PRADER WILLIJEV SINDROM DIJAGNOSTIKOVAN KOD …scindeks-clanci.ceon.rs/data/pdf/1821-1925/2017/1821-19251767120L.pdf · ce, denticija nepravilna. Visoko zasvođeno tvrdo nepce, nisko

Snežana Lešović1 PRADER WILLIJEV SINDROM DIJAGNOSTIKOVAN KOD EKSTREMNO GOJAZNE ADOLESCENTKINJE

Uvod: Nutritivna gojaznost je najčešći uzrok gojaznosti (95%) u detinjstvu i adolescenciji. Morbidna gojaznost (5%), koja obično počinje u ranom uzrastu, može biti prouzrokovana monogenskim poremećajima, različitim genetskim sidromima, endokrinim bole-stima, lezijama centralnog nervnog sistema ili jatrogenim uzrocima. Prikaz bolesnika: Prikazana je adolescentkinja uzrasta 13 godina koja je upućena na lečenje u Centar za prevenciju i lečenje gojaznosti kod dece i adolescenata u Specijalnoj bolnici „Čigota“ na Zlatiboru, zbog gojaznosti. Nizak rast i dizmorfična obeležja: lice sa uskim bifrontal-nim prečnikom, oči bademastog oblika, strabizam, sitne šake i stopala, kašnjenje u pubertetskom razvoju i zaostajanja u psihomotornom razvoju ukazala su na morbidnu gojaznost. Anamnestički podaci o hi-potoniji i otežanom hranjenju, zaostajanje u psihomotornom razvoju, gojaznost od treće godine pobudile su sumnju na Prader Willijev sin-drom. Sumnja na ovaj sindrom potvrđena je molekularnom analizom DNK, koja je ukazala na deleciju na dugom kraku 15q11.2.

Zaključak: Gojaznost, endokrinolpatije, zaostajanje u psihomotornom razvoju i poremećaji ponašanja kod osoba sa Prader Wiliijev sindromom zahtevaju kompleksno multidisciplinarno lečenje. Ranom dijagnozom i adekvatnim lečenjem sprečava se nastanak komplikacija i poboljšava kvalitet i dužina života kod obolelih.

Ključne reči: gojaznost, Prader Willijev sindrom, hormon rasta.

UVOD

Nutritivna gojaznost je najčešći uzrok gojaznosti (95%) u detinjstvu i adolescen-ciji. Važno je razlikovanje primarne, tj. egzogene ili nutritivne gojaznosti od retkih oblika sekundarne gojaznosti koji su prouzrokovani genetskim poremećajima, endo-

1 Specijalna bolnica za bolesti štitaste žlezde i bolesti metabolizma „Zlatibor“, e-mail: [email protected]

121MEDICINSKI GLASNIK – RADOVI

krinim bolestima, lezijama centralnog nervnog sistema ili jatrogenim uzrocima. Zbog sve većeg broja gojazne dece i adolescenata, sve je važnije što ranije identifikovati decu sa sekundarnom gojaznošću. Prader Willijev sindrom je najčešći uzrok genetske gojaznosti. Cilj rada je da se kroz prikaz slučaja ukaže na značaj blagovremenog di-jagnostičkog i terapijskog pristupa kod pacijenta kod koga je dijagnostikovan Prader Willijev sindrom.

PRIKAZ BOLESNIKA:

I. B je pacijentkinja primljena u Centar za prevenciju i lečenje gojaznosti kod dece i adolescenata u Specijalnoj bolnici „Čigota“ na Zlatiboru, u uzrastu od 12 godina i 10 meseci. Pacijentkinja je niskog rasta TV 143,00 cm (p 3,3, -1.84 SD), gojazna po opštem tipu, TM 66,4 kg, ITM 32,5 kg/m² (>p97, 2,95 SD), OS 96,00 cm (>p95), (grafikon 1 i 2). Po rečima majke, gojazna je od treće godine, ima hiperkalorijsku ishranu i hiperfagiju. Rekreativno trenira plivanje. Menarhu nije uspostavila. Učenica VI razreda i postiže slabiji uspeh. Razlikuje mirise, nije imala povrede glave, niti zapaljenje mozga.

Iz lične anamneze: Drugo dete iz druge kontrolisane trudnoće, porođaj u treminu, urednog toka. prirodnim putem. PTM 2950 g, PD 52 cm, AS 9. Po rođenju je bila hipotonična, otežano je sisala. Na prirodnoj ishrani do drugog meseca, nakon toga hranjena adaptiranom mlečnom formulom. Kontrolisana od strane fizijatra i ortopeda, do druge godine nosila Pavlikov aparat zbog luksacije kukova. Prohodala posle druge godine. Počela da govori posle treće godine i zbog poremećaja govora kontrolisana je kod logopeda. Zbog tepanja u školu krenula godinu dana kasnije. Alergije do sada nije ispoljavala. Redovno je vakcinisana za uzrast.

Podaci iz porodične anamneze: TV oca 173,9 cm, TV majke 167,8 cm, ciljna visina –(CV) 164,3 cm (P50-75). Majka je menarhu uspostavila u 16 godini. Starija sestra uzrasta 18 godina visoka je 166 cm. Baka po ocu i deda po majci su gojazni, a baka po majci i deda po ocu imaju hipertenziju.

