Archives of Disease in Childhood, 1989, 64, 83-86

The 'happy puppet' syndrome of Angelman:review of the clinical featuresS A ROBB, K R E POHL, M BARAITSER, J WILSON, AND E M BREPT

Hospital for Sick Children, Great Ormond Street, London

SUMMARY Thirty six children with typical features of Angelman's syndrome, including globaldevelopmental delay, ataxia, episodes of paroxysmal laughter, seizures, and microcephaly werestudied. The series included three sibships of three affected sisters, two affected brothers, andtwo affected sisters, respectively. The facial appearance is characterised by a prominent jaw, awide mouth, and a pointed chin. Tongue thrusting is common. The movement disorder consistsof a wide based, ataxic gait with frequent jerky limb movements and flapping of the hands. Toneis variable in the limbs with normal reflexes, and the plantar responses are usually flexor. Thesyndrome is being diagnosed more often, and attention is drawn to its diagnostic aspects.

In 1965 Angelman described a disorder affectingthree unrelated, mentally subnormal children whohad strikingly similar appearances, with unusualjerking movements, brachycephaly, protrudingtongues, episodes of unprovoked laughter, andseizures.' He remarked on the resemblance of thispicture to that of a marionette and used the term'puppet children' to describe the syndrome. Bowerand Jeavons,2 describing two similar children,emphasised their happy demeanour and suggestedthat 'happy puppet' more aptly described thedisorder. Further case reports followed,8 but theirsporadic nature and small numbers suggested a raresyndrome. Though Williams and Frias suggestedthat the incidence may have been underestimated,9fewer than 50 cases have so far been reported.

Since 1981 when Pampiglionel0 drew attention toa number of unusual electroencephalographic fea-tures that had previously been described by Bowerand Jeavons,2 we have identified 36 patients suffer-ing from Angelman's syndrome at the Hospital forSick Children, although the diagnosis was usuallynot made before referral. The correct diagnosis hasassumed greater importance with the recent reportsof familial cases'l-14 suggesting that-rather thanbeing sporadic-the syndrome may have geneticimplications.

This report reviews the clinical features atdiagnosis of our cases of Angelman's syndrome andby including three sets of siblings stresses theimportance of genetic counselling.

Patients and diagnostic criteria

All patients fulfilled the following diagnosticcriteria: delayed developmental milestones fromearly infancy; jerky ataxia; head circumferencebelow the 50th centile for age; typical facial featureswith prominent lower jaw, wide mouth, and fre-quent tongue thrusting; happy disposition, oftenwith episodes of paroxysmal or unprovoked laugh-ter; and electroencephalographic features asdescribed by Boyd et al.1Most of the patients had had seizures by the time

of presentation, but these were not a prerequisitefor the diagnosis. Thirty five of the patients werewhite and one was of east African Asian parentage.None of the parents was consanguineous. Allpatients were referred to the Departments ofNeurology or Genetics at the Hospital for SickChildren for investigation of unexplained neuro-developmental delay.

Results

The series comprised 18 boys and 18 girls agedbetween 18 months and 13 years 6 months at thetime of diagnosis. There were three sets of siblings(three girls, two boys, and two girls); two siblingpairs have previously been reported.13 Pregnancyand delivery had usually been normal, with a meanbirth weight for the group of 3060 g. Subsequentgrowth had usually been normal; there was one boy

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84 Robb, Pohl, Baraitser, Wilson, and Brett

Figure Facial features offour typical patients from theseries, including (a) twobrothers with the condition.

b C

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The 'happy puppet' syndrome of Angelman: review of the clinical features 85

aged 3 years 1 month whose height and weight werejust below the third centile for no obvious reason.All children had delayed developmental milestonesnoted from infancy.

FACIAL FEATURESThe facial features though not pathognomic arehighly suggestive, and are summarised in the tableand shown in the figure. All patients had widemouths, wide lower faces, rather prominent jaws,and pointed chins. Most had thin upper lips andbowed upper dentition that may have been causedby the frequent tongue thrusting.Though most reports have stressed that these

children have blonde hair and blue eyes, one third of

Table Main clinical features in 36 children withAngelman's syndrome

Sex:MaleFemale

Mental retardationFacial features:Wide mouthWide lower faceProminent jawPointed chinThin upper lipBowed teeth

Colouring:Blonde or red hair with blue eyesOther

Head circumference:Below second centileSecond to 50th centile

SeizuresJerky ataxiaWalking:

TotalUnaidedHands held

Speech:Less than three wordsMore than three words

Muscle tone:DecreasedIncreasedNormal

Tendon reflexes:NormalAbnormal

Plantar responses:NormalEquivocal

Computed tomography:NormalShowed mild atrophy

Electroencephalogram abnormal

181836

363636363219

2412

25112836

25187

70

71118

360

342

15 (of 23)8 (of 23)36

our series were dark. Episodes of paroxysmallaughter are common, but may not always occur ininfancy; some of our children (notably one childwith severe gastro-oesophageal reflux) were miser-able and difficult to manage as infants.

AGE AT DIAGNOSISThere may be an evolution of facial features (as seenfrom earlier family photographs) so that below theage of one year (when the movement disorder is lessobvious) clinical diagnosis may be difficult. Theyoungest age at diagnosis was 18 months. Twentyone cases (58%) were diagnosed before the age of5 years (median 2-3 years).

SEIZURESSeizures were present at the time of diagnosis in 28patients (78%). The mean age of onset was 2 years,but most (26, 93%) had developed seizures by theage of 4 years. Of the eight patients who had not hadseizures at the time of diagnosis, seven were aged25 months or less; the remaining patient, a girl aged13 years 6 months, fulfilled all other diagnosticcriteria and also has a sister with Angelman'ssyndrome who had seizures.

