the prader-willi syndrome - bmjand order of probes for prader-willi and angelman's syndromes,...

Archives of Disease in Childhood 1994; 70: 58-63

CURRENT TOPIC

The Prader-Willi syndrome

M D C Donaldson, C E Chu, A Cooke, A Wilson, S A Greene, J B P Stephenson

Since the original description by Prader,Labhart, and Willi in 1956,' there have beenover 700 case reports of the Prader-Willisyndrome and by the end of 1991 the Prader-Willi Association were aware of 1595 affectedindividuals in North America.2 Estimates ofprevalence vary: one group has reported aconsensus figure of one in 10 000 births,3 butwith modem techniques for laboratory diag-nosis this estimate will probably be shown tohave been too high.

It is now known that the Prader-Willisyndrome results from abnormality or loss of acritical region on the proximal part of the longarm of the paternal chromosome 15. Clinicallythe condition is expressed as a dysmorphicsyndrome that principally affects the centralnervous system, and has a particular predilec-tion for the hypothalamus.

In this paper we summarise the clinicalfeatures of the Prader-Willi syndrome andpresent the current understanding of its molec-ular basis. The laboratory and clinicalapproaches to diagnosis are discussed, as wellas some issues concerning the management ofthe metabolic, dietary, and growth problems.

Clinical featuresThe classic concept of the Prader-Willisyndrome is that of a two stage disorder withan infantile hypotonic phase followed by achildhood obese phase.4 This has beenextended by Whitman and Accardo to includea third, adolescent phase with particularbehavioural features,5 and we would developthis model further to include a fetal andneonatal phase, as shown in the table.

Department of ChildHealth, Fraser ofAllander Unit(Neurology and ChildDevelopment), andDuncan GuthrieInstitute ofMedicalGenetics, Yorkhill,Glasgow G3 8SJM D C DonaldsonC E ChuJ B P StephensonA Cooke

Department of ChildHealth, NinewellsHospital and MedicalSchool, DundeeA WilsonS A Greene

Correspondence to:Dr Donaldson.

FETAL AND NEONATAL STAGE

Decreased fetal movements presumablyaccount for the increased incidence of breechdelivery and there is also a higher incidence ofdelivery by caesarean section.3 At birth infantsare described as hypotonic, with abnormal,weak, or absent cry6 and an almost invariableneed for tube feeding. It is important to notethat the hypotonia mainly affects the neck7 8;the limbs commonly have normal tone or takeup dystonic postures.8 Sticky saliva is a helpfuland under recognised pointer to the clinicaldiagnosis.7 Genital hypoplasia is the rule ingirls, but is subtle and easily missed8; scrotalhypoplasia and cryptorchidism are common inboys, while the penis is small but not tiny.6 8.

INFANT AND EARLY CHILDHOOD STAGEAfter the neonatal period motor activitygradually increases and hypotonia becomesless marked, but the child remains difficultto feed with consequent failure to thrive.Development is delayed, particularly grossmotor and speech.9 Subsequently expressivelanguage and articulation difficulties becomeevident'0 with a peculiar high pitched nasalquality extending into adolescence."1 Thenarrow bifrontal diameter, almond shapedpalpebral fissures, thin downtumed upper lip,and narrow nose that may have been notedduring the neonatal period6 become more pro-nounced. Classically, affected subjects arehypopigmented with fair hair and blue eyes.'2

CHILDHOOD STAGEThis is marked by hyperphagia with conse-quent obesity (see below) and behaviourproblems, with outbursts oftemper in responseto frustration (for example, the withholding offood) making parenting unusually difficult. Atendency to skin pick is noticed by parents atthis stage, although it becomes much morepronounced later on, and this is combined withdecreased sensitivity to pain. "1 The pigmentaryand sensory disturbances observed raises thepossibility of an abnormality in the peptides

Clinicalfeatures in Prader-Willi syndrome

Fetal and neonatalDecreased fetal movementsPoor feeding/tube feedingAbnormal/no cryAxial hypotonia/limb dystoniaSticky salivaGenital hypoplasia and cryptorchidismInfancy and early childhoodFailure to thriveDevelopmental delayDelayed speechTypical faciesFair hair/blue eyesChildhoodVoracious appetiteObesityShort statureSmall hands and feet, straight ulnar borderScoliosisEasy bruisingSkin picking/other self abuseCariesExcessive daytime sleepinessTemper tantrumsSquintAdolescenceCataplexy/pseudoseizuresObsessional traitsBehaviour problemsParticular difficulties with handling moneyLack of independenceDelayed/incomplete secondary sexual development

