A neuropsychological-genetic profile of atypicalcri du chat syndrome: implications for prognosis

K M Cornish, G Cross, A Green, L Willatt, J M Bradshaw

AbstractCri du chat syndrome is associated with adeletion on the short arm of chromosome5. The main diagnostic feature is a highpitched, cat-like cry which has recentlybeen localised to 5p15.3 and is separatefrom the remaining clinical features of thesyndrome, which have been localised to5p15.2. The present study describes afamily of four who have a deletion slightlydistal (5p15.3) to the critical region.Detailed neuropsychological evaluationsindicated a similar pattern of cognitiveperformance to that reported for subjectswith typical CDCS but with only minimalintellectual impairment. In addition, inthis family the 5p deletion is transmittedin an autosomal dominant fashion, con-trasting with most cases of CDCS, whichare either de novo or occur as an unbal-anced product of a balanced translocationin a normal parent. This study confirmsthe importance of diVerentiating between5p deletions that coincide with the typicalcri du chat phenotype which includessevere to profound learning disability anddeletions that only delete the distal criticalregion that coincides with a milder degreeof cognitive impairment and a muchimproved prognosis.(J Med Genet 1999;36:567–570)

Keywords: cri du chat syndrome; neuropsychological-genetic profile; 5p15

Cri du chat syndrome (CDCS) is a relativelyrare chromosome disorder that aVects approxi-mately 1 in 40 000-50 000 live births. Thesyndrome is known to result from a variableterminal deletion of the short arm of chromo-some 5 and represents one of the mostcommon deletion syndromes in humans.1

Recent molecular studies2 3 have pinpointedthe critical region to a small region within5p15.2. Subjects with deletions in this regionpresent with the characteristic high pitched,“cat-like” cry, from which the syndromederives it name,4 and have a striking facialappearance which appears to change with age.In childhood, the face is round with hyperte-lorism, a broad nasal bridge, and low set ears,whereas in adolescence the length of the faceincreases to become long and slender.1 Otherfeatures such as respiratory and cardiac prob-lems have also been frequently cited.5 The cog-nitive and behavioural phenotype includessevere learning disability, slow psychomotordevelopment, failure to thrive, hyperacusis, anda receptive-expressive language discrepancy.6–10

The importance of the critical region to themanifestation of typical CDCS has beenfurther highlighted by the results of recentstudies that have described subjects with 5pdeletions outside the critical region and who donot present with the severity of clinical charac-teristics described above.2 3 11 12 These findingsindicate that deletions of diVerent segments of5p may result in distinct behavioural-cognitivephenotypes.

The present study examines a rare family offour (father and three oVspring) all of whomhave a del(5p) karyotype. Each oVspring wasdiagnosed at birth with the cri du chatsyndrome because of an unusual cry and lowbirth weight. However, their karyotypes allshowed a deletion slightly distal (5p15.3) to thecritical region (5p15.2). Chromosomal analysisof the children’s parents showed that theirfather also carried the same deletion. Detailedneuropsychological evaluations indicated asimilar pattern of cognitive performance to thatreported for patients with typical CDCS butwith considerably milder intellectual impair-ments. In addition, in this family the 5pdeletion is transmitted in an autosomal domi-nant fashion, contrasting with most cases ofCDCS, which are either de novo or occur as anunbalanced product of a balanced transloca-tion in a normal parent.

MethodsThe father is aged 391⁄2 years (right handed)and has no history of any developmental delay(remained in education until 16 years) and nofacial dysmorphism, although he is reported ashaving had an unusual cry as an infant. Theoldest sib (sib 1) is aged 13 years 9 months(right handed), the second sib (sib 2) is aged 10years 8 months (right handed), and the young-est sib (sib 3) is aged 6 years 7 months (righthanded). All sibs presented with the cat-like cryand slight facial dysmorphism in infancy. Fail-ure to thrive and mild psychomotor develop-ment were also reported in sibs 2 and 3 but notin the oldest child. Two of the sibs (1 and 3)attend mainstream school and sib 2 attends aschool for children with mild-moderate learn-ing disabilities. At the time of testing neitherthe father nor the sibs required the use of hear-ing aids and none reported any early middle earproblems that may have aVected their earlierspeech and language development.

