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PREZENTARE DE CAZ

12
SINDROMUL PRADER-WILLI PREZENTARE DE CAZ
Camelia Buil,, Carmen Niculescu, Maricica Gu, Michaela Dobre,
A. Nechita,
Facultatea de Medicin i Farmacie, Universitatea Dunrea de Jos, Galai
Spitalul Clinic de Urgen pentru Copii Sf. Ioan, Galai

REZUMAT
Obiectivul studiului. Obiectivul studiului este prezentarea etapelor de diagnosticare a unei boli rare, sindromul
Prader-Willi.
Materiale i metod. Pacienta, n vrst de 15 ani, s-a adresat Spitalului Clinic de Urgen pentru Copii Sf.
Ioan din Galai pentru tuse productiv i dispnee. Avnd n vedere obezitatea morbid, retardul mental i alte
aspecte fenotipice constatate la internare, au fost recomandate o serie de teste i examene de specialitate
(neurologice, ORL, endocrinologice, ortopedice, ginecologice). Corelarea istoricului bolii cu rezultatele exa-
menului clinic i paraclinic a suspicionat diagnosticul de sindrom Prader-Willi. Pentru evaluarea diagnosticului
s-a indicat analiza genetic.
Rezultate. Testele de laborator au evideniat tulburri de glicoreglare i hipotiroidism, examenul endocrinologic
sugernd o etiologie hipotalamo-hipofizar a obezitii morbide. Examenul ginecologic a constatat o conformaie
anatomic normal n condiiile absenei funciei hipofizare i n lipsa modificrilor de adrenarh, cu hormoni
sexuali aproape abseni. Deficitul de ACTH s-a corelat cu deficitul de cortisol. Analiza genetic (FISH, sonda
molecular D15S10) a evideniat microdeleia braului lung al cromozomului 15 ntre benzile q11-q13, confirmnd
diagnosticul de sindrom Prader-Willi.
Concluzie. Rezultatele examenelor de specialitate i investigaiile paraclinice uzuale au avut un rol important
n orientarea diagnosticului, dar confirmarea acestuia se datoreaz testrii genetice. Cazul prezentat subliniaz,
o dat n plus, necesitatea i valoare tehnicilor moleculare de diagnostic n practica medical.

Cuvinte cheie: boli rare, sindromul Prader-Willi, FISH

INTRODUCERE (<1% n caz de deleie genic sau disomie uni-


parental, 25% prin translocaie cromozomial pa-
Sindromul Prader-Willi este o afeciune genetic tern i 50% prin mutaie n zona de control), ceea
rar (1:12-15000) care afecteaz ambele sexe i ce demonstreaz importana testrii genetice pre-
toate rasele n aceeai msur. Acesta a fost descris natale (1,2). Studiile au artat c deleia a 29 de
pentru prima dat n 1956 de ctre Andrea Prader,
copii de pe C/D box sno ARN SNORD116(HB 11-
Labhart Alexis i Willi Heinrich. Boala este cauzat
85) este cauza primar a sindromului Prader-Willi.
de o anomalie cromozomial structural ce const
n mod tradiional diagnosticul bolii este clinic, dar
n eliminarea a apte gene de pe braul scurt al cro-
n prezent acesta se stabilete prin testare genetic
mozomului patern 15 (15q11-13) sau disomiei uni-
(tehnica FISH) ce detecteaz 97% dintre cazuri i
parentale materne, atunci cnd ambii cromozomi
se recomand i nou-nscuilor cu sindrom hipoton
15 sunt de origine matern. ntr-o msur mai mic,
boala se datoreaz unor translocaii sau mutaii spo- sever (3).
radice. n mod normal se motenete cte o copie
cromozomial de la fiecare printe, dar n cazul STUDIU DE CAZ
anumitor gene sunt activate numai copiile paterne.
Activarea specific a genelor transmise de la prini Pacienta noastr, o tnr de sex feminin n
e determinat de imprimarea genomic. Riscul de vrst de 16 ani i 7 luni, a fost internat pentru
apariie la frai depinde de mecanismul de producere prima dat n Spitalul Clinic de Urgen pentru

Adresa de coresponden:
Dr. Camelia Buil, Facultatea de Medicin i Farmacie, Universitatea Dunrea de Jos, Galai