58

on August 12, 2021 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.70.1.58 on 1 January 1994. D

ownloaded from

http://adc.bmj.com/

The Prader-Willi syndrome

Maternal Ch 15m EW

Normal

parents

Normal PWS ASFigure 1 Deletion ofIPrader-Willi/Angelman's (PW/AS)locus resulting in Prader-Willi syndrome (PWS) orAngelman's syndrome (AS) according to the parentalorigin of affected chromosome.

derived from pro-opiomelanocortin but studiesto date have not supported this hypothesis.'3 14Other cutaneous manifestations include easybruising, sometimes to an extent that childabuse is suspected, and marked erythema aftera hot bath. Caries affecting primary dentitionare common,9 and may be related to theviscous saliva. By school entry impairment oflinear growth (see below), typical phenotype,obesity, and genital hypoplasia, complete theclinical picture. Scoliosis may be noted atthis stage, but becomes more evident inadolescence." Severe intellectual impairmentis seldom seen, especially during the childhoodyears, and some subjects can attend normalschool,7 although virtually all will requirespecial education from secondary school levelonwards."I 12 The cognitive impairment isuneven. Skill at jigsaw assembly is character-istically excellent, reading ability is oftenreasonable, but arithmetic is usually poor.Particular difficulty with short term memoryprocessing has been demonstrated.'5

ADOLESCENT STAGEIn adolescence, specific behaviour and learningdifficulties become prominent.5 16 Adolescentswith Prader-Willi syndrome have particulardifficulty coping with the logistics of handlingmoney, and fall asleep easily when sitting on

journeys so that independent travel on publictransport is rarely possible. The obsessionalnature of the disorder is particularly evident so

that trivial alterations in routine, such as therescheduling of a favourite television pro-

gramme, may provoke a tantrum. Cataplexy17and pseudoseizures may occur and can bemistaken for true epilepsy (JBP Stephenson,

PWS minimal deletion

D15S9 D15S13 Srnpn D15S10

CEN

t tD15S11 D15S63

D15S12i

tGABRB3 GABRA5

As minimal deletionFigure 2 Diagram ofPrader-Willi syndrome (PWS) and Angelman's syndromechromosome 15.

personal observation). Despite reasonableskills in selected areas that can be amplifiedby appropriate youth training, Prader-Willisubjects are unable to be completely indepen-dent as adults." 15 18 Puberty is characteristi-cally delayed, although precocious puberty hasbeen reported. 19 In subjects with pubertaldelay the response to luteinising hormonereleasing hormone is blunted,9 while stimula-tion with human chorionic gonadotrophin inboys may show an abnormally low testosteroneresponse indicating an element of primaryhypogonadism.20 Girls will achieve secondarysexual development spontaneously but oligo-menorrhoea is the rule, while most boysrequire testosterone treatment to achievenormal development. Fertility has not beenreported in bonafide cases in either sex.

Molecular genetic aspects(1) PRADER-WILLI SYNDROME DUE TODELETION IN THE LONG ARM OF PATERNALCHROMOSOME 15Chromosomal abnormality was proposed as apossible cause in some patients as early as 1976with translocations involving chromosome 15being predominant.2' This led to studies ofchromosome 15 in patients with Prader-Willisyndrome using high resolution bandingtechniques. In 1981 cytogenetic deletionsinvolving the long arm ofchromosome 15 werefirst described,22 and approximately 50% ofpatients have an interstitial deletion of 15ql 1-13 visible on high resolution banding. Five percent of patients have duplications or trans-locations while the remainder have normalkaryotypes.23 By studying chromosome 15heteromorphism the deleted 15q in patientsPrader-Willi syndrome was found to bepaternal in origin in most cases, although bothparents had normal phenotypes and karyo-types.At the same time, studies in individuals with

Angelman's syndrome showed that affectedsubjects frequently showed deletions in thesame 15ql 1-13 area, but that the affectedchromosome was maternal in origin (fig 1).24The inference from these discoveries was thatboth maternal and paternal copies of 1 5ql 1- 13are required for normal development to occur.This phenomenon, whereby genetic material isexpressed differentially depending on whetherit is paternal or maternal, is called genomicimprinting.25 In more recent years DNA probesspecific for the 15qll-13 region have beenisolated and used to physically map the area ofinterest26 (fig 2). Kuwano et al in 199227 andKnoll in 199328 have defined a critical regionand order of probes for Prader-Willi andAngelman's syndromes, by the use of fluor-escence in situ hybridisation, and yeast artifi-cial chromosomes clones. The minimumregion of deletion for Prader-Willi syndromehas been shown to lie between the loci D 5S 13and D15S1O, and includes locus D15S63.Most individuals with Prader-Willi andAngelman's syndromes have deletions involv-ing a common set of markers that includeD15S9, D15Sll, D15SI3, and D15SO.