Agreement for publication of photographscould not be obtained.

MaterialsConventional G banded chromosome analysiswas undertaken on cultured blood samples.These studies showed the presence of a termi-

J Med Genet 1999;36:567–570 567

Neuropsychology ofGenetic DisordersResearch Unit, BFloor, Medical School,University ofNottingham, Queen’sMedical Centre,Nottingham NG7 2UH,UKK M Cornish

Department ofMolecular Genetics,Centre for MedicalGenetics, CityHospital, Nottingham,UKG Cross

National Centre forMedical Genetics, OurLady’s Hospital forSick Children,Crumlin, Dublin 12,IrelandA Green

Department ofCytogenetics,Addenbrooke’sHospital, Cambridge,UKL WillattJ M Bradshaw

Correspondence to:Dr Cornish.

Received 11 June 1998Revised version accepted forpublication 23 March 1999

on 10 July 2018 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.36.7.567 on 1 July 1999. D

ownloaded from

nal deletion of the distal short arm of onechromosome 5 (p15.3-pter) in all family mem-bers (fig 1). Fluorescence in situ hybridisation(FISH) studies with a chromosome 5 telomericregion painting probe (Biovation probeSPBP5) confirmed the deletion of 5p15.3.Further FISH studies with the cri du chatcritical region D5S23 locus specific probe(Oncor) which maps to p15.2 showed thepresence of signals on both chromosome 5homologues in all family members. Thedeletion breakpoint was therefore localised toproximal p15.3.

COGNITIVE MEASURES

Level of cognitive functioningThis was measured by the Wechsler Intelli-gence Scale for Children-Revised (WISC-III)13

and the Wechsler Adult Intelligence Scale(WAIS-R).14 This battery of tasks comprisestwo scales, a verbal scale and a performancescale. On the verbal scale, subtests measure anumber of abilities related to general knowl-edge (Information), verbal reasoning (Similari-ties), mental arithmetic, vocabulary skill (oraldefinition of words), verbal short term memory(Digit Span), and verbal comprehension. Onthe performance scale, subtests measure abili-ties related to perceptual analyses (PictureCompletion), manual sequencing of blocks toform a story (Picture Arrangement), visuocon-struction skill (Object Assembly, Block Design,and Coding), visuospatial skill (SymbolSearch), and visuomotor skill (Mazes).

Language skillsReceptive and expressive language abilitieswere assessed using the following measures.Comprehension of vocabulary was measuredby the British Picture Vocabulary Scales(BPVS)15 and has an age range of 2.0 to 19.0years. The subject is presented with an array offour pictures and must indicate which one rep-resents the word spoken by the experimenter,for example, “ball”. Arrays of increasingdiYculty are presented until the child reaches aceiling. The BPVS allows the calculation of avocabulary age.

Comprehension of grammar was measuredby the Test of the Reception of Grammar(TROG)16 which assesses the understanding ofselected aspects of grammar in children aged 4to 13 years plus, using a picture pointingresponse format that eliminates the need forexpressive language ability. Each subject is pre-sented with an array of four pictures and has toindicate which one represents the sentencespoken by the examiner, for example, “he issitting on the table” as opposed to thegrammatical distracter “she is sitting on thetable”. This test is concerned with understand-ing parts of speech, simple and complexsentences, pronouns, word inflections, relativeclauses, and embedding. The TROG alsoallows the calculation of an age equivalentscore.