204 REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013


REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013 205

Copii Sf. Ioan, n perioada 2-16.06.2010 pentru


tuse productiv i dispnee debutate cu 4 zile n
urm, care s-au accentuat progresiv.
Antecedente personale fiziologice: sarcina fizio-
logica, natere spontan la termen, greutate la
natere 2.500 g, dezvoltarea psihomotorie ntrziat
(ine capul la 1 an i 7 luni, st n ezut la 2 ani,
merge fr sprijin de la 3 ani).
Antecedente personale patologice: retard psiho-
motor sever i infecii respiratorii repetate. Exa-
menul clinic la internare evideniaz starea general
mediocr, facies infiltrat, obezitate morbida (Fig.
1), G = 90 kg, hipotonie muscular, mini i picioare
de dimensiuni mici (Fig. 2), dispnee, tahipnee, di-
minuarea murmurului vezicular, expir prelungit,
Sat O2 = 90%, tahicardie, tensiune arterial 100/65
mm Hg (n evoluie: 140/80 mm Hg, 135/85 mm
Hg), abdomen marit de volum, nedureros la palpare,
caractere sexuale secundare absente. Avnd n
vedere obezitatea morbida, retardul psihomotor i
aspectul fenotipic al pacientului, au fost recoman-
date o serie de investigatii paraclinice ulterioare
care mpreun cu examinrile clinice au stabilit
diagnosticul de sindrom Prader-Willi. FIGURA 2. Aspectul clinic al pacientului:
mini i picioare

nmol/L, TSH = 6,153 UI/mL, LH < 0,2 UI/ml,


FSH < 0,25 UI/ml, progesteron < 0,2 ng/ml, tes-
tosteron = 0,073 ng/dL, estradiol 18,5 pg/ml, ACTH
26,8 pg/ml, cortizol 28 ng/ml);
Hiperglicemii (152-208 mg/dl).
Examenul neurologic descrie: pacient supra-
ponderal, facies infiltrat, nasul i ochii mici, ure-
chile normal implantate, gtul scurt i gros, minile
i picioarele mici, cu plantele n rotaie extern. Se
deplaseaz singur, cu dificultate, din cauza exce-
sului ponderal.
Alte specificaii: hipotonie generalizat impor-
tant, fr tulburri de coordonare sau de sensi-
bilitate, reflexe osteo-tendinoase simetrice bilateral,
Babinski negativ, examenul nervilor cranieni n
FIGURA 1. Aspectul fenotipic al pacientului limite normale, retard mental sever (QI = 25).
Anamnestic: dificulti alimentare neonatale,
Testele de laborator evideniaz: apoi hiperfagie cu obezitate i hipotonie n timpul
Hemoleucograma: leucocitoza (19.100/mm3) copilriei, dezvoltarea motorie ntrziat pe etape
cu neutrofilie, anemie uoar (Hb = 11,6 g/dL, Ht = de vrst, retard mental sever.
38,3%); Imagistic: Rezonan magnetic nuclear
Testele inflamatorii relev o protein C reactiv (RMN) relev demielinizarea substanei albe din
crescut = 4,72 mg/dl (cu VSH i fibrinogen nor- regiunea frontal, radiografia de a turceasc fr
male); modificri, radiografia de pumn indic nuclei de
Hepatocitoliza AST (78 U/L), ALT (133 cretere prezeni i cartilaje de cretere fertile.
U/L), GGT (155 U/L); Examenul endocrinologic a remarcat obezitate
Dozrile hormonale evideniaz o disfuncie morbida suspicionnd etiologia hipotalamo-hipo-
hipotalamo-hipofizar (T3 = 0,93 ng/L, T4 = 110 fizar, nanism i retard psihomotor.
206 REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013