Paternal Ch 15

PW/AS ,,locus ~ m

59



j.com/

Arch D


ownloaded from

http://adc.bmj.com/

Donaldson, Chu, Cooke, Wilson, Greene, Stephenson

However, a family have been described byHamabe et al where a small 1 5q deletion trans-mitted to a woman from her father resulted ina normal phenotype rather than Prader-Willisyndrome, while transmission to her childrenresulted in Angelman's syndrome.29 Thisobservation shows that the critical region forPrader-Willi syndrome must be separate fromthe critical region for Angelman's syndrome.

(2) PRADER-WILLI SYNDROME DUE TOMATERNAL DISOMYIn 1989 Knoll et al carried out DNA studiesusing probes and confirmed the paternaloriginal of the deleted chromosomes in somePrader-Willi subjects.24 However, they alsofound that in some karyotypically normalpatients both chromosomes were maternal inorigin (uniparental maternal disomy). In someinstances both apparently intact maternalchromosomes were present (heterodisomy)and in other instances two copies of thesame maternal chromosome were present (iso-disomy) (fig 3). In Angelman's syndrome thephenomenon of uniparental paternal disomyhas been reported in 5°/O of cases.30

(3) MECHANISMS FOR AND EXPRESSION OF THEMOLECULAR ABNORMALITIES IN PRADER-WILLISYNDROMEEnvironmental factors have been postulated inthe aetiology of deletions in the paternallyderived chromosome. Strakowski and Butlerin 1987 found that an increased incidence(21%) of fathers of children with Prader-Willisyndrome were employed in occupationswhere hydrocarbons were used at the time ofconception compared with the fathers ofchildren with Down's or fragile X syndromes(1/2%).31 Cassidy et al looked at 81 individualswith Prader-Willi syndrome and found thatapproximately half of the fathers wereemployed in jobs where they were exposed tohydrocarbons around conception.32 Whateverthe specific cause, it seems likely that the 15qdeletion occurs in the father's gametes atthe stage of meiosis. Uniparental disomypresumably results from a sequence ofnon-disjunction and duplication events occur-ring at the time of gamete formation and con-ception.As one would expect, the Prader-Willi

Paternal Maternal

Normal Normal Heterodisomy IsodisomyFigure 3 Diagram showing maternal disomy.

syndrome is sporadic in almost all cases.Indeed, the only mechanisms by which thedisorder might be expected to have a familialbasis are:

(A) In the very rare instances where a fathercarries a balanced translocation involving thecritical area for Prader-Willi syndrome so thatthose of his children receiving unbalancedtranslocations will have the condition.33

(B) When a father has inherited a deletionspecific for Prader-Willi syndrome from hismother. This could explain the familydescribed by Lubinsky et al who reported twobrothers and two sisters in a single sibship withclassic Prader-Willi phenotype and normalchromosomes on cytogenetic examination.34

It is not known how the molecular abnor-mality (Snrpn) in Prader-Willi syndrome istranslated into the predominantly neuro-logical disorder seen clinically. It is of interest,however, that Ozcelik et al have mapped agene encoding a small nuclear ribonucleo-protein polypeptide to the critical regionfor Prader-Willi syndrome between D15S13and D15S10 (fig 2).35This is the first geneencoding a characterised protein to bemapped to this area. The protein is expressedpredominantly in the brain and is thoughtpossibly to affect alternative splicing oftranscripts. Mutations in this gene maytherefore have effects on the development orfunction of the nervous system. In the mouse,Snrpn gene is imprinted and only thepaternally derived allele is expressed in thebrain. If this gene is the Prader-Willisyndrome gene, there is a possibility thatpoint mutations may be found in those rarenon-deleted patients who appear to havePrader-Willi syndrome.

Diagnosis of Prader-Willi syndrome(1) LABORATORY DIAGNOSISIt is now known that deletions seen bymicroscopy do not necessarily correlate withmolecular deletions. Hamabe et al describedsix patients with cytological deletions that werenot demonstrable at the molecular level.36 Theexplanation for this may be that these patientseither had deletions outside the critical areafor Prader-Willi syndrome, or that apparentcytogenetic deletions may in fact be normalvariations, pericentric inversions, or balancedinsertions. We suggest that conventionalcytogenetic analyses are no longer appropriatein the diagnosis of Prader-Willi syndrome.There are three approaches currently

favoured in the molecular diagnosis of Prader-Willi syndrome. One is to use specific DNAprobes for the region 15q1 1-13 together withrestriction digests (which allow for detection ofrestriction fragment length polymorphisms)and Southern blotting, comparing the resultingbands with those of the parents and recordingany absence of a paternal allele. RecentlyDittrich et al have developed a more refinedtechnique involving probe PW71 (which mapsto locus D15S63) in conjunction with a doublerestriction digest using the enzymes HindIIIand HpaII, the latter being methylation

