Chromosome 22q11.2 Interstitial Deletions AmongChildhood-Onset Schizophrenics and‘‘Multidimensionally Impaired’’

WenLiang Yan,1,2* Leslie K. Jacobsen,1 Donna M. Krasnewich,2 Xin-Yuan Guan,3 Marge C. Lenane,1Sharon P. Paul,2 Harnisha N. Dalwadi,2 Hongen Zhang,3 Robert T. Long,2 Sanjiv Kumra,1Brian M. Martin,2 Peter J. Scambler,4 Jeffrey M. Trent,3 Ellen Sidransky,2 Edward I. Ginns,2 andJudith L. Rapoport1

1Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland2Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, Maryland3Laboratory of Cancer Genetics, National Human Genome Research Institute, Bethesda, Maryland4Hospital for Sick Children, University of London, London, United Kingdom

Since its first description almost a centuryago schizophrenia with childhood onset, arare yet devastating disorder, has been di-agnosed in children as young as age 5. Re-cently, the velocardiofacial syndrome,whose underlying cause is interstitial dele-tions of 22q11.2, was found in 2 of 100 casesof schizophrenics with adult onset [Karay-iorgou et al., Proc Natl Acad Sci USA 92:7612–7616, 1995]. No study has documentedthe prevalence of velocardiofacial syn-drome and the 22q11.2 deletion in a popula-tion of schizophrenics with childhood onset.Here we describe the result of such a studyin a sample originally selected for a trial ofatypical antipsychotic drugs. A separategroup of patients was also included in thestudy; they can best be accounted for as avariant of childhood-onset schizophrenia(COS) and had been provisionally termed‘‘multidimensionally impaired.’’ Fluores-cent in situ hybridization screening of 32COS and 21 multidimensionally impairedpatients revealed 1 COS patient with an in-terstitial deletion spanning at least 2.5megabases. Am. J. Med. Genet. (Neuropsy-chiatr. Genet.) 81:41–43, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: childhood schizophrenia;psychosis; velocardiofacialsyndrome; DiGeorge syn-drome; chromosome 22; mu-tation

Except for the subtypes, the clinical features or di-agnostic criteria for childhood-onset schizophrenia(COS) are the same as for adult-onset schizophrenia,including the development of hallucinations, delusions,and disorganized speech before age 12 [Asarnow, 1994;Werry, 1996; Jacobsen and Rapoport, 1997]. In the onlymajor twin study of childhood schizophrenia with onsetbefore age 15, Kallman and Roth [1956] discovered amuch higher concordance in monozygotic than in dizy-gotic twins. The role of genetic abnormalities in COS isfurther supported by a similar or higher rate of schizo-phrenia and schizophrenia spectrum disorders amongfirst-degree relatives of COS probands [Lenane et al.,unpublished data; Asarnow, 1994]. A single case ofCOS with reciprocal translocation involving chromo-some 1p22 and 7q21 has also been reported [Gordon etal., 1994]. The major anomalies of velocardiofacial syn-drome (VCFS) include cleft palate, hypernasal speech,characteristic facies, cardiac anomalies, hypospadias,learning disabilities, and mental retardation [Shprint-zen et al., 1978]. Its prominent psychiatric manifesta-tions are schizophrenia [Shprintzen et al., 1992], bipo-lar spectrum and attention deficit hyperactivity disor-ders [Carlson et al., 1997].

The COS patients in this study were those initiallyrecruited nationally for an inpatient trial of atypicalantipsychotic drugs who met the DSM III-R criteria forschizophrenia with onset of psychotic symptoms by age12. A prepsychotic IQ of lower than 70, somatic ill-nesses, neurological diseases, major affective disorder,or schizophrenia with onset after age 12 were exclu-sionary. Conventional antipsychotic treatment failurewas the other selection criterion. The clinical inter-view, the rating instruments and interrater reliabili-ties, the diagnostic criteria, and the other psychiatricdiseases being differentiated from COS during thescreening are discussed in detail elsewhere [McKennaet al., 1994a,b]. The multidimensionally impaired(MDI) patients were identified during the course of thisrecruitment. These patients manifested a history of

*Correspondence to: WenLiang Yan, M.D., Ph.D., Child Psy-chiatry Branch, National Institute of Mental Health, NIH,Building 49, Room B1EE16, Bethesda, MD 20892-4405.E-mail: wlyan@helix.nih.gov

Received 22 July 1997; Accepted 24 July 1997.

American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:41–43 (1998)

© 1998 Wiley-Liss, Inc.

only transient episodes of schizophrenia; they wouldbest be accounted for as a variant of COS based on theiroverall psychiatric profiles but not by any entities inDSM III-R or DSM IV [McKenna et al., 1994b; Kumraet al., 1997]. They have been provisionally termedMDI, although they would be grouped in Psychosis NotOtherwise Specified in DSM III-R or DSM IV. Reflect-ing the severity of diseases in both COS and MDIsamples, the lengths of neuroleptic exposure the chil-dren received before being referred to the NIMH clinicare 22.6 ± 15.3 months for COS patients (n 4 32) and27.0 ± 28.6 for MDI subjects (n 4 19); the Scale for theAssessment of Negative Symptoms (SANS) and of Posi-tive Symptoms (SAPS) [Andreasen, 1983, 1984] are77.6 ± 28.4/53.2 ± 22.7 for COS and 17.2 ± 12.8/21.7 ±15.0 for MDI, respectively.