Expressive vocabulary was measured usingthe One Word Expressive Language Scale(EOWPVT).17 There are two versions of thistask. The first is designed for children aged2-12 years and the second for use with olderchildren aged 12-16 years. In both versions thechild is presented with a series of black andwhite pictures and must verbally name theobject in each picture. Items of increasing diY-culty are presented until the child reaches aceiling. The EOWPVT yields an age equivalentscore, deviation IQs, and centile ranks.

ArticulationThis was measured by the Goldman-FristoeTest of Articulation (GFTA),18 which assessesspontaneous production of all except one of theEnglish consonant sounds as well as 11 conso-nant blends. The total score is 68.

Reading skillsThese were assessed using the Wechsler Objec-tive Reading Dimensions (WORD).19 Thiscomprises three sections: Basic Reading, Read-ing Comprehension, and Spelling. Each sec-tion allows for the calculation of an age equiv-alent score.

ResultsTable 1 summarises scores across the measuresof IQ, language, articulation, and reading skills.

INTELLECTUAL LEVEL

FatherFull scale IQ on the WAIS-R was 95 which fallswithin the average range of ability (IQs of90-109) with both verbal IQ and performanceIQ also within the average range (verbal 93,performance 100). Examination of the indi-vidual subtests indicate that on the verbal scaleperformance was best on the Digit Span taskand the Similarities task and worse on theVocabulary task. On the performance scale,performance was best on the Picture Comple-tion task and Object Assembly task and worseon the Digit Symbol task.

SibsFull scale IQs on the WISC-III were as follows.The oldest sib (sib 1) was 92 which falls withinthe average range of ability with performanceIQ also within the average range (PIQ 101) but

Figure 1 Ideogram of chromosome 5 with deletion breakpoint arrowed and partialkaryotypes, (A) G banded, (B) FISH with telomeric probes pcp5, (C) FISH with cri duchat critical region probe D5S23. The deleted chromosome is on the right hand side of eachpair.

568 Cornish, Cross, Green, et al

on 10 July 2018 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.36.7.567 on 1 July 1999. D

ownloaded from

verbal IQ within the low average range (VIQ86). The diVerence between the two scores wassignificant at the 0.05 level of significance. Sib2 was 70 which falls within the low range ofability with performance IQ (PIQ 75) and ver-bal IQ (VIQ 70) also within the low range. Sib3 was 105 which falls within the average rangewith performance IQ also within the averagerange (PIQ 113) and verbal IQ within the aver-age range (VIQ 99). The diVerence betweenthe two scores was significant at the 0.05 levelof significance. Examination of the individualsubtests indicate that on the verbal scale allthree sibs performed best on the Digit Spantask, irrespective of IQ, and worse on the verbalcomprehension and vocabulary tasks. On theperformance scale, both sib 1 and sib 3performed best on the Picture Completion taskwhile sib 2 performed best on the ObjectAssembly task. Interestingly, all three per-formed worse on the Digit Symbol task.

LANGUAGE AND ARTICULATION SKILLS

All three sibs had age equivalent estimateswithin one to two years of their chronologicalages on the measures of receptive language(BPVS and TROG). In contrast, all age equiv-alent estimates on the measure of expressivelanguage (EOWPVT) fell three to five yearsbelow their chronological age (table 1). Inaddition, misarticulations were common, withall sibs falling within or below the 50th centilefor their age range. When errors occurred theyincluded sound substitutions and distortion ofvowels and consonants.

READING AND SPELLING SKILLS

On a measure of basic reading, sibs 2 and 3both had age equivalent estimates within twoyears of their chronological age. The oldest sib,however, produced an age equivalent scorethree years above chronological age. In con-trast, on a measure of reading comprehension,sib 1 performed four years below chronologicalage, while sibs 2 and 3 both fell below floorlevel (<6.0 years) on this measure. Perform-ance was also reduced on a measure of spellingability with age equivalent estimates one tothree years below their chronological ages(table 1).