60



j.com/

Arch D


ownloaded from

http://adc.bmj.com/

61The Prader-Willi syndrome

sensitive.37 As the locus D15S63 is methylatedon maternally derived chromosomes, andunmethylated on paternally derived chromo-somes, it is possible to screen patients usingSouthern blotting techniques. In 27 patientswith Prader-Willi syndrome and 16 withAngelman's syndrome, Prader-Willi patientshad only one 6 kilobase (kb) band indicatingeither deletion in the paternally derivedchromosome or maternal disomy, and patientswith Angelman's syndrome only one 4-4 kbband indicating either deletion in the matern-ally derived chromosome or paternal disomy.Normal subjects will have both the 6 kb and4-4 kb bands. This method is currently themost efficient in diagnosing affected individ-uals without the need for parental samples, butdoes not definitely distinguish between deletedand disomic patients.

Rapid diagnosis of Prader-Willi andAngelman's syndromes has been described byMutirangura et al using dinucleotide repeatmarkers and the polymerase chain reaction.38This method is quicker and less labour inten-sive than studies using DNA probes, but isonly informative in 70% of cases and requiressamples from both parents.

Fluorescent in situ hybridisation withmapping of cosmids to the 1 5ql 1-13 region isan alternative approach and gives fairly rapidresults in deleted cases, but will not detectdisomy.

(2) CLINICAL DIAGNOSISDespite advances in molecular genetics, thePrader-Willi gene has not yet been identifiedwith certainty so that the diagnosis remainsclinical. Holm et al have developed two scoringsystems for the diagnosis in children aged 0 to3 years and from 3 years to adulthood.39 In a

multidisciplinary Prader-Willi clinic held inGlasgow since the beginning of 1992, 24subjects have been seen by a team consisting ofa neurologist, clinical geneticist, endocrino-logist, and dietitian. Sixteen patients satisfiedthe criteria for Prader-Willi syndrome both inthe view of the Glasgow team and on the con-

sensus criteria devised by Holm et al. Of these12 were deleted, three disomic, while no

abnormality could be detected in one girl withcertain atypical features. The diagnosis ofPrader-Willi syndrome was rejected on clinicalgrounds in eight of the other subjects andnone of these showed any molecular geneticabnormality.

Reversing the diagnosis of Prader-Willisyndrome in these eight patients has inevitablyresulted in considerable distress among some

of the parents. This situation can be largelyavoided by carrying out molecular geneticstudies in all suspected cases and reconsideringthe diagnosis if the results are negative. Theconsensus diagnostic criteria of Holm et al are

useful and we would highlight the importanceof tube feeding during infancy as well as stickysaliva and weak/absent cry (the latter twofeatures are listed as minor criteria by Holm et

al). By contrast, we consider the phenotype,especially the facies, to be more difficult to

assess objectively while the uncontrolled eatinghabits also lack specificity.

Metabolic and dietary aspectsClassically the obesity of Prader-Willi syn-drome begins in the childhood phase, after theage of 1-5-2 years, although rarely it canbecome manifest from as early as 6 months ofage.40 41 The deposition of excess fat may besevere in many subjects, especially in adoles-cence and adulthood.11 Characteristically thesubcutaneous fat is distributed mainly overthe trunk, buttocks, and thighs.42 Untreatedobesity is the most serious and commoncomplication of Prader-Willi syndrome, con-tributing significantly to the morbidity andmortality.11

Hyperphagia is the major cause of obesity.Prader-Willi subjects are notorious for theirpersistent and often ingenious ways of obtain-ing food. Common strategies include stealing,with night time raids on the kitchen and larder,finishing the uneaten lunches of classmates atschool, and persuading carers to give food.Refusal to do so often leads to a tantrum.With unrestricted eating, energy intakes of21 736±+209 kJ (5200±50 kcal)/day have beenreported.43

Increased intake is not the only factor incausing the obesity in Prader-Willi syndrome.Total energy expenditure, attributable toreduced activity, is reduced.44 Body composi-tion is abnormal with increased fat mass andpercentage body fat.45 However, in contrast tosimple obesity, fat free mass is not increased sothat there is a relative reduction in musclemass.45 Resting energy expenditure is normalwhen adjusted for the fat free mass content.44The composition of adipose tissue differs fromsimple obesity, with an increase in longchained polyunsaturated fatty acids.45

Diabetes mellitus occurs in up to 20% ofsubjects with long standing Prader-Willisyndrome." 46 The insulin resistance found issimilar to that of simple obesity,47 and clini-cally the diabetes behaves as type II non-ketotic diabetes responding to weightreduction and/or oral hypoglycaemic agents. Ifinsulin is required a simple once daily longacting preparation is usually effective.

