.J Am Acad Child Adolesc Psychiatry 1999; 38:1536–1543

13. Horowitz A, Shifman S, Rivlin N, Pisante A, Darvasi A:A survey of the 22q11 microdeletion in a large cohort ofschizophrenia patients. Schizophr Res 2005; 73:263–267

14. Williams HJ, Monks S, Murphy KC, Kirov G, O'DonovanMC, Owen MJ: Schizophrenia two-hit hypothesis in velo-cardio-facial syndrome. Am J Med Genet B 2012; 162B:177–182

15. AhnK, GotayN, Andersen TM, et al: High rate of disease-related copy number variations in childhood onset schizo-phrenia. Mol Psychiatry 2013 [Epub ahead of print]

16. Girirajan S, Rosenfeld JA, Coe BP, et al: Phenotypicheterogeneity of genomic disorders and rare copy-numbervariants. N Engl J Med 2012; 367:1321–1331

17. Debanne M, Lazouret M, Lagioia A, Scheider M,Van De Ville D, Eliez S: Resting-state networks in adoles-cents with 22q11.2 deletion syndrome: associations withprodromal symptoms and executive functions. SchizophrRes 2012; 139:33–39

18. Sachdev P: Schizophrenia-like illness in velo-cardio-facialsyndrome: a genetic subsyndrome of schizophrenia? JPsychosom Res 2002; 53:721–727

19. American Psychiatric Association: DSM5 Diagnostic andStatistical Manual of Mental Disorders, Fifth Edition

6 www.psychosomaticsjournal.org

(DSM-5(TM)). Arlington, VA: American Psychiatric Pub-lishing, 2013; pp 99–105.

20. Cross-Disorder Group of the Psychiatric Genomics Con-sortium. Identification of risk loci with shared effects on fivemajor psychiatric disorders: a genome-wide analysis. Lan-cet 2013; 381:1371–1379

21. Shaffer LG, Bejjani BA: A cytogeneticist's perspective ongenomic microarrays. Hum Reprod Update 2004; 10:221–226

22. Hodgkinson KA, Murphy J, O'Neill S, Brzustowicz L,Bassett AS: Genetic Counseling for Schizophrenia in theera of molecular genetics. Can J Psychiatry 2001;46:123–130

23. Starling J, Harris AW: Case reports: an opportunityfor early intervention: velo-cardio-facial syndromeand psychosis. Early Interv Psychiatry 2008; 2:262–267

24. Gladston S, Clarke DJ: Clozapine treatment of psychosisassociated with velo-cardio-facial syndrome: benefits andrisks. J Intellect Disabil Res 2005; 49:567–570

25. Gothelf D, Frisch A, Munitz H, et al: Clinical character-istics of schizophrenia associated with velo-cardio-facialsyndrome. Schizophr Res 1999; 35:105–112

26. Kao A, Mariani J, McDonald-McGinn DM, et al:Increased prevalence of unprovoked seizures in patientswith 22q11.2 deletion. Am J Med Genet 2004; 129A:29–34

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