Objektivnim pregledom postoji eumetabolično stanje, početna akantoza na vratu, sedefaste strije na dojkama i bokovima. Zube menja, ima sve šesti-ce, denticija nepravilna. Visoko zasvođeno tvrdo nepce, nisko pozicionirane ušne školjke, trouglaste usne. Štitasta žlezda normalne veličine i konzisten-cije, bez palpabilnih nodusa. Nalaz na srcu i plućima uredan, normotenzivna, jetra i slezina se ne palpiraju, nema edeme. Dojke uvećane na račun masnog tkiva. Aksilarna kosmatost A2. Male šake i stopala. IV metakarpalne kosti šake su kratke. Spoljašnje genitalije su ženskog tipa, P3. Neurološki nalaz je uredan.

122 SIMPOZIJUM – GOJAZNOST JE BOLEST

Grafikon 1. Telesna visina (TV)

Grafikon 2. Indeks telesne mase (ITM)

Od dopunskih dijagnostičkih procedura obavljeni su:Laboratorijske analize: negativan zapaljenski sindrom, bez anemije, gli-

kemija, lipidogram, hepatogram, elektroliti – referentne vrednosti. Hormon-ske analize: Kortizol u 8 h 731 a u 18 h 210 nmol/l, FSH 0,4 IJ/l, LH <0,14


IJ/l, prolaktin 228 mIJ/l, estradiol 6 pmol/l, TSH 3,1 mU/l, fT4 13,5 pmol/l. Radiografija leve šake i doručja: Koštana zrelost odgovara uzrastu devojčice od oko 12,5 godina. Nalaz psihologa: Intelektualni razvoj disharmoničan, ukupno funkcio-nisanje u kategoriji lake mentalne insuficijencije IQT 68 (verbalni IQ 82 neverbalni IQ 58). Ponašanje i emotivni razvoj odgovra mlađem uzrastu.

Otpuštena 14. dana pri čemu je telesnu masu smanjila za 2,1 kg i obim struka za 4 cm. Zbog anamnestičkih podataka, ekstremne gojaznosti, niskog rasta i prisutnih stigmata koji upućuju na Prader Willijev sindrom upućena u tercijarnu ustanovu.

Nakon dve godine, kada ima 14 godina i 11 meseci, ponovo se javlja na pregled. Po rečima majke, nije ispitivana u tercijarnoj ustanovi. Zbog niskog rasta TV 146,2 cm (ispod P3), ekstremne gojaznosti ITM 32,3 kg/m², problema u ponašanju, hiperin-sulinemije tokom OGTT i neophodne genetske analize ponovo upućena u tercijarnu ustanovu. Učinjena ispitivanja nakon hospitalizacije:

Ultrazvučni pregled abdomena: nalaz uredan. Pregled oftalmologa: Strabisam. ORL pregled: nalaz uredan. Zbog sekundarnog hipogonadizma upućena ginekologu, nakon čijeg pregleda je u dogovoru sa roditeljima, započeta indukcija puberteta. Ko-lonidisnski test je ukazao na nedostatak hormona rasta, ali zbog dostignute koštane zrelosti (14,5 godina) nije započeto lečenje hormonom rasta. Molekularna analiza DNK je ukazala na deleciju karakterističnu za Prader Willijev sindrom: 15q11.2(P064-c). Ima redovne kontrole kod endokrinologa i ginekologa i terapiju: Metformin a 500 mg 1+0+1 tableta i estradiol.

DISKUSIJA

Prader Willijev sindrom prvi put je opisao 1887. godine J. Langdon Down, ali sindrom ostaje nepoznat do 1956. godine, kad su A. Prader, A. Lambhart i H. Willi objavili prikaz devet osoba istih kliničkih osobina (1). Sindrom se ispoljava mišićnom hipotonijom u uzrastu odojčeta, poteškoćama u hranjenju, niskim rastom, sitnim ša-kama i stopalima, hipogonadizmom i ekstremno izraženom hiperfagijom. Hiperfagija uslovljava razvoj patološke gojaznosti koja je glavni uzrok nastanka dijabetesa tipa 2, koji se kod oko 10% bolesnika dijagnostikuje u adolescentnom uzrastu. Deca su niskog rasta zbog nedostatka hormona rasta, hipogonadalna su i većinom infertilna, a mogu razviti i hipotireozu i adrenalnu insuficijenciju. Većina bolesnika ima kognitivnu disfunkciju i zaostajanje u razvoju. Dizmorfična obeležja u kliničkoj slici prisutna su kod većine bolesnika (2). Pacijenti imaju karakteristično lice sa uskim bifrontal-nim prečnikom, tanku gornju usnu i spuštene uglove usana, oči bademastog oblika, oskudnu, gustu pljuvačku i hipoplastičnu gleđ. Strabizam ima 60–70%, a skoliozu 40–80% obolelih (3).

Incidencija bolesti u Europi iznosi 1: 30.000 živorođene djece. Kod oko 65–70% pacijenata sindrom je prouzrokovan delecijom ili strukturnim poremećajem na dugom


kraku hromozoma 15q11-13 i to onom koji je poreklom od oca. Drugi hromozomski poremećaj koji dovodi do ovog sindroma je postojanje dve kopije maternalnog hro-mozoma 15 (maternalna uniparentalna disomija) i javlja se kod 25% obolelih, a 5% obolelih ima poremećaje metilacije (4).

Zbog hipotonije, slabe fizičke aktivnosti i smanjene mišićne mase smanjena je i potrošnja energije, pa su promene u telesnoj kompoziciji kod obolelih prisut-ne rano, već kod odojčeta. Većina dece s Prader Willijevim sindromom kasni u psihomotornom razvoju (sede tek sa 12 meseci, prohodaju sa 24 meseca, posle 36. meseca usvajaju desetak reči). Intelektualno zaostajanje postaje upadljivo u školskom uzrastu (5).