STRATEGIES FOR MANAGING THE OBESITY OFPRADER-WILLI SYNDROMEConstant supervision by parents, restriction ofaccess to food by locking cupboards andrefrigerator, and cooperation on the part ofcare givers (including the school and extendedfamily) remain the cornerstone of manage-ment in preventing morbid obesity.48 49 Withearly diagnosis the obese phase of the disordercan be pre-empted.48 In obese individuals, theenergy intake must be adjusted to causeweight reduction, but success is more difficultto achieve in older subjects.49 Guidelines havebeen given for the energy intakes requiredfor weight loss (29-3-33.4 kJ (7-8 kcal)/cm height), and for weight maintenance(41-8-58-5 kJ (10-14 kcal)/cm height),42 48



j.com/

Arch D


ownloaded from

http://adc.bmj.com/

Donaldson, Chu, Cooke, Wilson, Greene, Stephenson

with 20% of energy from protein, 20-25%energy from fat, and the remaining 55-60%from carbohydrate. Other dietary approacheshave been used including low carbohydratediets,40 very low energy diets,50 and ketogenicdiets,45 with some success but their value lieslargely in achieving control in the short term.Behavioural management approaches haveproved helpful in weight reduction,45 50and these techniques, combined with energyrestriction under the guidance of anexperienced dietitian, form the basis of con-ventional care.The inevitable problems of achieving

satisfactory weight control in some individualshas prompted the search for other forms oftreatment. Surgical management with gastricbypass is a drastic but effective strategy in thetreatment of morbid obesity.51 Various drugtreatments have been tried with limitedsuccess. Appetite suppressants such as fenflu-ramine have been used with mixed results, andfurther studies of longer term treatment arerequired to determine their effectiveness.52Naltrexone, a blocker of the endogenousopioids, has proved ineffective in reducingnutrient intake in Prader-Willi individuals,53although the possibility that other similarantagonists may be more successful remains tobe tested.

Growth hormone, with its effect on proteinsynthesis and lipid metabolism might beexpected to have a beneficial role in thePrader-Willi syndrome, especially given theabnormal body composition with increased fatand reduced muscle. In Dundee a recent studyon 12 Prader-Willi subjects aged 5-16 yearshas shown an encouraging increase in fat freemass over a six week period using growthhormone in doses of 15 and 20 units/m2/weekin children and adolescents respectively.However, all but one subject gained weightwhile a particularly obese 14 year old boydeveloped type II diabetes mellitus withinthree weeks of starting treatment, respondingto dietary restriction and oral hypoglycaemicagents. There was also a subjective impressionon the part of several parents that theirchildren showed an increase in appetite ongrowth hormone treatment. A future role forgrowth hormone in preventing the obesity ofPrader-Willi syndrome is doubtful, but furtherwork is required to investigate its value inimproving muscle mass.

Growth aspectsThe growth pattern of children with Prader-Willi syndrome is characteristic with low ornormal birth length and poor growth duringinfancy.54 In contrast to simple obesity wherechildren are relatively tall with enhancedheight velocity and advance in bone age, obesePrader-Willi subjects are short, usually 10thcentile and below, with normal or low heightvelocity for age, and bone age delay until latechildhood. There is also a selective aspect to

the reduced growth affecting the hands andfeet particularly, while the lower body segmentis relatively short compared with the sitting

height.55 These factors, combined with poorgrowth at adolescence, contribute towards thelow final adult height.1' 56The existence of growth hormone defi-

ciency in the Prader-Willi syndrome isdebated. Several studies have demonstrated asubnormal growth hormone response toinsulin induced hypoglycaemia,57 but thisresponse is similar to the blunting effect ofsimple obesity.58 59 However, one study hasreported an abnormally low growth hormoneresponse to clonidine stimulation in leanchildren with Prader-Willi syndrome suggest-ing that growth hormone deficiency is agenuine feature of the condition and not anartefact of the obesity.60 In Glasgow, of 11patients tested for growth hormone deficiencyusing insulin hypoglycaemia, peak con-centrations were less than 10 mU/l in sixpatients, 10-20 mU/l in three, and greaterthan 20 mU/l in only two. Pituitary imagingwas carried out in only one patient andshowed marked pituitary hypoplasia on highresolution computed tomography that wassubsequently confirmed by magneticresonance imaging. Given the difficulties ininterpreting dynamic tests of growth hormonestimulation in obese subjects, the value ofdetailed pituitary imaging in the Prader-Willisyndrome should be examined prospectively.The role of growth hormone treatment in