DiscussionThe present study assessed the pattern of cog-nitive functioning in a family of four (a fatherand three children) initially diagnosed with cridu chat syndrome. Subsequent FISH analysisshowed that the deletion breakpoint was local-ised to 5p15.3 and did not include the criticalregion. The main clinical characteristic thathad led to diagnosis had been the presence of acat-like cry at birth. Additional clinical featureshad included failure to thrive, slow psychomo-tor development, and slight facial dysmor-phism in the sibs, although the father himselfhad no dysmorphic facial features. In terms oftheir neuropsychological profile, however, thepresent study found no evidence to indicatesevere levels of intellectual impairment, but itdid indicate a pattern of cognitive strengthsand weaknesses that were similar to, but moresubtle in characterisation, than those displayedby patients with typical CDCS (5p15.2).

Of potential significance is the finding thatthe father and all three sibs appear to havestrengths in non-verbal skills, particularly thoserequiring manipulation of spatial designs, butweaknesses in verbal skills, such as thoserequiring comprehension and expression ofverbal information. Closer examination of ver-bal skills in the sibs showed a pattern ofreduced expressive language and articulationskills compared to receptive language skills.Interestingly, an expressive-receptive discrep-ancy has also been reported in children withtypical CDCS but to a much greater degree ofseverity.9 In addition, reading skills weresignificantly impaired in all but one of the sibs(sib 1) who displayed enhanced basic readingskills compared to reading comprehension andspelling skills. In contrast, sibs 2 and 3 bothperformed at floor level on almost all of thereading and spelling tasks.

These findings are important for two mainreasons. Firstly, they confirm the results of pre-vious genetic studies of distinct phenotypicfeatures associated with deletions of diVerentsegments of distal 5p.2 3 11 Secondly, theyprovide a detailed neuropsychological profileof subjects with a deletion of 5p15.3 in whomthere is minimal intellectual impairment, butwho display a specific verbal-performance dis-crepancy in the direction of reduced verbalskills, and in particular delayed expressive lan-guage skills. Recent evidence from two molecu-lar studies has also indicated that deletions of5p15.3 may result in specific speech delay withno major intellectual impairment,2 20 althoughauthors from both studies relied almost exclu-sively upon IQ data. Taken together, theserecent findings indicate the possibility ofanomalous cerebral lateralisation underlyingcognitive functioning in subjects with a 5p15.3deletion. It may be that abnormal gene expres-sion within this region has influenced earlybrain development, specifically area(s) associ-ated with phonological processing. Indeed,Church et al2 have identified a candidate gene(DAT121) located in 5p15.3 which encodes atype 1 dopamine transporter. Further molecu-lar work is clearly needed to define deletionsrelative to the actual genes and to understand

Table 1 Summary of scores across the measures of verbal and performance intelligence,receptive and expressive language, articulation and basic reading, comprehension andspelling

Measures Sib 1 (13.9 y) Sib 2 (10.8 y) Sib 3 (6.7 y)

Intellectual levelVerbal IQ 86 70 99Performance IQ 92 75 113Full Scale IQ 101 70 105Language skills(Age equivalent score in years and months)Receptive

BPVS 12.6 8.9 6.4TROG 11.0> 8.0 6.0

ExpressiveEOWPVT 8.0 5.0 3.4

Articulation(Centile score)GFTA <50th <50th <50th

Reading skills(Age equivalent in years and months)Basic reading 16.0 8.0 6.4Reading comprehension 9.9 <6.0 <6.0Spelling 12.6 7.6 <6.0

Atypical cri du chat syndrome 569

on 10 July 2018 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.36.7.567 on 1 July 1999. D

ownloaded from

the role of variable gene expression in theresulting phenotype.

In conclusion, the present study clearly indi-cates the importance of accurately diVerentiat-ing between 5p deletions that result in a typicalcri du chat syndrome phenotype and the sever-ity of cognitive impairment that is associatedwith it and deletions that result in a milder cridu chat phenotype and much better prognosis.