U oba pola gojaznost je prvenstveno centralna (6). U osoba s Prader Willije-vim sindromom dominira nedostatak osećaja sitosti, nivo grelina je trajno povišen i to pre razvoja hiperfagije. Povećanje telesne mase nastaje obično između 2,1 i 4,5 godine. Hiperfagija i dalji porast telesne mase razvijaju se između 4,5–8 godina i nastavljaju se, uz gubitak osećaja sitosti, pa dolazi do nastanka morbidne gojaznsoti. Ukoliko se ne kontroliše ishrana, telesna masa kod adolescenata može biti veća od 150 kg.

Klinički i dijagnostički kriterijumi predstavljeni numeričkom skalom korišćeni su za dijagnozu ovog sindroma pre dostupnosti genetske analize. (Tabela 1) Skala je laka za upotrebu i sadrži 6 velikih i 11 malih kriterijuma, od koji svaki vredi 1, odnosno 1/2 boda. Za kliničku dijagnozu ovog oboljenja potrebno je 5 bodova, od kojih 4 iz grupe velikih kriterijuma za uzrast do tri godine. U starijih od tri godine potrebno je 8 bodova, od toga 5 iz grupe velikih kriterijuma (7).

Tabela 1. Dijagnostički kriterijumi za Prader Willijev sindrom

Veliki kriterijumi (1 bod) Mali kriterijumi (2 boda)

Neonatalna/ hipotonija i slabo sisanje Smanjena fetalna pokretljivost

Poteškoće pri hranjenju, nenapredovanje Problemi u ponašanju

Dobijanje u težini 1–6 godine, gojaznost, hiperfagija Apneja u snu

Dizmorfične crte lica Nizak rastHipoplazija spoljašnjih genitalija, izostali ili nepotpuni pubertet

Svetlija kosa, oči i ten u odnosu na ostale članove porodice

Zaostajanje u psihomotornom razvoju Male šake i stopala

Uske šake, ravna granica ulne

Strabizam, miopija

Gusta, viskozna pljuvačka

Poremećaji artikulacije govora

Čupkanje kože


Kliničke odlike i endokrinološki poremećaji

Nizak rast se često uočava već tokom ranog detinjstva. Nizak rast, goja-znost, telesni sastav sa dominacijom masnog tkiva, nizak nivo insulina sličnog faktora rasta i slab odgovor hormona rasta u farmakološkim testovima stimula-cije, jasno upućuju na deficit hormona rasta. Niskom rastu doprinosi i izostanak pubertetskog ubrzanog rasta zbog hipogonadizma. Bez terapije hormonom rasta konačna visina muškaraca je prosečno 155 cm a žena 148 cm (8).

Osobe sa Prader Willijevim sindromom imaju hipogonadizam, hipoplaziju spoljašnjih genitalija, izostali ili kasni pubertet i infertilnost. Kriptorhizam ima 80–90% obolelih. Hipogonadizam je posledica disfunkcije hipotalamusa, ali i primarnog oštećenja gonada (9).

Centralni hipotiroidizam sa niskim slobodnim tiroksinom (fT4) i normal-nim ili sniženim tireotropnim hormonom (TSH) ima oko 25% dece sa Prader Willijevim sindromom.

Disfunkcija hipotalamusa može dovesti do centralne insuficijencije nadbu-brežnih žlezda i iznenadne smrti tokom akutnih bolesti. Učestalost insuficijencije nadbubrežnih žlezda je 14–60%. Procena funkcije nadbubrežnih žlezda uklju-čuje određivanje kortizola i ACTH u 8 h. Nivo kortizola >500 nmol/l potvrda je uredne sinteze i izlučivanja kortizola (10).

Šećernu bolest tipa 2 ima 25% odraslih bolesnika sa Prader Willijevim sindrom.

Poremećaji ponašanja prisutni su kod 70–90% osoba sa ovim sindromom i opisuju se kao izlivi besa, tvrdoglavost, kompulzivno-opsesivno ponašanje, a česti su i poremećaji iz autističnog spektra.

Disfunkcija hipotalamusa dovodi do nastanka centralnih apneja i poremećaja sna. Opstruktivne apneje tokom spavanja posledica su gojaznosti, hipertrofije tonzila i neuromuskularne slabosti. Polisomnografsko snimanje potrebno je učiniti pre uvođenja terapije hormonom rasta.

Disfunkcija hipotalamusa uzrok je nestabilnih temperatura, visokog praga za bol i nemogućnosti povraćanja. Time je otežana dijagnoza akutnih bolesti. Poseban oprez potreban je kod prejedanja koje može dovesti do gušenja, di-latacije želuca s nekrozom i perforacijom. Stopa smrtnosti obolelih od Prader Willijevog sindroma u uzrastu 6–56 godina iznosi 3% godišnje (4). Najveća smrtnost je kod dece do 5. godine života, a najčešći uzroci smrti su inflamacija disajnih puteva i aspiracioni sindrom. U adolescentnoj i odrasloj dobi visoka smrtnost posledica je uglavnom komplikacija uzrokovanih gojaznošću (11). Iznenadnom smrtnom ishodu doprinose i poremećaji disanja u spavanju, cen-tralnog ili opstruktivnog tipa.


