The Psychiatric, psychological and Behavioural functioning of a Boy with terminal Deletion of the Long Arm of Chromosome 10

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  • RESUME Elevation roniqiie paroxysmiqiie benigne du rqgard vers le haul avec araxie: un syndrome neuro- ophtalmologique dorigine /amiliale? Un nouveau syndrome neuro-ophtalmologique a ete decrit recemment, consistant en deviations des yeux vers le haut, toniques et paroxystiques, avec ataxie. Les episodes surviennent le jour et sont disparaisent avec le sommeil suspendus par Ienfance. Le debut se fait habituellement avant un an et les s y r n p t h e s disparaissent progressivement a ILge adulte. Yrois nouveaux cas sont decrites chez qui on retrouve constarnrnent un mode de transmission autosomal dominant, ainsi quune rnaladresse et un retard dans ICge de la marche. Le traiternent par L.Dopa fut nettement benefique.

    ZUSAMMENFASSUNG Benigne paroxysmale ronische Blickrichriing nacti oben tn i t A rasie im Kindesolrer: ein neuro- optrlhalmologisches Syndrom mir familiurer Ursuche? Ein neues neuro-ophthalmologisches Syndrorn wurde kurzlich beschrieben, es besteht aus paroxysrnaler tonischer Abweichung der Augen nach oben rnit Ataxie. Die Episoden treten taglich auf und verschwinden im Schlaf. Der Beginn ist gewohnlich irn ersten Lebensjahr und die Symptome verschwinden allmahlich irn Kindheit. Bei den bescriebenen drei neuen Patienten fand sich ein autosomal dominanter Erbrnodus, sie waren unbeholfen und lernten erst spat frei laufen. Die Behandlung mit L-Dopa zeigte eine gute Wirkung.

    RESUMEN Desviacion tonica paroxisrica de 10s ojos hacia arriba con alaxia en la infancia. i Un sindrome neuro-oftalmologico benign0 de origen familiar? Recienternente se ha descrito un sindrorne neuro-oftalrnologico de la infancia consistente en la desviacion paroxistica de 10s ojos hacia arriba acornpanado de ataxia. Los episodios ocurren diariarnenre y se alivian siernpre con el sueilo. El debut tiene lugar generalrnente antes del aflo de vida y 10s sintomas desaparecen gradualrnente con la edad. Los autores describen tres nuevos pacientes en 10s que era constante un tip0 de herencia autosomico dominante, junto con un retardo en la adquisicion de la rnarcha y torpeza motriz. El tratamiento con levodopa produjo una Clara rnejoria.

    References tonic upward gaze. Pedialric Neurology, 8, Ahn, J . C . . Hoyt. W. F., Hoyt, C. S. (1989) Tonic 154-155.

    upgaze in infancy. Archives of Ophrhalrnology, Nygaard, T. C., Marsden, D., Fahn, S. (1991) 107, 51-58. Dopa-responsive dystonia: long-term treatment

    Deonna, Th., Roulet, E., Meyer, H. U. (1990) response and prognosis. Neurology, 41, 174-181. Benign paroxysmal tonic upgaze of childhood. A Owner, R. A., Billson, F. (1988j Benign paroxysmal new syndrome. Neuropediurrrcs, 21, 2 13-2 14. ronic upgaze of childhood. Journal o j Child

    Echenne, B., Rivier, F. (1992) Benign paroxysmal Neurology, 3, 177-180.

    T he Psyc h i CI t r i c , Psycholog ica I and Behavioural Functioning of a Boy with Terminal Deletion of the LonQ Arm of Chr6mosome 10 Jeremy Turk Deborah Christie Joanna Sales Robert Surtees

    Deletion of the long arm of chromosome 10 is a rare condition: only 18 cases have been reported since its original description by Lewandowski et a/. in 1978. The chromosomal anomaly can vary. Terminal deletion of both long and short arms with ring formation is the most common form, although terminal deletion of the long arm and interstitial deletions also occur.