the statural management of Prader-Willisyndrome is undecided. While an improve-ment in short term height velocity has beendocumented60 there are no satisfactory data onfinal height. In Glasgow our experience of finaland near final height is limited, but cautiouslyoptimistic. Three subjects aged 13-7, 16-3, and17-6 years have received growth hormone for aminimum of three years with no additional sexsteroid treatment and height SD scores havechanged from -3 5 to 0-7, -5.2 to -2-7, and-4 3 to -1-5 respectively, with final heightachieved in the latter two patients. Given therarity of the condition, the effect of growthhormone on final height will be difficult toevaluate unless data from different centres arepooled, restricting analysis to patients in whomthe diagnosis has been confirmed by molecularstudies.

ConclusionThe Prader-Willi syndrome results from a dis-turbance ofmolecular arrangement in a criticalarea of 15q, with widespread effect on thecentral nervous system. Correct diagnosis isessential, and can be achieved by combiningclinical diagnostic criteria with moleculargenetic (as opposed to cytogenetic) tech-niques. Dietary supervision remains the main-stay in management of the obesity. Furtherwork to explore a potential role for growthhormone in improving body composition isjustified. Detailed studies of hypothalamo-pituitary function including high resolutionimaging may clarify the endocrine pathology,and collaborative work is needed to examinethe effect of growth hormone treatment onfinal height.

62



j.com/

Arch D


ownloaded from

http://adc.bmj.com/

63The Prader-Willi syndrome

1 Prader A, Labhart A, Willi H. Ein Syndrom von Adipositas,Kleinwuchs, Kryptorchismus und Oligophrenie nachmyatonieartigem Zustand im Neugeborenenalter. SchweizMed Wochenschr 1956; 86: 1260-1.

2 Cassidy SB. Recurrence risk in Prader-Willi syndrome(letter). Am _J Med Genet 1987; 28: 59-60.

3 Holm VA. The diagnosis of Prader-Willi syndrome. In:Holm VA, Sulzbacher S, Pipes PL, eds. The Prader Willisyndrome. Baltimore: University Park Press, 1981: 27-44.

4 Zellweger H. Diagnosis and therapy in the first phase ofPrader-Willi syndrome. In: Holm VA, Sulzbacher S, PipesPL, eds. The Prader Willi syndrome. Baltimore: UniversityPark Press, 1981: 55-68.

5 Whitman BY, Accardo P. Emotional symptoms of Prader-Willi adolescents. Am Med Genet 1987; 28: 897-905.

6 Aughton DJ, Cassidy SB. Physical feature of Prader-Willisyndrome in neonates. Am Dis Child 1990; 144: 1251-4.

7 Stephenson JBP. Neonatal presentation of Prader-Willi syn-drome (letter). Am Dis Child 1992; 146: 151-2.

8 Stephenson JBP. Prader-Willi syndrome: neonatal presenta-tion and later development. Dev Med Child Neurol 1980;22: 792-9.

9 Dunn HG, Tze WJ, Alisharan RM, et al. Clinical experiencewith 23 cases of Prader-Willi syndrome. In: Holm VA,Sulzbacher SJ, Pipes P, eds. Prader- Willi syndrome.Baltimore: University Park Press, 1981: 69-88.

10 Kleppe SA, Katayama KM, Shipley KG, Foushee DR. Thespeech and language characteristics of children withPrader-Willi syndrome. journal of Speech and HearingDisorders 1990; 55: 300-9.

11 Laurence B, Brito A, Wilkinson J. Prader-Willi syndromeafter 15 years. Arch Dis Child 1981; 56: 181-6.

12 Dunn HG. The Prader-Labhart-Willi syndrome: review ofthe literature and report of nine cases. Acta Paediatr Scand1968; 186 (suppl): 1-38.

13 Butler MG, Jenkins BB, Orth DN. Plasma immunoreactivebeta-melanocyte stimulating hormone (lipotropin) levelsin individuals with Prader-Labhart-Willi syndrome. AmMed Genet 1987; 28: 839-44.

14 Margules DL, Inturrisi CE. Beta-endorphin immunoreac-tivity in the plasma of patients with the Prader-Labhart-Willi syndrome and their normal siblings. Experientia1983; 39: 766-7.

15 Warren JL, Hunt E. Cognitive processing in children withPrader-Willi syndrome. In: Holm VA, Sulzbacher S, PipesPL, eds. The Prader-Willi syndrome. Baltimore: UniversityPark Press, 1981; 161-78.