Terapijske mogućnosti

Lečenje bolesnika s Prader Willijevim sindromom zahteva multidisciplinar-ni tim koji uključuje pedijatra, genetičara, endokrinologa, dijetetičara, fizijatra, logopeda, psihologa, psihijatra, pulmologa i prema potrebi druge supspecijaliste. Cilj lečenja je da se spreči nastanak morbidne gojaznosti i komorbiditeta. Osnov lečenja je kontrolisana uravnotežena hipokalorijska ishrana, supstitucija hormonom rasta uz nadoknadu l-tiroksina, polnih hormona i glikokortikoida u slučaju da se razvije njihov nedostatak. Potrebno je podsticati psihomotorni razvoj bolesnika i lečiti komplikacije.

Od trenutka potvrde dijagnoze, ne čekajući razvoj tipične kliničke slike, važno je planirati uravnoteženu ishranu. Važna je količina, ali i izbor namirnica koje treba da imaju i manju energetsku vrednost. Od uzrasta odojčeta do odrasle dobi telesnu masu i ITM treba održavati između 25. i 75. percentila. Za procenu nutritivnog statusa koriste se grafikoni rasta za decu s Prader Willijevim sindro-mom. Raspored i sastav obroka moraju biti planirani, pa je potrebno obezbediti 8 do 11 kcal na centimetar telesne visine. Kalorijski unos može biti veći u osoba koje su na terapiji hormonom rasta i ako su fizički aktivni 30–60 minuta na dan, a kod odraslih do 1800 kcal na dan.

Hiperfagija je glavni poremećaj Prader Willijevim sidromom i prisutna je tokom celog života. Za sada nema farmakološke terapije, a ne postoji ni mogućnost hirurškog zbrinjavanja ovog problema. Svakodnevna fizička aktivnost prilagođena uzrastu i nutritivnom statusu povećava mišićnu masu i snagu, potrošnju energije time doprinosi kontroli telesne mase.

Od ranog detinjstva važna je procena i praćenje psihomotornog razvoja. Fi-zikalna terapija je značajna za jačanje mišićnog tonusa i snage, a kod bolesnika sa poremećajem u razvoju govora potrebna je logopedska podrška.

Terapija hormonom rasta dovodi do ubrzanja rasta, postizanja poželjne visine, a lečenje dovodi do povećanja mšične mase, snage i tonusa mišića, pri čemu se povećava fizička aktivnost i dolazi do redukcije masnog tkiva (12). Optimalno vreme uvođenja terapije hormonom rasta nije definisano, ali prema mišljenju veći-ne autora terapiju je potrebno započeti pre nastanka gojaznosti, oko druge godine života. Početna doza hormona rasta iznosi 0,5 mg/m2/dan, uz postepeno povećanje do 1 mg/m2/dan, i ta doza osigurava pozitivan uticaj na telesnu kompoziciju.

U dogovoru sa roditeljima indukcija puberteta može započeti oko 12. godine kod devojčica i oko 14. godine kod dečaka. Lečenje dovodi do postepenog razvoja sekundarnih polnih karakteristika, povećanje mišićne mase i mineralizacije kostiju, što sve dovodi do unapređenja zdravlja i kvaliteta života. Kod dečaka se lečenje započinje enantatom testosterona 50 mg intramuskularno svake četiri nedelje i doza se postepeno povećava za 25–50 mg svakih šest meseci. Doza za odrasle


osobe iznosi 250 mg svake dve nedelje. Doza leka se usklađuje s bolesnikovim raspoloženjem i ponašanjem. Poželjna je primena najniže doze koja osigurava klinički i biohemijski eugonadizam. Kod devojčica se za indukciju puberteta daje 17β estradiol 0,25 mg/dan oralno ili 14 μg/dan transkutano flasterom dva puta nedeljno. Dve godine posle primene estrogenske terapije, ili nakon uspostavljanja menstrualnog krvarenja, da bi se sprečila hiperplazija endometrijuma, u lečenje se dodaje progesteron 200 mg/dan oralno, 10–14. dana ciklusa (13).

Razvoj hipotireoze češći je u ranom detinjstvu, pa kontrolu funkcije štitaste žlezde određivanjem fT4 i TSH treba započeti od trećeg meseca života, i pored urednog rezultata neonatalnog skrininga. Kontrole TSH potom ponavljati jedanput godišnje, posebno u bolesnika koji su na terapiji hormonom rasta. U slučaju razvoja hipotireoze uvodi se terapija levotiroksinom. Adrenalnu insuficijenciju je potrebno blagovremeno dijagnostikovati i obolele lečiti hidrokortizonom (Tabela 2).

Tabela 2. Lečenje bolesnika sa Prader Willijevim sindromom

Uravnotežena ishrana

Odojče 0–12 meseca: uredan rast, TM 25–75 percentila za Prader Willijev sin-dromKada TM počne rasti, uvesti ograničenja u ishrani – oko 10 kcal/ cm TV Ukupni kalorijski unos čine: 45% ugljeni hidrati, 25% belančevine i 30% mastiFizička aktivnost: 30–60 minuta na danRekombinantni humani hormon rasta (rhHR) – početna terapija 0,5 mg/m2, postepeno povećati do 1 mg/m2 subkutano uvečeIndukcija pubertetaDečaci oko 14. godine (u dogovoru s roditeljima) testosteron Djevojčice oko 12. godine (u dogovoru s roditeljima)17β estradiol u tabletama ili transkutano, uz dodatak progesteronaHipotireoza – supstitucija l-tiroksinom 1–2 μg/kg na danAdrenalna insuficijencija – supstitucija hrokortizonom 10 mg/m2/dan podeljeno u tri doze, pri stresnim situacijama daje se 2–3 puta veća dozaPodsticanje psihomotornog razvoja – fizikalna terapija, psihoterapija, vežbe kod logopeda

ZAKLJUČAK

Ekstremna gojaznost, endokrinolpatije, zaostajanje u psihomotornom razvoju i poremečaji ponašanja kod osoba sa Prader Willijevim sindromom zahtevaju kom-


pleksno multidisciplinarno lečenje. Terapijske mogućnosti za obolele su ograničene, posebno, ako se oboljenje kasno dijagnostikuje. Primer naše pacijentkinje, kod koje je Prader Willijev sindrom dijagnostikovan u 15-oj godini to potvrđuje. Ranom dijagnozom i adekvatnim lečenjem sprečava se nastanak komplikacija i poboljšava kvalitet i dužina života kod obolelih.