    Physical features associated with the disorder are extremely variable in nature and prevalence (Table I). Commonly associated physical anomalies, occurring in at leas one-third of reported cases, include preterm birth, respiratory distress, growth retardation, microcephaly, strabismus, malformed ears which may be low-set or rotated, congenital heart disease and anogenital anomalies. However, even the most common physical abnormality- malformed ears-has been reported in 439

  • 'A .d

    t j 3

    s V

    440

    TABLE I Physical and neurological findings in reported cases of deletion of the long arm of chromosome 10 b ' ,. 1

    .-I B C D E F G

    Age (yrsVgender

    Nature of deletion

    Preierm birth

    Respiratory distress

    Grovdh retardation

    hlicrocephaly

    Brachycephaly

    Long triangular l i m e s

    Ejebrows abseni laterall)

    Scant l o w eyelashes

    Sirabismus

    E)er deeply set

    Palpcbral fissures

    Upward slanting

    Downward slmting

    Horizontal

    Long ard narrow

    Shon

    Epicanthic folds

    H ypertclorism

    Nasal bndge prominent

    Nose small, narcs rntevcrted

    Ears

    hlalformed

    Low-set

    Rotated

    Large

    Long philtrum

    Dcntal/palatal anomalics

    Cupid.bow upper lip

    Mandibular anomalies

    Widely spaced nipples

    Shon nech

    Hand and foot defects

    Congerutal heart disease

    Flexion contractures

    Syndactyl y

    Clinodact yly

    Pcs planus

    Dislowtable hips

    Anogenital anomalies

    Central nervous system anomalies

    Cognitive/developmental aspects

    Eehavioural aspects

    4/F

    lCq2Ster

    + + + + +

    + + + -

    +

    -

    +

    +

    + -

    +

    +

    + -

    + A.

    -

    + t

    + - + - + -

    IQ = 26 (Cattell)

    -

    I I / F NeonateIF Neonate/hl

    IOq26ter ICq25ter

    +

    t

    -

    +

    -

    Severe mental

    retardation

    Affectionatc but restless and cvtn a plated-covered

    with scratches

    IOqZSter

    +

    + +

    t

    1 , 3 / M 5 mths/M

    ICq26tcr IOq26tcr

    - - -

    t +

    t

    t

    -

    +

    - +

    - - - t t +

    - -

    + + - -

    Mental Psychomotor retardation development

    globally delayed -

  • TABLE I (continued) B- i

    H I J E;

    Age (yrs)/gender

    Nature of dcletion

    10 months/f

    IOq23ier

    Prererm birth

    Respiratory distrcsr

    Growth retardwon

    hlicrocephrl y

    Brachycephaly

    Long trrangular f3cic1

    Fyebrour abreni Irtcrally

    Scant lower c)cl~thes

    Sir~bismus

    Eycs deeply rei

    Palpebral fissurcr

    Upward slaniing

    Downuard slaming

    Horizontal

    Long and narrow

    Short

    Epiianihic fold,

    Hypcrtelorism

    Nasal bridge prominent

    Nore small. nares antevericd

    Ears

    hlalformed

    Low-set

    Rotated

    Large

    Long philtriim

    Dcntal/palatal momalizi

    Cupid-bow upper lip

    Mandibular snomalies

    Widely spaced nipples

    Short neck

    Hand and fooi dcfcctr

    Congenital hean direare

    Flexion contrsciures

    Syndactyly

    Clinodaci y lv

    Pes planus

    Dislocatable hips

    Anogeniial anomalies

    Central nervous system anomalies

    Renal anomalies

    Cognitive/developmental arpecis

    Behavioural specis

    +

    -

    Severe menial rciardaiion

    NeonxeiF

    1042hter

    2 mrh>/F ?8/F

    IOq26.lter (duplicrrion Sq24 .3 )

    +

    +

    +

    - -

    +

    - Obvious

    dsvelopmental delay

    - Some

    developmental delay ..

    tieonatr/F

    IOq25.2icr

    t

    +

    -

    -

    Sewe developmental

    delay

    NeonareiF

    lOq2S or 26tcr

    +

    t

    +

    +

    +

    +

    + -

    +

    -

    +

    +

    -

    +

    T - . -

    m 7

    7 - m 7

    n

    m a Q'

    2 2

    44 1

  • v)

    L - 0

    z 3 x G

    442

    TABLE I (continued)