16 Clarke DJ, Waters J, Corbett JA. Adults with Prader-Willisyndrome: abnormalities of sleep and behaviour. R SocMed 1989; 82: 21-4.

17 Stephenson JBP. Funny turns and funny attacks. In:Stephenson JBP, ed. Fits and faints. Oxford: MackeithPress, 1990: 144.

18 Greenswag LR. Adults with Prader-Willi syndrome: asurvey of 232 cases. Dev Med Child Neurol 1987; 29:145-52.

19 Vanelli M, Bernasconi S, Caronna N, Virdis R, Terzi C,Giovannelli G. Precocious puberty in a male with Prader-Labhart-Willi syndrome. Helvetica Paediatrica Acta 1984;39: 373-7.

20 Jeffcoate W, Laurence B, Edwards C, Besser G. Endocrinefunction in the Prader-Willi syndrome. Clin Endocrinol(Oxf) 1980; 12: 81-9.

21 Hawkley CJ, Smithies A. The Prader-Willi syndrome with a15-15 translocation: case report and review of the litera-ture. Med Genet 1976; 13: 152-7.

22 Ledbetter DH, Riccardi VM, Youngbloom SA, Strobel RJ,Keenan BS, Crawford JD. Deletions of chromosome 15 asa cause of the Prader-Willi syndrome. N EnglJrMed 1981;304: 325-9.

23 Butler MG. Prader-Willi syndrome: current understandingof cause and diagnosis. Am J7 Med Genet 1990; 35:319-32.

24 Knoll JHM, Nicholls RD, Magenis RE, Graham JM, Jr,Lalande M, Latt SA. Angelman and Prader-Willisyndromes share a common chromosome 15 deletion butdiffer in parental origin of the deletion. Am Med Genet1989; 32: 285-90.

25 Hall JG. Genomic imprinting: review and relevance tohuman diseases. AmJ Hum Genet 1990; 46: 857-73.

26 Donlon TA, Lalande M, Wyman A, Bruns G, Latt SA.Isolation of molecular probes associated with the chromo-some 15 instability in the Prader-Willi syndrome. ProcNadtAcad Sci USA 1986; 83: 4408-12.

27 Kuwano A, Mutirangura A, Bittrich B, et al. Molecular dis-section of the Prader-Willi/Angelman syndrome region(15qI 1-13) by YAC cloning and FISH analysis. HumanMolecular Genetics 1992; 1: 417-25.

28 Knoll JHM, Sinnett D, Wagstaff J, et al. FISH ordering ofreference markers and of the gene for the 5 subunit of the-aminobutyric acid receptor (GABRA5) within theAngelman and Prader-Willi syndrome chromosomalregions. Human Molecular Genetics 1993; 2: 183-9.

29 Hamabe J, Kuroki Y, Imaizumi K, et al. DNA deletion andits parental original in Angelman syndrome patients. AmMed Genet 1991; 41: 64-8.

30 WagstaffJ, Knoll JHM, Glatt KA, Shugart YY, Sommer A,Lalande M. Maternal but not paternal transmission of15qll-13-linked nondeletion Angelman syndrome leadsto phenotypic expression. Nature Genetics 1992; 1: 291-4.

31 Strakowski SM, Butler MG. Paternal hydrocarbonexposure in Prader-Willi syndrome. Lancet 1987; ii: 1458.

32 Cassidy SB, Gainey AJ, Butler MG. Paternal hydrocarbonexposure at conception of Prader-Willi syndrome patientswith and without deletions of chromosome 15q. Am J7Hum Genet 1989; 44: 806-10.

33 Fernandez F, Berry C, Mutton D. Prader-Willi syndrome insiblings, due to unbalanced translocation betweenchromosomes 15 and 22. Arch Dis Child 1987; 62: 841-3.

34 Lubinsky M, Zellweger H, Greenswag L, Larson G,Hansmann I, Ledbetter D. Familial Prader-Willisyndrome with apparently normal chromosomes. Am JMed Genet 1987; 28: 37-43.

35 Ozcelik T, Leff S, Robinson W, et al. Small nuclear ribo-nucleoprotein polypetide N (SNRPN), an expressed genein the Prader-Willi syndrome critical region. NatureGenetics 1992; 2: 265-9.

36 Hamabe J, Fukushima Y, Harada N, et al. Molecular studyof Prader-Willi syndrome: deletion, RFLP and pheno-type analysis of 50 patients. Am J Med Genet 1991; 41:4-63.

37 Dittrich B, Robinson WP, Knoblauch, et al. Molecular diag-nosis of the Prader-Willi and Angelman syndromes bydetection of parent-of-origin specific DNA methylation in15ql-13. Hum Genet 1990; 90: 313-5.