LITERATURA:

Prader A, Labhart A, Willi H. Ein syndrom von adipositas, klainwuchs, kryptorchismus 1. und oligophrenie nach myatonieartigen zustand im neugeborenenalter. Schweiz Med Wochenschr. 1956; 6: 1260–1261. Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical 2. genetic and endocrine fi ndings. J Endocrinol Invest. 2015; 38: 1249–1263.Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 3. 2011; 14: 10–26.Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Pra-4. der-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001; 34: 917–23.Miller JL. Approach to the child with Prader-Willi syndrome. 5. J Clin Endocrinol Metab. 2012; 97: 3837–3844.6. Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome. 7. Am J Med Genet Part A. 2011; 155A: 1040–9.Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic 8. criteria Pediatrics. 1993; 91: 398–402. Angulo MA, Castro-Magana M, Lamerson M, Arquello R, Accacha S, Khan A. Final 9. adult height in children with Prader Willi syndrome with and withaut human growth hormone treatment. Am J Med Genet. 2007; 143A: 1456-61.Siemensma EP, de Lind van Wijngaarden RF, Otten BJ, de Jang FH, Hokken-Koelega 10. AC. Testicular failure in boys with Prader-Willi syndrome: longitudinal studies of reproductive hormones. J Clin Endocrinol Metab. 2012; 97: E452–9. Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics 11. and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016; 12: 136–66. Whitman BY, Myers SE. Prader-Willi syndrome and growth hormone therapy: take 12. a deep breath and weigh the data. J Pediatr. 2013; 162: 224–226. Carrel A, Allen D, Myers S, Whitman B. Growth hormone improves body composition, 13. fat utilization, physical strength and agility, and growing in Prader-Willi syndrome: a controlled study. J Pediatr. 1999; 215–21. Crino A, Schisffi ni R, Ciampalini P, et al. Genetic Obesity Study Group of Italian 14. Society of Pediatric endocrinology and diabetology (SIEDP). Hipogonadisam and pu-bertal development in Prader-Willi syndrome. Europ J Pediat. 2003; 162: 327–33.

Snežana Lešović1 PRADER WILLY’S SYNDROME DIAGNOSED IN EXTREMELY OBESE FEMALE ADOLESCENT

Introduction: Nutritional obesity is the most common cause of obesity (95%) in childhood and adolescence. Morbid obesity (5%), which usually begins at an early age, can be caused by monogenic disorders, various genetic syndromes, endocrine diseases-disorders, central nervous system lesions or iatrogenic causes.

Presentation of the patient: A female adolescent aged 13 is presented who was due to obesity referred to the Center for the Prevention and Treatment of Obesity in children and adolescents at the Special Hospital “Cigota” at Mt. Zlatibor. Low height/stature and dysmorphic features: a face with a narrow bifrontal diameter, almond-shaped eyes, strabismus, small hands and feet, delay in puberty development and lagging in psyc-homotor development have indicated the morbid obesity. Anamnestic data on hypotonia and difficulty in feeding, psychomotor lagging behind, obesity since the third year of age, triggered a suspicion of Prader Willy’s syndrome. The suspicion of this syndrome was confirmed by a molecular DNA analysis which indicated a deletion on the long arm 15q11.2.

Conclusion: Obesity, endocrinolopathies, retardation in psychomotor development and behavioral disorders in people with Prader Willy’s syndrome require a complex multidisciplinary treatment. Early diagno-sis and adequate treatment prevent the occurrence of complications and improve the quality and length of life of the patients.

Key words: obesity, Prader Willy’s syndrome, growth hormone

INTRODUCTION

Nutritional obesity is the most common cause of obesity (95%) in childhood and adolescence. It is important to distinguish the primary, i.e. exogenous or nutritional obesity from rare forms of secondary obesity caused by genetic disorders, endocrine

1 Special Hospital for thyroid gland diseases and metabolic diseases Zlatibor, e-mail: [email protected]


diseases, central nervous system lesions, or iatrogenic causes. With the increase of obesity in children and adolescents, it is increasingly important to identify children with secondary obesity as early as possible. Prader Willy’s syndrome is the most common cause of genetic obesity. Through the case study, the aim of this paper is to point out the importance of a timely diagnostic and therapeutic approach in a patient diagnosed with Prader-Willy’s syndrome.

PRESENTATION OF THE PATIENT:

I. B is a patient who was admitted at the Center for Prevention and Treatment of Obesity in Children and Adolescents at the Special Hospital “Cigota” at Mt. Zlatibor at the age of 12 years and 10 months. The patient is obese by a general type, with the body mass of 66. 4 kg, BMI 32.5 kg/m² (> p97, 2.95 SD), waist size of 96.00 cm (> p95), and low body height (short stature) of 143.00 cm (p3.3, -1.84 SD) (Graphs 1 and 2). According to the mother, the girl has been obese since the age of three, she has a hypercaloric diet and hyperphagia. She does a recreational swimming training. She has not established a menstruation. She attends the sixth grade of primary school and achieves poor results (2). She distinguishes odors, has not had any head injuries, nor brain inflammation.