1 Niebuhr E. Cytologic observations in 35 individuals with5p- karyotype. Hum Genet 1978;42:143-56.

2 Church DM, Bengtsson KV, Nielson JJ, Wasmuth JJ, Nieb-hur E. Molecular definition of deletions of diVerentsegments of distal 5p that result in distinct phenotypic fea-tures. Am J Hum Genet 1995;56:1162-72.

3 Overhauser J, Huang X, Gersch M, et al. Molecular andphenotypic mapping of the short arm of chromosome 5:sublocalisation of the critical region of the cri-du-chat syn-drome. Hum Mol Genet 1994;3:247-52.

4 Lejuene J, Lafourcade J, Berger R, et al. Trois cas de deletionpartielle du bras court d’un chromosome 5. C R Acad SciParis 1963;257:3098-102.

5 Wilkins LE, Brown JA, Nance W, Wolf B. Clinicalheterogeneity in 80 home-reared children with the cri-du-chat syndrome. J Pediatr 1983;102:528-33.

6 Carlin ME. The improved prognosis in cri-du-chat (5p-)syndrome. In: Fraser WI, ed. Key issues in mental retardationresearch. London: Routledge, 1990:64-73.

7 Cornish KM, Pigram J. Behavioural and developmental pat-terns in children with cri-du-chat syndrome. Arch Dis Child1996;75:448-50.

8 Cornish KM, Cross G, Green A. Defining the cognitivephenotype in cri-du-chat syndrome: the importance ofcareful characterisation of a 5p deletion before clinical pre-

dictions are made. Paper presented at the International Sym-posium of the Society for the Study of Behavioural Phenotypes,Cambridge, November 1997.

9 Cornish KM, Munir F. Receptive and expressive languageskills in children with cri-du-chat syndrome. J Communica-tion Disord 1998;31:73-82.

10 Cornish KM, Bramble D, Munir F. Adaptive and maladap-tive behaviour in children with cri-du-chat syndrome. JAppl Res Learning Disabilities 1998;11:239-46.

11 Gersh M, Goodart SA,. Pasztor LM, Harris DJ, Weiss L,Overhauser J. Evidence for a distinct region causing a cat-like cry in patients with 5p deletions. Am J Hum Genet1995;56:404-10.

12 Church DM, Yang J, Bocian M, Shiang R, Wasmuth JJ. Ahigh-resolution physical and transcript map of the cri-du-chat region of human chromosome 5p. Genome Res 1997;7:787-801.

13 Wechsler, D. Wechsler intelligence scale for children (WISC-III). London: Psychological Corporation, 1992.

14 Wechsler D. Wechsler adult intelligence scale (WAIS-R).London: Psychological Corporation, 1981.

15 Dunn L, Dunn P, Whetton C, Pintilie D. British picturevocabulary scale. Windsor: NFER-Nelson, 1982.

16 Bishop DVM. Test of the reception of grammar. London:Medical Research Council, 1983.

17 Reynell JK. Reynell developmental language scales. Windsor:NFER-Nelson, 1985.

18 Dodd B. A comparison of the phonological systems ofmental-aged matched normal, subnormal and Downsyndrome children. Br J Disord Communication 1976;11:27-42.

19 Wechsler D. Wechsler objective reading dimensions (WORD).London: Psychological Corporation, 1992.

20 Baccichetti C, Lenzini A, Artifoni L, Caufin D, Maranogi P.Terminal deletion of the short arm of chromosome 5. ClinGenet 1998;34:219-23.

21 Giros B, El Mastikawy S, Godinet N, et al. Cloning pharma-cological characterisation and chromosome assignment ofthe human dopamine transporter. Mol Pharmacol 1992;42:383-90.

570 Cornish, Cross, Green, et al

on 10 July 2018 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.36.7.567 on 1 July 1999. D

ownloaded from