Examenul ginecologic: conformaie anatomic diabet zaharat tip II, boli cardiopulmonare, trom-
normal, funcia hipofizar absent, absena modi- boflebit, edem cronic, i pot avea grade diferite de
ficrilor de adrenarh, nivelul hormonilor sexuali ntrziere psihomotorie, hipogonadism cu pubertate
aproape absent, nu are indicaie de tratament sub- ntrziat i infertilitate, strabism (50%) (1,6).
stitutiv. Pot s apar i manifestrile obsesiv-compulsive
Examenul ORL a constatat devierea septului (skin-picking), anxietate, tulburri de compor-
nazal, aspect normal al meatului i cornetelor na- tament, i, uneori, halucinaii i depresie (5-10%
zale, fr secreii, posibil mucoasa sinusal uor dintre tinerii aduli) care s necesite spitalizare (7).
ngroat. Sindromul Prader-Willi nu are tratament curativ
Examenul ortopedic a remarcat torsiune extern dar are nevoie de o abordare multidisciplinar: o
de schelet gambier i a recomandat nclminte diet stabilit de un nutriionist, fizioterapie pentru
ortopedic. mbuntirea tonusului muscular, logopedie, tera-
Aspectul fenotipic i rezultatele paraclinice au pie ocupaional, care s ofere integrarea social i
determinat suspiciunea de sindrom Prader-Willi, profesional a pacientului, tratamentul endocrino-
necesitnd astfel testul genetic specific. Analiza logic cu hormoni de cretere care ajut la mbun-
FISH a diagnosticat microdeleie pe braul scurt al tirea tonusului muscular i scderea esutului
cromozomului 15 ntre benzile de q11-q13, care adipos i un tratament hormonal pentru a restabili
corespund sindromului Prader-Willi: obezitate nivelul sczut de hormoni sexuali, scznd astfel
morbid, hipotiroidism, hipogonadism, tulburri riscul de osteoporoz, ventilaia cu presiune pozitiv
glicemice, retard mental. n caz de apnee obstructiv n somn din cauza obe-
n timpul spitalizrii, pacientul a primit diet zitii morbide. Pacienii care beneficiaz de diag-
srac n sare (1.600 calorii) i tratamentul bolii
nostic i tratament precoce au un prognostic mai
respiratorii acute (antipiretice, aerosoli, glucocor-
bun, iar sperana de via ajunge la aproximativ 40
ticoizi) i al complicaiilor (diuretice, antihiper-
de ani (2,8).
tensive i protectoare hepatice). La externare pa-
cientul a primit, de asemenea, recomandarea pentru
diet hiposodat i bogat n proteine, de substituie CONCLUZII
hormonal (Eutyrox), hipoglicemiante orale (met-
formin) i antihipertensive (Bisoprolol). Tratamentul precoce cu hormon de cretere de-
termin normalizarea greutii pacientului i crete
tonusul muscular, dar n cazul nostru iniierea tra-
DISCUII tamentului a fost ntrziat de stabilizarea statusului
Simptomele sindromului Prader-Willi sunt con- glicemic. O diet bogat n proteine nsoit de
siderate a fi cauzate de disfuncii hipotalamice care exerciiu fizic este necesar pentru a reveni i a
joac un rol crucial n reglarea diferitelor funcii: menine o greutate normal (9). Netratat, boala
foame/saietate, termoreglare, durere, echilibrul dezvolt complicaii, cum ar fi obezitatea morbid,
somn /veghe, emoie i a fertilitii (4). Manifestrile apnee obstructiv de somn, osteoporoz i tulburri
clinice pot varia n funcie de vrst, astfel nct n mentale, care afecteaz calitatea vieii i scurteaz
perioada intrauterin se pot ntlni micri fetale sperana de via. Manifestrile clinice i retardul
reduse, polihidramnios, iar n perioada perinatal mental pot varia n severitate, pacienii cu afectare
hipotonie generalizat, plns slab, tulburri de ali- uoar fiind capabili de integrare n comunitate,
mentaie din cauza afectrii reflexului de suciune, avnd o eficien social bun n grupuri mici de
tulburri respiratorii, tulburri de somn (5). n lucru i programe profesionale (10).
timpul copilriei i adolescenei pot fi observate Particularitatea cazului nostru este faptul c
statura mic, densitatea osoas redus, mini i diagnosticul a fost stabilit tardiv, de aceea trata-
picioare mici, tmple nguste, nas proeminent, mentul cu hormon de cretere poate avea o eficien
facies infiltrat, ochi migdalai, tegumente palide. sczut. Pacientul nostru va avea nevoie n con-
Dup o perioad tranzitorie de malnutriie, se in- tinuare de urmrire multidisciplinar, care cuprinde
staleaz obezitatea, sindromul Prader-Willi fiind implicarea familiei i monitorizarea de ctre medici
cea mai frecvent cauz a obezitii morbide la (medic pediatru, medic endocrinolog i neurolog).
copii. Copiii cu sindrom Prader-Willi pot dezvolta
REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013 207

Prader-Willi syndrome case report


Camelia Busila1,2, Carmen Niculescu1, Maricica Gusa1, Michaela Dobre2,
A. Nechita1,2
1
Department of Pediatrics, Clinical Emergency Hospital for Children Sf. Ioan,
Galati
2
Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati

