Prader-Labhart-Wil l i svndromeUrs E ho zer and Udo Me nhdfd t

Ped atrc Endocrinoogy Center (PEZZ), Zrlrch, Swtzerand (urs.e hozer@pezz.ch)

ln t roduct on

Prader Labhart-W I syndrorne (PWS), firstdescrbed n 1956 (Ftg 1)[1], s a compexmLrl tsystemic congenital d sorder assoc ätedwth an abnorma i ty of genet ic nrater ialon chrornosome l5 [2] t is character izedby reduced feta actvty, nfant i le hypotonia,and fai lure to thr ive n nfancy, folowedby the emergence of hyperphagra andthe development of severe obesity n ch ld-hood [2] Aso character ist c of PWS aredevelopmental and speech de ayvcognit ivedysfunction, cryptorch dism, hypogenita ism/hypogonadism, a panicular facäl appeaFance (narrow forehead, alrnond-shaped ey-"s,trangular mouth) that rs present at or soonaiter bir th, short stature, smal hands andieet, strabigmus, and behavora and psychoogical problems nclud ng compuls ve behavor and skin picking fFl j ls 2 and 3)12 41.Ihemutpe c nca abnormal i t ies associatedwth PWS suggest an underly ng dysfunct ionIn several hypolhalamic centers, ncudingthose concerned with energy balänce, tem-perature regulat on and secreton of p tuitaryhormones, ncuding qonadotropins, GH andpossib y ACTH [5-71.

The prevalence of PWS has been est-mated at 1 n 15,000-25,000 binhs [8, 9] Inone populat ion b.sed study in the l jn ted

Kingdom, the bfth incdence of PWS wasestmated at 1 in 22,000 and the death rateat 37o annLraly l9l . Unt i the eary 1980s,death due to cardioresp ratory comp icat onsol morbid obesity often occurred n m d tolate adolescence, but, n recent years, ifeexpectancy has been extend€d as mpfovedmethods ol management have been deve -oped. Respiratory comp catons, however,reman a malor source oi morb d ty, andnearly 50% of people wth PWS across alage qroups have a h story of fecurrent respi-ratory infect ons [10].

Hypothala m ic obesi ty andhypoact v l ty make i t d i f f icul t toprove GHD

Srnce the 1990s i t has been known that theGH response to nsu n, arg n ne, c onidineand L dopa in PWS were ow norrna orb unted, as were s eep- nduced GH secretionand 24 h integrated cH concentrat ions [3,1 11. Simple obes ty s also known to be assoc ated wth a decreased circulat ng concentraton of GH, änd spontaneous 24 h GHsecret on in PWS turned out to be low ands mrlar to that of hea thy obese controls [12].

Ftg 1: An.lreas Pradet, Alt:xtrLabhaft and Heinrich Willi.

Heinr ich Wil

Fig. 2 sit ntanth ald lnfa(tv/ it h .l itn n. l ht potanta

Ftq 3 fhrt€cn,lear oltl tvtns,the bal an the right std-. ,xith

, (

However, GH secretion in simple obesity isnot disiurbed but downregu ated, and isfully reversibie by weight loss. Thereforethere js some contToversy a5 to whetherinsufflcient GH secret on in PWS s the con-sequence of obesity or whether it representsgenuine GHD due to hypothalam c dysfunc-Iion (Table l).

In order to explore the presence orabsenceof GHD in PWS, we published in 2000 acomparison of the cLinical and biochemicaaspects of PWS with those of non-syndromalobesity and GHD without PWS [13]. The aimwas to identfy arguments for the presenceof genuine GHD as part of PWs. Decreasinggrowth velocity in spite of onset of obesity,reduced lean body mass in the presence adi-posity, sma I hands and feet, relatively lowIGF- and low insulin levels, as well as thedrarnatic effect of GH treatment on groMhvelocity were arguments that supported thepresence of hypothalam c GHD in PWs. Thearticle remains valid and s stilL cited anddownloaded. Even though ii rnay be difflcultult mately to prove GHD in PWS because of

. Ch ldren with PWs äe short in comrast tochiLdren with noniyndromal obesLly

. catch-upgmv!4h under human GH in PWs s@mparable to thar n GHD

. Hands and feet are shod in PWs, as they aß nGHD

' Lean ma$ is decrcased both in PWS and GHD,in contan to non-syndromal obesity

. IGF-I is orer in PWslhan in nomal obesity

. Insolln s€cretlon isdecrcäsed in PVVS, as in GHD

obesity-induced etfects on GH secretion,rnany papers continue to con{irm that GHDindependenty account5 for several featuresof PWS and that GH therapy dramatica lychanges the phenorype of PWS in childhood.Height and weight become normaland thereis a sustained impact on the net oss of bodyIaI (Fig. 4). äaweve\ GN therapy is unable toconrp etely norma lze body compostion eventhough fat mass decreases and lean massncreasesto some extentwith treatment [14].