Fluorescent in situ hybridizations (FISH) were per-formed on the Epstein–Barr virus-transformed B lym-phoblastoid cell lines obtained with parental consentfor each of the patients studied. The cosmid probesused for screening were N25 (D22S75, Oncor, Gaithers-burg, Maryland), sc11.1A and -1B (D22S139), D0832(D22S502), and c350 (D22S695) together with eitherD22S39 (Oncor)—which hybridizes to 22q13.3—or theRhodamine 110 chromophore labeled chromosome22qter painting probe [Guan et al., unpublished data]as control probes. At least 30 metaphase chromosomeswere scored for each case before a cytogenetic diagnosiswas made. Of 32 COS and 21 MDI patients screened, 1COS patient was found to harbor the deletion.

The patient is a white male who has a history ofsocial anxiety beginning in the preschool years and on-set of separation anxiety and multiple fears (of peers,thunderstorms, the dark) at age 9. He developed delu-sions of paranoia and reference at age 11, with furtherdevelopment of auditory hallucinations, Capgras delu-sions (believing his parents were imposters), and wors-ening of social withdrawal by age 12. There was noevidence of persistent affective disturbance in his his-tory or presentation. Prenatal, perinatal, and neonatalhistory were unremarkable. Early language and motormilestones were delayed (first words and unassistedwalking at age 2). Social immaturity and learning dis-abilities were noted early on, with mathematic and vi-sual-motor integration being particular areas of weak-ness. A brief stimulant trial at age 6 or 7 targetinginattention and distractibility was ineffective.

Intellectual assessments at ages 6.5, 8, and 11 yearsindicated full-scale IQ scores of 93, 86, and 96, respec-tively. With development of psychosis, his IQ declined.Full-scale IQ scores at ages 13, 14, 15, and 17 were 90,77, 72, and 77, respectively. Physical examination atthe NIH (age 15) revealed mild dysmorphic featuresincluding a high arched palate, small cupped ears,doli-chostenomelia (increased arm span compared withheight), and hypospadias. Unilateral ureteropelvic ob-struction was also demonstrated. His electrocardio-gram was normal. Neurologic examination showedmultiple frontal release signs, motor overflow to thecontralateral side during rapid alternating move-ments, choreiform movements, and tremor. Laboratoryevaluations, including thyroid function, amino/organicacid screen, cerebrospinal fluid studies, routine chem-

istries, complete blood count, high-resolution karyotyp-ing, and fragile X chromosome testing with folate-thymidine deficient culture, were normal. Brain mag-netic resonance imaging (MRI) quantitative analysisrevealed that right and left lateral ventricular volumeswere increased by more than one standard deviationabove the mean for a group of normal children (Rapo-port, unpublished data). His clinical condition steadilydeteriorated despite multiple trials of antipsychotics.At the NIH, he appeared to respond to clozapine (5weeks with dose up to 350 mg/day) but developed in-tractable seizures and thus could not be maintained onthe drug. He is hemizygous for marker D22S75 andalso for markers D22S139, D22S502, and D22S695. To-gether, these probes cover a minimal region of 2.5 mb.This deletion occurred de novo since it was not found ineither biological parent.

The discovery of psychiatric illnesses in VCFS pa-tients with 22q11.2 deletions has spurred interest inisolating genes that may yield susceptibility to schizo-phrenia or affective disorders [Karayiorgou et al., 1995;Carlson et al., 1997]. The rate of VCFS in our COScohort, albeit biased because of selective sampling,seems comparable to that in the adult cohort studied byKarayiorgou et al. [1995]. Although high-resolution ge-nomic fingerprinting or DNA sequencing is needed foran exact comparison of the two studies, the extent ofthe deletion seen in this COS Patient and in the VCFScases in Karayiorgou et al.’s sample (all of whom hadadult-onset schizophrenia) argues against the exis-tence of exclusive determinant(s) in this region thatpredispose to very early-onset schizophrenia. In fact,no correlation has been found between the extent of thedeletion and the expression of the phenotypes amongVCFS patients with or without schizophrenia [Kara-yiorgou et al., 1995], bipolar illness [Carlson et al.,1997], or cardiac malformations [McLean et al., 1993;Holder et al., 1993]. This suggests that other factors,such as epistatic modifying loci, allelic variations onthe undeleted 22q11.2, and/or environmental distur-bances, might play important roles.

Although no chromosome 22q11.2 deletion was ob-served in patients with atypical childhood psychosis(MDI), our sample size is too small to draw any conclu-sions. Because two of our MDI patients had sex-chromosome aneuploidy with 47, XYY and 47, XXYkaryotypes, respectively [Kumra et al., submitted], it islikely that genetic abnormalities in these patients arealso complex and heterogeneous.

Because VCFS patients exhibit great variations intheir dysmorphism, this COS Patient (who bears only afew features of the syndrome, including high archedpalate, small cupped ears, short stature, and hypospa-dias) was suspected but only diagnosed as havingVCFS after FISH screening. He lacks cardiovascularabnormalities detected by electrocardiogram, as do15% of VCFS patients diagnosed by routine tests[Young et al., 1980]. Thus, this case suggests that be-fore the diagnosis of COS is made, routine screening for22q11.2 deletions may be appropriate for COS patientswho are suspected to have dysmorphisms.

42 Yan et al.

ACKNOWLEDGMENTS

The authors thank Amy Smith of CPB, MichaelBittner, Yuan Jiang of NHGRI for technical assistance,and Kay Kuhns and Elizabeth Alzona of NSB for helpin preparing this manuscript.

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