ABSTRACT
Study objective. The objective of the present study is to introduce the diagnosis steps of a rare disease, Prader-Willi
Syndrome.
Materials and methods. The patient, aged 15 years, was admitted to the Clinical Emergency Hospital for Children
Sf. Ioan with productive cough and dyspnea.
Considering the morbid obesity, mental retardation and other phenotypic aspects noticed when she was admitted,
further specialized tests and examinations were recommended (neurological, ENT, endocrinology, orthopedics,
gynecology). After the correlation of this disease history with clinical examination and laboratory results, the suspected
diagnosis was that of Prader-Willi Syndrome. The genetic analysis was recommended for diagnostic evaluation.
Results. Laboratory tests revealed glucose metabolism disorder and hypothyroidism, endocrinological examination
suggesting hypothalamic-pituitary etiology of morbid obesity. Gynecological exam found normal anatomically
conformation, absent pituitary function, no changes on adrenarche, sex hormones almost absent, no indication of
substitutive treatment.
ACTH deficiency was correlated with cortisol deficiency. Genetic analysis (FISH, molecular probe D15S10) showed
microdeletion on the long arm of chromosome 15 between bands q11-q13, confirming the diagnosis of Prader-Willi
syndrome.
Conclusion. The results of expert examination and laboratory investigations played an important role in setting the
diagnosis but its confirmation is due to genetic testing. Our case highlights once again the need and importance of
molecular diagnostic techniques in clinical practice.

Key words: rare diseases, Prader-Willi Syndrome, FISH

INTRODUCTION Studies have shown that deletion of the29 cop-


ies of the C/DboxsnoRNASNORD116 (HB11-85)
Prader-Willi Syndrome is a rare genetic disorder is the primary cause of Prader-Willi Syndrome (2).
(1:12-15000) that affects both sexes and all races Traditionally, diagnosis of the disease is estab-
equally. It was described for the first time in 1956 lished by clinical investigations confirmed by ge-
by Andrea Prader, Alexis Labhart and Heinrich netic testing (FISH), which detects 97% of cases
Willi. The disease is caused by a structural chromo- and is recommended in infants with severe hypo-
somal abnormality consisting in deletion of seven tonic syndrome(3).
genes on short arm of the paternal chromosome
15(15q11-13) and maternal uniparental disomy,
when both chromosomes15 are of maternal origin. CASE STUDY
To a lesser extent, the disease is due to transloca- Our patient, a young female aged 16 years and 7
tions or sporadic mutations. Usually, individual months, was admitted for the first time in Clinical
sinheritone copy of chromosome 15 from each par- Emergency Hospital for Children Sf. Ioan during
ent but in Prader-Willi Syndrome the genes are ac- 2-16.06.2010 for productive cough and dyspnea
tive only on paternal copy. Specific activation of debuted 4 days behind which increased progres-
genes passed from parents is caused by genomic sively.
imprinting. The risk to siblings depends on the Physiological patient history: physiological
mechanism (< 1% in case of gene deletion or uni- pregnancy, spontaneous birth at term, birth weight
parental disomy, 25% in case of paternal chromo- 2500g, delayed psychomotor development (head
somal translocation and 50% in case of mutation in held from 1 year and 7 months, sitting position at 2
the control region), which proves the importance of years, walks without support at 3 years).
prenatal genetic testing (1,2).
208 REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013

Medical history: severe psychomotor retarda-


tion and repeated respiratory infections.
Clinical examination at admission highlights
mediocre general condition, facies looking infil-
trated, morbid obesity (Fig.1), excess subcutaneous
tissue, muscle hypotonia, small hands and small
feet (Fig. 2), dyspnea, tachypnea, decreased lung
vesicular murmur, prolonged expiration, Sat O2 =
90%, tachycardia, blood pressure 100/65 mmHg
(in evolution: 140/80 mmHg, 135/85 mmHg), en-
larged abdomen, painless on palpation, absent sec-
ondary sexual characters. Considering morbid obe-
sity, psychomotor retardation and phenotypic
appearance of the patient, a series of paraclinical
investigations was further recommended along
with complex clinical examinations, suspecting
Prader-Willi Syndrome.