From a personal history: she is the second child from the second controlled pregnancy, the labor was in due time and of a regular flow, in a natural way. Body mass at birth was 2,950 g, height 52 cm, AS 9. After birth, she was hypotonic, she was breast fed with difficulty. She had natural nutrition until the second month, then fed with an adaptive milk formula. Controlled by a physiatrist and orthopedic surgeon, by the second year she had been wearing the Pavlich’s apparatus due to the luxation of the hips. She started to walk after the second year. She began to speak after 3 years of age and because of a speech disorder, she was controlled by a speech therapist. Because of her poor speech, she started to go to school one year later than normal. Allergies so far have not been shown. She was vaccinated regularly for her age.

Family history: The body height of her father is 173.9 cm, of her mother is 167.8 cm, C height 164.3 cm (P50-75). The mother got the menstration at the age of 16, the elder sister is 18 years old, she is 166 cm tall. Her father’s mother and mother’s father are obese, and mother’s mother and father’s father have hypertension.

An objective examination has shown that there is an eumetabolic condition, an initial acanthosis on her neck, nacrous stretch marks on the breasts and hips. The teeth have been naturally changed, she has all teeth sixs, the dentition is irregular. A high shaped hard palate, low positioned earlobes, triangular lips. The thyroid gland is of the standard size and consistency, without palpable noduses. The finding related to the heart and lungs is normal, normotensive, liver and spleen are not palpable, there are


no edemas. Breasts are enlarged due to fatty tissue. Axial hairness A2. Small hands and feet. IV metacarpal bones of hands are short. External genitals are of a female type, P3. Neurological finding is normal.

Graph 1. Body height

Graph 2. ITM

The following additional diagnostic procedures were performed:Laboratory analyses: negative inflammatory syndrome, without anemia, glyce-

mia, lipidogram, hepatogram, electrolytes -referential values. Hormone analysis: Cortisol at 8 a.m. was 731 and at 6 p.m. it was 210 nmol / l, FSH 0.4 IJ / l, LH <0.14 IJ / l, prolactin 228 mLi / l, estradiol 6 pmol / l, TSH 3.1 mU / L, fT4 13.5 pmol/l.


Radiography of the left hand and low arm: Bone maturity corresponds to the age of a girl of about 12.5 years. Finding of a psychologist: Intellectual development is disharmonic, the overall functioning is in the Light Mental Illness Category IQT 68 (verbal IQ 82 Non-verbal IQ 58). Behavior and emotional development correspond to the younger age.

She was released on the 14th day, the body weight was decreased by 2.1 kg and the waist size by 4 cm. Due to anamnestic data, extreme obesity, low height and present stigmata which indicate to Prader Willy’s syndrome, she was referred to a tertiary institution.

In two years, when she was 14 years and 11 months old, she was to check in for an examination again. According to the mother, she was not examined at the tertiary institution. Due to the low body height of 146.2 cm (below P3), extreme obesity, BMI of 32.3 kg/m², behavioral problems, hyperinsulinemia during OGTT and necessary genetic analysis, she was referred to a tertiary institution again. Post-hospitalization tests were done:

Ultrasonic examination of the abdomen: the finding was normal. The examination was done by an ophthalmologist: Strabismus. The examination was done by otorhyno-laryngolost: the finding was normal. Molecular DNA analysis revealed the deletion characteristic of the Prader Willy’s syndrome: 15q11.2 (P064-c). Due to secondary hypogonadism, she was referred to a gynecologist and after the examination and in agreement with the parents, the induction of puberty was started up. The colonidine test indicated a lack of growth hormone, but as she reached skeletal maturity (14.5 years), no growth hormone treatment was initiated. There are regular controls by an endocrinologist and gynecologist and the therapy: Metformin a 500 mg 1 + 0 + 1 tablets and estradiol.

DISCUSSION

Prader-Willy’s syndrome was first described in 1887 by J. Langdon Down, but the syndrome remains unknown until 1956 when A. Prader, A. Lambhart and H.Willy published a presentation about nine people who show the same clinical characteristics (1). The syndrome is manifested with muscle hypotonicity at the age of infants, difficulty in feeding, a short stature, small hands and feet, hypogonadism and extremely expressed hyperphagia. Hyperphagia conditions the development of pathologic obesity, which is the main cause of diabetes type 2, which is in about 10% of patients diagnosed in the adolescent period. The children of short stature due to growth hormone deficiency, they are hypogonadal are mostly infertile, and they also might develop hypothyroidism and adrenal insufficiency. Most patients have cogni-tive dysfunction and developmental lag. Dysmorphic features in the clinical picture are present in most patients (2). The patients have a characteristic face with a narrow


bifrontal diameter, a thin upper lip and lowered angles of lips, almond-shaped eyes, sparse, thick saliva and hypoplastic look. About 60-70% of the diseased have strabismus and 40-80% have scoliosis (3).

The incidence of the disease in Europe is 1:30 000 live-born children. In about 65-70% of the patients, the syndrome is caused by deletion or structural disorder on the long arm of the chromosome 15q11-13 on the one that originates from the father. Another chromosomal disorder that causes this syndrome is the existence of two copies of the maternal chromosome 15 (maternal uniparental disomy), occurring in 25% of patients, and 5% of patients are with the disorder of methylation (4).

Due to hypotonia, a poor physical activity and decreased muscle mass, energy consumption is reduced, so changes in body composition in patients are present early, already at the infant age. Most of the children with Prader Willy’s syndrome are late in psychomotor development ( they sit only when they are 12 months old, they start to walk when they are 24 months old, after 36 months they adopt a dozen words). Intellectual lagging behind is becoming noticeable at the school age.(5).