MENTAL HANDICAPAll patients were severely mentally handicapped,with a particularly profound language deficit. Onlyseven patients could speak any words at all, and themaximum number was three.

MOVEMENT DISORDERThe movement disorder, present in all, consisted ofa jerky ataxia affecting all limbs with a wide basedgait and frequent flapping of the hands. Mostchildren learned to walk though this was delayed,the earliest age at walking being 19 months. Twentyfive patients (69%) could walk at the time ofdiagnosis, most having walked between the ages of2 and 3 years; of the 11 children who could notwalk, six were still less than 2 years old and maywalk later.

NEUROLOGICAL SIGNSTwenty five of the patients (69%) were microcepha-lic (head circumference below the second centile),and of the remainder none had a head circumfer-ence above the 50th centile for age. Muscle tone wasvariable being normal or slightly decreased belowthe age of 3 years; limb tone was mildly increased in11 children, 10 of whom were aged over 3 years.Tendon reflexes were brisk in these children, butnormal in the rest. Plantar responses were flexor in34 and equivocal in two.

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86 Robb, Pohl, Baraitser, Wilson, and Brett

INVESTIGATIONSThe electroencephalograms were abnormal in allpatients, the abnormalities consisting of generalised,rather rhythmic intermediate slow waves at 4-6cycles/second (c/s) and runs of 2-3 c/s activityanteriorly often with discharges. On closure ofthe eyes spikes with 2-4 c/s activity were seenposteriorly. Details of these changes are describedelsewhere.15 Computed tomography of the brainwas normal in 15 of the 23 patients examined andshowed mild cerebral atrophy in eight. One of thescans also showed a small left temporal arachnoidcyst that was not considered to be of clinicalimportance.The results of biochemical screening (including

estimations of renal and hepatic function, andplasma ammonia and amino acid, urine amino acid,and organic acid concentrations) were normal, aswere haematological measurements. After an inter-stitial deletion of 15qll-13 was detected in onechild, reassessment of chromosome preparationsfrom 10 further children showed four similardeletions. 16

Conclusion

The aim of this report was to draw attention to thediagnostic features of Angelman's syndrome, whichmay be recognised in children presenting withunexplained neurodevelopmental delay, and topoint out that this condition (when specificallylooked for) is commoner than has been hithertothought. The combination of the facial features,profound retardation, ataxic movement disorder,seizures, and happy disposition strongly suggests thediagnosis and this may be confirmed by electro-encephalographic analysis. The reports of familialcases both in this series and in other publications'-114highlight the need for accurate recognition of thesyndrome in order to be able to discuss theprognosis and management and to refer the parentsfor appropriate genetic counselling.

We thank Drs Ann Harden and Stewart Boyd for providingelectroencephalographic data on the patients, and Dr BrianKendall for reviewing the computed tomograms.

References

' Angelman H. 'Puppet' children, a report on three cases. DevMed Child Neurol 1965;7:681-8.

2 Bower BD, Jeavons PM. The 'happy puppet' syndrome. ArchDis Child 1967;42:298-302.

3 Berg JM, Pakula Z. Angelman's ('happy puppet') syndrome.Am J Dis Child 1972;123:72-4.

4 Mayo 0, Nelson OM, Townsend HRA. Three more 'happypuppets'. Dev Med Child Neurol 1973;15:63-74.

5 Moore JR, Jeavons PM. The 'happy puppet' syndrome: two newcases and a review of previous cases. Neuropadiatrie 1973;4:172-9.

6 Elian M. Fourteen happy puppets. Clin Pediatr 1975;14:902-8.7 Dooley JM, Berg JM, Pakula Z, MacGregor DL. The puppet-

like syndrome of Angelman. Am J Dis Child 1981;135:621-4.8 Hersh JA, Bloom AS, Zimmerman AW, et al. Behavioural

correlates in the happy puppet syndrome: a characteristicprofile? Dev Med Child Neurol 1981;23:792-800.

9 Williams CA, Frias JL. The Angelman ('happy puppet')syndrome. Am J Med Genet 1982;11:453-60.

10 Pampiglione G, Martinez A. Evolution of Angelman syndrome.Follow up of three new cases. Electroencephalogr Clin Neuro-physiol 1983;56:72P.

l Kurohi Y, Matsui I, Yamamoto Y. The 'happy puppet'syndrome in two siblings. Hum Genet 1982;56:227-9.

12 Pashayan HM, Singer W, Bove C, Eisenberg E, Seto B. TheAngelman syndrome in two brothers. Am J Med Genet1982;13:295-8.

13 Baraitser M, Patton MA, Lam STS, Brett EM, Wilson J. TheAngelman (happy puppet) syndrome: is it autosomal recessive?Clin Genet 1987;31:323-30.

14 Fisher JA, Burn J, Alexander FW, Gardner-Medwin D.Angelman (happy puppet) syndrome in a girl and her brother.J Med Genet 1987;24:294-8.

s Boyd SG, Harden A, Patton MA. The EEG in early diagnosis ofAngelman's (happy puppet) syndrome. Eur J Ped 1988;147:503-13.

16 Pembrey M, Fennell J, van den Berghe J, et al. The associationof Angelman syndrome and deletions within 15qll-13. J MedGenet 1988;25:274.

Correspondence to Dr SA Robb, Department of Neurology,Hospital for Sick Children, Great Ormond Street, London WC1N3JH.

Accepted 25 February 1988

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