Table 1: six aryunents to suppattthe presence of hypothalamicGHD in PWs [13].

Figure 4: DY,A scan. Left sidepatient with PWS, right side nor-mal obesity'. Fat in blue, nusclesin rcd. Despite of a huge anountaf fat in PWS, muscle mass is.learly reduced camparcd to nar-mal obesily in which nusclemass is known to be increasedconpated to nan-abese healthy

H g h q h h l o l 1 9 . r o I 2 0 l

Why do {fat mass and leanmass not normal ize w th Gltreatment?

Greaty red!ced spontaneous act iv i ty s oneof the ma n symptoms ot PWS and was mentoned n 1956 by Pfader et al . [1] Sponta-neous acrivity was Later found to be reducedto less than 50% of that of normal controlchi dren desprte ong-term GH treatment andn the absence of severe obeslty [15] Fromthe lact that dur ing tra n ng of the ca f mus-cle, caf crcumference increased, and calfsklnfo d decr-"ased siqnf icant ly n chidrenwith PWS as n healthy controls, we deducedthat musc e mass in PWS adequatelyresponds to enhanced physical actlvity. Thispo nts 10 d rninished spontaneous physcaact vty as the pr imary cause for decreasedTfusce mass in PWS In dddi lon, sponta-neous physical activty ncre.sed threetold atthe end of a tra n ng program [15]. l t seemstherefore possible to inarease musce massand spontaneous phys ca actvi ty andrnprove physca capacty by means oi ashort da ly physical tra ninq program.

Would gonadal hormonesncrease muscle mass fur ther?

As consequence of hypogonadism, sexuamäturation stops at mid puberty and lat massfuather lncreases durinq the eady stages 01

puberty, even with GH treatment. Theabsence of a pubertal qrowth spufi and annsuffcent increase n musce mass duringpuberty [3, 5] fudher reduce the a readydecreased energy expend ture [16, 17]. Nencehypogonadism contrbutes to lat accumulaton and morbid obesity due to the lack ofpubefta muscle mass accretion in PWS ma es.Only when hCG was added d d fat mass stabi-ze, most like y as a consequence ot the noF

ma zed muscle rnass aFlg. 5) [18].We chose hCG injectons to m mic physo'

ogca deveopment and prevent sgnif icantfluctlrations in testosterone evels, becauseanecdotal repofts suggened that behavoraproberns deteriorated during testosteronetreatment n PWS patents and ncreased therisk of psychotic exacerbation. However, nostudy hasexamlned whether hCG therapy car-ries a smaLler risk n this regard than teslos-terone. The m}th that gonadal rcplacementmay ead to more aggressive behavior andaggravate temper tantrLrms was nol con-f rmed by our observations. We think that Lna PWS boys with hypogonadism, adeqlaterep acement therapy shou d be staded whengonadal maturat on s absent or stops at theage of 13-14 years. However, it should beborne n mnd that adolescence Ls a crt icaperod in PWs [19], wth psychot ic episodesoccurr ing n oneff th of young aduts [20,211. Even in healthy men, testosterone rn hlghdoses may lnduce psychotic dsorders [22].Sex hormone replacement in PWS patientsmLrst therefore be under the contro ol anexperenced c nican

Figure s:hcrcasing nusde nassSDS in nale PWS patient aftelstanig hCG treatment.

I

hCG therapy (y€ars)

Norma izat ion of muscle massncreases quality of ife in PWS,but what else is neededho \ / ^n r l h^ rm^na ran : . a .nan i?