    Age lyrs)/gender

    Nature of dcletion

    Prcterm binh

    Respirators distres

    Growlh retardation

    Mtcrocephaly

    Brichyccphaly

    l o n g triangular facies

    Eyebrous abrent lalerally

    S i m lowcr eyelashes

    Strabismus

    Eyes deeply set

    Palpebral fissures

    U p w r d s l ~ n ~ i n g

    Downward rlantins

    Hortzont.4

    Long and narrow Shon

    Eprianthis folds

    Hypenclorim

    Nasal bridge promincnr

    Nose rma\l. nares anteberled

    Ears

    hlalformcd

    Lou.set

    Rotared

    Large

    Long philtrum

    DentaVpalatal anomahe5

    Cupid.bow upper lip

    Mandibular anomalics

    Widely spaced nipples

    Shon neck Hand and foot defects

    Congenital hean disease

    Flcaion conrraclures

    Syndact yly

    Clinodact yly

    Per planuc

    Dislocatable hips

    Anogenilal anomalies

    Central nervous sbstem anomalies

    Cognili~e/derelopmenlal aspects

    Bchrvioural aspects

    7/M 3 / hl

    invl)plq? I mat 1Oq25.3tet tOq?!.3 or ?6.lrer

    +

    +

    -

    +

    + - - + -

    Moderate mental retardation. speech delay. best on visuo-

    motor tells

    Hyperkinesir. aggressive. lirniled attenlion span.

    diminished need for slecp. often deliberately provocative and destructive. prone to spit

    when thwarted or rcprimmded, could dso be very affectionate

    + + + +

    + -

    - + +

    +

    + +

    + + + + +

    + - -

    -

    NconarcIF NeonateCF

    IOq?6 . l i e i

    +

    +

    Severe developmental

    delay

    1*?6ier

    +

    +

    +

    +

    + -

    +

    -

    -

    + + +

    - + +

    -

    NeonateIF 7/M --z 18 months

    IOq?6. lter IOq3.2ler

    t

    +

    + +

    +

    + + +

    + - + +

    +

    + Psychomotor development

    mildly delayed -

    -

    + + + c

    See man l C X l

    &&.. - 1

    A = Lewandowski el al. 1978; B = Turleau et a!. 1979; C = Wagner era/. 1981; D = Mulcahy er a/. 1982: E = Taysi el at. 1982; F = Zatterale er a/. 1983; G = Evans-Jones el at. 1983; H = Chieri and lolster 1983; I = Shapiro el a/. 1985; J = Curtis el a/. 1986; K = Vanlieferinghen el a/. 1987; L = Mehta el a/. 1987; M = Wulfsberg el a/. 1989; N =Gorinati el a/. 1989; O= present study. *Three other patients described had interstitial or ring deletions. **Two first-cousins with same chromosomal anomaly were described as developmentally delayed and hyperactive.

  • only 10 of the 18 individuals on record; thus associated physical features are not pathognomic of the condition. None is essential for the diagnosis to be made, and all occur in other genetic disorders as well as in the general population.

    Of equal, if not greater, interest are accounts of associated cognitive-develop- mental and behavioural features. 12 reports have commented on develop- mental level, always describing sub- stantial intellectual impairment, and almost all these observations have been anecdotal, with failure to mention any systematic, standardised cognitive evalu- ation. IQ estimates have been reported only twice: values of 26 (Lewandowski et al. 1978) and 18 (Shapiro et al. 1985), suggesting severe learning disabilities. Three papers have described behavioural disturbance (Turleau ef af. 1979, Shapiro et al. 1985, Mehta el al. 1987). Despite differences in descriptive labels applied and the anecdotal nature of the reports, a common theme emerges of agitation, restlessness and hyperactive tendencies.

    No attempts have been made to date to evaluate the behaviour of children with deletion of the long arm of chromosome 10 using reliable, standardised behavioural inventories. Research has demonstrated the usefulness of this approach in clari- fying characteristic behavioural profiles attributable to underlying genetic anom- alies in a variety of conditions in which the physical features may be variable; for example tuberous sclerosis (Hunt and Dennis 1987), fragile x syndrome (Turk 1992), Schwachman syndrome (Kent et al. 1990) and Williams syndrome (Udwin el al. 1987). A large number of rating schedules exist which have been used successfully in the study of possible behavioural phenotypes (OBrien 1992).