In both genders, obesity is primarily central (6). In people with Prader Willy’s syndrome, a lack of sense of satiety is dominant, the level of grelin is permanently elevated before the development of hyperphagia. Weight gain usually occurs between 2.1 and 4.5 years. Hyperphagia and further increase in body weight develop between 4.5 and 8 years and continue, with a loss of sense of satiety, and it comes to the onset of morbid obesity. If a diet is not controlled, the body mass of adolescents may be greater than 150 kg.

The clinical and diagnostic criteria presented by the numerical scale were used to diagnose this syndrome before the availability of a genetic analysis. (Table 1). The scale is easy for use and contains 6 large and 11 small criteria, of which each is valued 1 or 1/2 points. For the clinical diagnosis of this disease, 5 points are needed, of which 4 are from the gupe of large criteria for the age of up to three years. In older than three years, 8 points are needed, of which 5 from the group of large criteria (7).

Table 1. Diagnostic criteria for Prader Willy’s syndrome

Large criteria (1 point) Small criteria (2 points)

Neonatal/ hypotonic and poor breast feeding Reduced fetal motility

Difficulties in feeding, no progress in development Behavioral problems

Weight gain between the age of 1-6; obesity, hyperphagia Apnea in sleep

Dysmorphic face features Low stature

Hypoplasia of external genitalia, lack of or incomplete puberty

Lighter hair, eyes and tan in comparison to other family members


Lagging behind In u psychomotor development Small hands and feet

Narrow hands, flat border of ulna

Strabismus, myopia

Dense, viscose saliva

Disorders in speech articulation

Skin twitching

Clinical features and endocrinological disorders

Low stature/growth is often observed during early childhood. Low stature, obe-sity, body composition with dominant fatty tissue, low levels of insulin-like growth factor and poor growth hormone response in pharmacological stimulation tests, cle-arly indicate a growth hormone deficit (22). Low stature is caused by the absence of puberty rapid growth due to hypogonadism. Without a growth hormone therapy, the final height on average of men is 155 cm and women 148 cm (8).

People with Prader Willy’s syndrome have hypogonadism, external genital hypoplasia, absent or late puberty and infertility. 80-90% of the patients have cryp-torchism. Hypogonadism is a consequence of dysfunction of the hypothalamus, but also of primary damage to the gonads (9).

About 25% of the children with Prader Willy’s syndrome have central hypot-hyroidism with low free thyroxine (fT4) and normal or lowered thyrotropic hormone (TSH). Dysfunction of the hypothalamus can lead to central insufficiency of adrenal glands and sudden death during acute illnesses. The incidence of adrenal gland insuffi-ciency is 14-60%. Assessment of the adrenal gland function includes the determination of cortisol and ACTH at 8 a.m. The cortisol level > 500 nmol / l confirms the normal synthesis and excretion of cortisol. (10).

25% of the adult patients with PraderWilly’s syndrome have diabetes of type 2.Behavioral disorders are present in 70-90% of the people with this syndrome

and are described as anger outbreaks, stubbornness, compulsive-obsessive behavior, and disorders from the autistic spectrum are often.

Dysfunction of the hypothalamus leads to the formation of central apnea and sleep disturbances. Obstructive sleep apnea results from obesity, tonsillitis hypertrophy and neuromuscular weakness. Polysomnographic recording should be done prior to the introduction of growth hormone therapy.

Dysfunction of the hypothalamus is caused by unstable temperatures, a high threshold for pain and inability to vomit. By that, a diagnosis of acute illnesses is made difficult. Particular caution is required in overeating which can lead to choking, dilatation of the stomach with necrosis and perforation. The death rate of the patients with PWS at the age of 6-56 years is 3% per year. The highest mortality is in children


up to 5 years of age, and the most common causes of death are respiratory inflammation and aspiration syndrome. In adolescence and adulthood, a high mortality rate is due mainly to complications caused by obesity (11). Breathing disorders during sleep, of a central or obstructive type, also contribute to sudden death.

Therapeutic possibilities

The treatment of patients with PWS requires a multidisciplinary team that inclu-des a pediatrician, geneticist, endocrinologist, dietician, physiatrist, speech therapist, psychologist, psychiatrist, pulmologist and, if necessary, other subspecialists. The objective of the treatment is to prevent the onset of morbid obesity and comorbidity. The basis of treatment is a controlled balanced hypocaloric diet, substitution with a growth hormone with the addition of l-thyroxine, sexual hormones and glycocorticoids in case that their deficiency is developed. It is necessary to stimulate the psychomotor development of the patients and to treat complications.

From the moment of confirmation of the diagnosis, without waiting for the deve-lopment of a typical clinical picture, it is important to plan a balanced diet. A quantity is important, but also a selection of foods that should have less energy values. From the age of infants to adults, the body mass and BMI should be maintained between the 25th and 75th percentile. Growth charts are used to assess the nutritional status for children with PWS. The timetable and the amount of meals must be planned, so it is necessary to provide 8 to 11 kcal per centimeter of the body height. Caloric intake may be higher in people who are on growth hormone therapy and if they are physically active for 30-60 minutes per day, and in adults up to 1800 kcal per day.

Hyperphagia is the main disorder of PWS and is present throughout the whole life. For now there is no pharmacological therapy, and there is no possibility of sur-gical treatment of this problem. Daily physical activity adapted to age and nutritional status increases muscle mass and strength, energy consumption and thus contributes to the control of the body mass.