PWS is a complex syndrome. This is i l lstrated by the numerous spe.ialsts usualyrequ red to treat the same patient fable /r. tis very diff cu t and harmfu for pat ents andtheir fami ies i f any member of th s special storchestra pays hs or her melody wthoutregard for the other lnstruments and theirmelod es. Parents may feel bew ldered bythed fferent special sts and numerous separateappoinlments, by hearing many differentexp anations and sometmes contradictorycomments. Patients' qualty of life may besevere y impaired, du€ to imited famiyresources, by unnecessary inveltigations. lt isdes rable for one person to take charge andassume the role of case manager wilh thesupport of hs or her colLeagues and thechid3 fam ly.

ln most countries, pediatr ic endocrnoo-glsts have a privieged long-standing re aton-ship wlth the famiies and chidren with PW5.It lstherefore a duty of the endocr nologist toassume the eadershlp as case rnanager andprotect the chidren and the r fam les fromtoo many investigations and routine visits.S/he should also act as counselor to the famiiy and provde continuing education aboutPWs:s wel as explain each symptom in tscorrecl pathophysioloqical context.

f the parents have unrea istic expedrat ons,they shou d be told of this. At present, aladuts with PWS ive in care hones or wththeir parents, irrespectve of the r lQ and/orqLra i ty of care received durng chidhood.Unfortunate y, there are no aston sh ng newfindings that w I change thls inevitable out-come. lrrespective of treatment, even adultswth PWs must be supervised 24 h a day norder to prevent obesty. Parental unrealsticexpectatons may transform nto unrealst icexpectatons placed on the teenager withPWS and may promote a catastrophic out-come in the form of psychosis and depressonLt is hard wofk facing these fami ies in än honest way notjLrst once, but repeatedly, fromthe birth of the baby through 10 aduthood.c eary, only experienced cl lnicians should bein charqe offam l ieswith a PWS child, and notinexperenced doctors st I undergoing tran-inq. These vsts take rnuch more t ime anddemand much rnore experience, knowledgeand engagemenvempathy than, for instance,a vislt by an average ch d with isolated GHDwho s otherryse hea thy.

References1. Prad€r A, Labhart A, Wil H Ein syndrom von Ad-

positas, K einwuchs, Kryptörhsmuslnd Oigophren e nach myaton eartqem zlstand im Nelqeboren-al\et khweiz Med Wachenschr 1956: 86 1260 1

2 Holm VA, cassdy 58, Butler Mc et a PradeFwlisyndrome conansüs dagnostc dteria. tudlbtrtß1 991; 91 : 398-402.

GHD, gonadotrop n del c ency, hypoactivity. hypephagia, body compostion,

Scol osis, hypoa.t v ty, body compos tion

h{ant leeding dilfculties, d ag.osis

Psy.homotor d@elopment

Table tt: Conplexity of PwSdemands nany specialists ta care

' I q . lLgh t5 !o i9 , no 1 , 2011

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3 Bray GA, Dahms WT, Swerdloff RS et al. ThePrader-W isyndrome:a studyol40 patientsand arev ew of the itefature Mecli.ine (Baltinard 19a31621 5910.

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syndrome afiects inear groMh and body compos-r on favo! rab y. ada Padärr I 99ai a7: 2a-31

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14. Eholze. U, l 'A lemand D, van der s lu is le t a. Bodycomposition abnormaltier in children with Pr.de.Wl syndome and longterm eflects of qroMhhomonetherapy Horn AeJ2000;53 200 6.

15. Eholzer U, Nordman. Y 'Ail€mand D et a

lmproving body compos ton and phys cal aarivtyin Pfaderwi li syndrome. / Pediat 2403:142 1a8.

16. vän M I EA, Westerterp KR, Gerver Wl et ä1. Energyexpendlture at resl and durnq seep n ch drenwth Praderw I I syndrome s explained by bodycompositioi. Än ,r c/ln NLrr/ 2oa0; 71: 752-6.

17. SchoelLer D, Levitsky L, Band n L et al Energyexpend ture and body compositon n Präderw lisyndrone. Meäbollsz, 1988; 37: 1l5-20.

18 E holzer U, Grieser l, Schlumpf M, l'Alemand D.C inka efiecls ol veatment lor hypoqonad sm inmae adoescents with PfaderLabharr W li syndtone. Hoth Res 2041,6A: 178-84.

19.steinhausen HC, Eiholzer U, Hauffa BP, Main Z.Behaviolra and emotiona dsturba.ces in peoplew th PradeFW ll syrdrorne. ./ /rrel/ed Disabl Aes2O04t 4a:41 52

20. Boer N, Foland A, Whitti.gton I etal. Psychot c ll-ness in people with Praderwili syndrome du€ tochrcmosom€ l5 matenra ufipare,rtal d somy.larcet2002;359: 135 6.

21. Vogels A, De Hert N,l, Descheemaeker |\,,1J €tal Psy-chotk diso.deß n Praderwili syndrome. 4m -/Med Genet A2004,,127:23a 43.

22 Hartgens I Ku peß H. Efiects of andrcsen c-ana-bolic neroids in arh etes Sports Med 2004j 34:513 54.

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