38 Mutirangura A, Greenberg F, Butler M, et al. MultiplexPCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15ql 1-ql3): moleculardiagnosis and mechanism of uniparental disomy. HumanMolecular Genetics 1993; 2: 143-51.

39 Holm VA, Cassidy SB, Butler MG, et al. Prader-Willisyndrome: consensus diagnostic criteria. Pediatrics 1993;91: 398-402.

40 Coplin S, Hine J, Gormican A. Out-patient dietary manage-ment in the Prader-Willi svndrome.JAm DietAssoc 1976;68: 330-4.

41 Zellweger H. The Prader-Willi syndrome. JAMA 1984;251: 1835.

42 Hoffman C, Aultman D, Pipes P. A nutrition survey of andrecommendations for individuals with Prader-Willisyndrome who live in group homes.JAm DietAssoc 1992;92: 823-33.

43 Holm V, Pipes P. Food and children with Prader-Willisyndrome. Am_J Dis Child 1976; 130: 1063-7.

44 Schoeller D, Levitsky L, Bandini L, Dietz W, Walczak A.Energy expenditure and body composition in Prader-Willisyndrome. Metabolism 1988; 37: 115-20.

45 Nelson R, Huse D, Holmanetal R. Nutrition metabolism,body composition and response to the ketogenic diet inPrader-Willi syndrome. In: Holm V, Sulzbacher S, PipesP, eds. The Prader-Willi syndrome. Baltimore: UniversityPark Press, 1981: 105-20.

46 Illig R, Tschumi A, Vischer D. Glucose tolerance anddiabetes mellitus in patients with Prader-Labhart-Willisyndrome. Modern Problems ofPediatrics 1975; 12: 203-10.

47 Kousholt A, Beck-Nielsen H, Lund H. A reducted numberof insulin receptors in patients with Prader-Willisyndrome. Acta Endocrinol (Copenh) 1983; 104: 345-51.

48 Pipes P, Holm V. Weight control of children with Prader-Willi syndrome. JAm Diet Assoc 1973; 62: 520-4.

49 Pipes P. Nutritional management of children with Prader-Willi syndrome. In: Holm VA, Sulzbacher S, Pipes PL,eds. The Prader Willi syndrome. Baltimore: University ParkPress, 1981: 91-103.

50 Bistrian B, Blackburn G, Stanbury J. Metabolic aspects of aprotein-sparing modified fast in the dietary manage-ment of Prader-Willi obesity. N Engl J Med 1977; 296:774-9.

51 Soper R, Mason E, Printen K, Zellweger H. Gastric bypassfor morbid obesity in children and adolescents. J PediatrSurg 1975; 10: 51-8.

52 Selikowitz M, Sunman J, Pendergast A, Wright S.Fenfluramine in Prader-Willi syndrome: a double blind,placebo controlled trial. Arch Dis Child 1990; 65: 112-4.

53 Zlotkin S, Fettes I, Stallings V. The effects of naltrexone, anoral b -endorphin antagonist, in children with Prader-Willi syndrome. Jf Clin Endocrinol Metab 1986; 63:1229-32.

54 Butler M, Meaney J. An anthropometric study of 38individuals with Prader-Labhart-Willi syndrome. Am JMed Genet 1987; 26: 445-55.

55 Butler M, Meaney J. Standards for selected anthropometricmeasurements in Prader-Willi syndrome. Pediatrics 1991;88: 853-60.

56 Parra A, Cervantes C, Schultz R. Immunoreactive insulinand growth hormone responses in patients with Prader-Willi syndrome. J Pediatr 1973; 83: 587-93.

57 Van Vilet G, Bossons D, Rummens E, Robyn C, Wolter R.Evidence against growth hormone releasing factor defi-ciency in children with idiopathic obesity. Acta Endocrinol(Copenh) 1986; (suppl) 279: 403-10.

58 Tolis G, Lewis W, Verdy M, et al. Anterior pituitary func-tion in Prader-Labhart-Willi syndrome. 7 Clin Endocrinol

_Metab 1974; 39: 1061-6.59 Costeff H, Holm V, Ruvalcaba R, Shaver J. Growth

hormone secretion in Prader-Willi syndrome. ActaPaediatr Scand 1990; 79: 1059-62.

60 Lee P, Wilson D, Rountree L, Hintz R, Rosenfeld R. Lineargrowth response to exogenous growth hormone in Prader-Willi syndrome. AmJ7Med Genet 1987; 28: 865-71.



j.com/

Arch D


ownloaded from

http://adc.bmj.com/

the prader-willi syndrome - bmjand order of probes for prader-willi and angelman's syndromes,...

Documents