Since early childhood, the assessment and monitoring of psychomotor develo-pment are important. Physical therapy is important for strengthening muscle tonus and strength, and in with speech-impaired patients, a speech therapy is needed.

The therapy with a growth hormone results in accelerating of growth, achieving the desired height, and the treatment results in a muscle mass increase, he increase of muscle strength and tonus, while increasing the physical activity and reducing fat tissue (12). The optimum time for the administration of growth hormone therapy is not defined, but according to the majority of authors, the therapy should be started prior to the onset of obesity, around the second year of life. The initial growth hormone dose is 0.5 mg / m³/ day with a gradual increase of up to 1 mg / m² / day, as this dose provides a positive effect on the body composition.


In agreement with parents, puberty induction can be started at the age of about 12 years in girls and about 14 years in boys. The treatment leads to a gradual deve-lopment of secondary sexual characteristics, an increase in muscle mass and bone mineralization, which results in the improvement of health and quality of life. In boys, the treatment begins with testosterone 50 mg intramuscularly every four weeks and the dose is gradually increased by 25-50 mg every six months. The dose for adults is 250 mg every two weeks. The dose of the medicine is harmonized with the patient’s mood and behavior. It is desirable to apply the lowest dose that ensures clinical and biochemical eugonadism. For induction of puberty, girls are given 17β estradiol 0.25 mg / day orally or 14 μg / day transcutaneously with an adhesive plaster twice a week. Two years after the application of the estrogen therapy or after the establishment of menstrual bleedingin order to prevent endometrial hyperplasia, progesterone is added 200 mg / day orally, 10-14 days of the period (13).

The development of hypothyroidism is more common in early childhood, and the control of the thyroid gland function by determining fT4 and TSH should be started from the third month of life, despite the normal neonatal screening results. TSH con-trols are then to be repeated once a year, especially in the patients who are on growth hormone therapy. In case of development of hypothyroidism, levothyroxine therapy is introduced. Adrenal insufficiency needs to be diagnosed in time and the patients are to be treated with hydrocortisone. (Table 2).

TABLE 2. Treatment of patients with PWS

Balanced dietInfants 0-12 months – normal growth, BM 25 – 75 percentile for PWSWhen BM starts to grow, to introduce restrictions in diet- about 10 kcal / cm of body heightThe total calorie intake consists of: 45% carbohydrates, 25% proteins and 30% fatPhysical activity – 30-60 minutes per dayRecombinant human growth hormone (rhHR) – initial therapy0.5 mg / m2, gradually to be increased to 1 mg / m2 subcutaneously in the eveningInduction of pubertyBoys aged about 14 (in agreement with parents) testosteroneGirls aged about 12 (in agreement with parents)17β estradiol in tablets or transcutaneously, with the addition of progesteroneHypothyroidism – substitution with l.thyroxine 1 – 2 μg / kg per dayAdrenal insufficiency – hydrocortisone substitution 10 mg / m2 / day divided into three do-ses, in stressful situations a 2-3 times higher dose is givenStimulation of psychomotor development – physical therapy, psychotherapy, exercises with a speech therapist


CONCLUSIONExtreme obesity, endocrinolopathies, lagging behind in psychomotor develo-

pment, and behavioral disorders in people with Prader Willy’s syndrome require a complex multidisciplinary treatment. Therapeutic options for the ill are limited, especially if the illness is diagnosed late. The example of our female patient, who was diagnosed at the age 15, confirms this. An early established diagnosis and an adequate treatment prevent the occurrence of complications and improve the quality and length of life of the patients.

References: Prader A, Labhart A, Willi H. Ein syndrom von adipositas, klainwuchs, kryptorchismus 1. und oligophrenie nach myatonieartigen zustand im neugeborenenalter. Schweiz Med Wochenschr. 1956; 6: 1260–1261. Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical genetic 2. and endocrine fi ndings. J Endocrinol Invest. 2015; 38: 1249–1263.Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 3. 2011; 14: 10–26.Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Prader-Willi 4. and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001; 34: 917–23. Miller JL. Approach to the child with Prader-Willi syndrome. 5. J Clin Endocrinol Metab. 2012; 97: 3837–3844.6. Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome. Am 7. J Med Genet Part A. 2011; 155A: 1040–9. Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic 8. criteria Pediatrics. 1993; 91: 398–402. Angulo MA, Castro-Magana M, Lamerson M, Arquello R, Accacha S, Khan A. Final adult 9. height in children with Prader Willi syndrome with and withaut human growth hormone treatment. Am J Med Genet. 2007; 143A: 1456–61.Siemensma EP, de Lind van Wijngaarden RF, Otten BJ, de Jang FH, Hokken-Koelega AC. 10. Testicular failure in boys with Prader-Willi syndrome: longitudinal studies of reproductive hormones. J Clin Endocrinol Metab. 2012; 97: E452–9. Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and 11. Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016; 12: 136–66. Whitman BY, Myers SE. Prader-Willi syndrome and growth hormone therapy: take a 12. deep breath and weigh the data. J Pediatr. 2013; 162: 224–226. Carrel A, Allen D, Myers S, Whitman B. Growth hormone improves body composition, 13. fat utilization, physical strength and agility, and growing in Prader-Willi syndrome: a controlled study. J Pediatr. 1999; 215–21.

Crino A, Schisffi ni R, Ciampalini P, et al. Genetic Obesity Study Group of Italian Society of Pediatric endocrinology and diabetology (SIEDP). Hipogonadisam and pubertal deve-lopment in Prader-Willi syndrome. Europ J Pediat. 2003; 162: 327–33.

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