    We describe a boy with deletion of the long arm of chromosome 10 who pre- sented with developmental delay, marked hyperactivity and associated behavioural problems. Thorough developmental and behavioural evaluation clarified the nature of his disturbances and allowed for adaptations to, and improvements in, his complex rehabilitation programme.

    Case report A.M. was born to unrelated middle-aged parents by

    elective caesarean section at 38 weeks gestation following persistent vaginal bleeding with clots that had failed to respond to hospital admission and bed- rest. An enlarged fetal kidney had been demon- strated on ultrasound scan. At delivery, A.M. was noted to have a squashed head, although there was no mention of microcephaly or brachycephaly. There were no neonatal problems. Bottle-feeding was introduced because of poor breast-feeding. with failure to gain weight satisfactorily. Early develop- mental milestones were unremarkable, apart from some difficulty in picking up toy bricks and gross motor delay. However. he was noted to be very active from an early age and failed to develop the usual fear of strangers towards the end of his first year. All vaccinations were received, wirh no adverse reactions.

    A.M. commenced play-school at three years. Within a year he was described as disruptive and unstructured in his play. Subsequently he w-as noted to be left-handed and -footed, and to have delayed development of reading and writing skills.

    Numerous hospital admissions and visits were required duri,ng the first years of life for renal-tract investigations and surgery. Congenital dislocation of the hip required splinting for about a year. He also had several eye operations for srrabismus.

    Physiotherapy was provided up to the age of two years three months for gross motor delay. A.M. received speech therapy until 4V: years of age. at which time his speech and language were felt to be appropriate for age.

    Poor concentration with markedly impulsive behaviour, restlessness, fidgetiness and clumsiness continued. This culminated in referral, a t six years 10 months, to the developmental neuropsychiatry team at the Hospitals for Sick Children. Presenting behavioural features were reported by parents as being continuous and independent of time, setting and company. He was also reported as being indiscriminately affectionate towards others. Socially he was able to relate warmly and to be polite.

    His parents had noted that from an early age A.M. reacted to the ingestion of red dyes with facial oedema, requiring oral antihistamines. Fruit squashes and brightly coloured sweets also seemed to exacerbate his overactivity.

    A variety of behavioural approaches had been tried, with few long-term benefits. These included positive reinforcement, extinction programmes-in which problematic behaviours were systematically ignored-and punishment. Methylphenidate (2.5mg b.d.) had worsened his hyperactivity, so had been discontinued. Placement at a special school for children with emotional , and behavioural disturbances had improved his academic skills and concentration-span a little, but he had started to mimic other childrens aggressive behaviours. Family history was unremarkable.

    Physical examination demonstrated dysmorphic ears and deeply set eyes, with strabismus and epicanthic folds, although palpebral fissures were unremarkable. Lower eyelashes were scant. A cupid- bow upper lip was noted, 3s was clinodactyly, slight generalised joint laxity and flat feet. Head circumference, weight and height were all within normal parameters.

    03 7

    P - m 7

    v1 m

    443

  • v) d

    6 n B

    TABLE I 1 Scaled scores for WPPSI subtests

    Subresi Score I - i

    Performance Object assembly Geometric design Mazes Picture completion Verbal Information Comprehension Arithmetic Vocabulary Sentences

    444

    A clinical -diagnosis of DSM-III:R attention deficit hyperactivity disorder was made on the basis of his pervasive overactivity, poor concentration, restlessness and fidgetiness (American Psychiatric Association 1987).

    Generic studies Chromosomal analysis was undertaken due to A.M.'S multiple medical problems and dysmorphic features. An unbalanced translocation was identi- fied, in which the distal fragment of the long arm of chromosome 10 had been replaced by a segment of unknown origin, producing monosomy for part of IOq and trisomy for an unidentified chromosomal segment-break point at IOq25.2. No fragile sites a t Xq27.3 were identified in 60 cells analysed using folate-deficient medium. DNA probing revealed no evidence that A.M. might have fragile X syndrome in addition to the ch...

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