FIGURE 2. Image of patients hands and


feet

Neuropsychological examination described im-


portant overweight, facies looking infiltrated, small
eyes and nose, normally implanted ears, thick and
short neck, small hands and feet with plants in ex-
ternal rotation. Patient moves with difficulty due to
overweight. Other specifications: generalized im-
portant hypotonia, without coordination or sensi-
tivity disorders, bilaterally symmetrical deep ten-
FIGURE 1. Phenotypic appearance of don reflex, negative Babinski sign, normal cranial
patient nerve examination, severe mental retardation (IQ =
25). Anamnestic: neonatal feeding problems, hy-
Laboratory tests highlights: perphagia with obesity, hypotonia during infancy,
On hematological investigation: leukocytosis age delayed motor development, severe mental re-
(19100/mm3) with neutrophilia, very mild anemia tardation.
(Hb = 11.6g/dL, Ht = 38.3%); Imaging investigation (MRI) reveals cerebral
Inflammatory test reveals a high level of C reac- demyelination of white matter in the frontal region,
tive protein = 4.72 mg/dL (with normal ESR and Turkish saddle radiograph without modifications;
fibrinogen); fist radiography indicates the presence of growth
Hepatic imbalance due to raised levels of liver nuclei and fertile growth cartilage.
enzymes AST (78 U/L), ALT (133 U/L), GGT Endocrinological examination noted morbid
(155 U/L) and -globulin; obesity of suspicioned hypothalamic-pituitary eti-
Hormonal investigation shows a dysfunction of ology, short stature, and psychomotor retardation.
hypothalamic-hypophysial axis (T3 = 0.93 ng/L, Gynecological examination stated normal ana-
T4 = 110nmol/L, TSH = 6.153UI/mL, LH <0.2 tomically conformation, absent pituitary function,
UI/mL, FSH<0.25 UI/ml, progesterone< 0.2 ng/ no changes on adrenarche, sex hormones almost
mL, testosterone = 0.073 ng/dL, estradiol 18.5 pg/ absent, no indication of substitutive treatment.
mL, ACTH 26.8 pg/mL, cortisol 28 ng/mL; ENT examination found large deviation of the
High blood glucose levels (152-208 mg/dL). left nasal septum, normal appearance of nose me-
REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013 209

atus and cones without secretions, and thickened chronic edema, and different degrees of psychomo-
sinus mucosa. tor delay, hypogonadism with delayed puberty and
Orthopedic examination noted external torque infertility, strabismus (50%) (1,6).
of leg skeleton and recommended orthopedic Obsessive-compulsive manifestations (skin-
shoes. picking) and anxiety, behavioural disorders, and
Based on phenotypic appearance and paraclini- sometimes hallucinations and depression (5-10%
cal results, the suspicion of PraderWilli Syndrome of young adults), may also occur and require hospi-
diagnosis emerged, thus the specific genetic test talization (7).
was required. FISH investigation diagnosed the mi- In the absence of a cure, Prader-Willi Syndrome
crodeletion of short arm of chromosome 15 be- needs a multidisciplinary approach: a diet estab-
tween bands q11-q13, corresponding to Prader- lished by a nutritionist, physiotherapy for improv-
Willi syndrome symptoms: morbid obesity, ing muscle tone, speech therapy, occupational ther-
hypothyroidism, hypogonadism, glycemic disor- apy that provides social and professional integration
ders, mental retardation. of the patient, endocrinological treatment with
During hospitalization, the patient received low growth hormones that helps improve muscle tone
salt diet (1600 calories) and treatment for acute re- and decrease body fat and hormone treatment to re-
spiratory disease (antipyretic therapy, aerosols, store low levels of sex hormones, thereby decreas-
glucocorticoids) and for complications (diuretics, ing the risk of osteoporosis, positive pressure ven-
antihypertensive and liver protective medication). tilation in case of obstructive sleep apnea due to
When leaving the hospital, patient also received morbid obesity. Patients benefiting of early diagno-
recommendation for low-salt and protein diet, thy- sis and treatment have a better prognosis and a life
roid hormone replacement (Eutyrox), oral hypogly- expectancy reaching about 40 (2,8).
cemic agent (metformin) and antihypertensive
medication (Bisoprolol). CONCLUSIONS

DISCUSSION Early treatment with growth hormone induces


patient weight normalization and increases muscle
Prader-Willi Syndrome symptoms are believed tone, but in our specific case, treatment was delayed
to be caused by hypothalamic dysfunction that by stabilization of glycemic status. A low protein
plays a crucial role in regulating various functions: diet accompanied by physical exercise is needed to
hunger/satiety, thermoregulation, pain, sleep/wake return to a normal weight and to maintain it (9).
fullness balance, emotions, and fertility (4). Clini- Untreated, the disease develops complications such
cal manifestations may vary according to age, so as morbid obesity, obstructive sleep apnea, osteo-
that it may encounter reduced fetal movements and porosis, and mental disorders, affecting quality of
polyhydramnios during intrauterine period, and life and shortening life expectancy. Clinical mani-
generalized hypotonia, weak cry, eating disorders festations and mental retardation may range in se-
due to impaired suction reflex, respiratory disor- verity, mild impaired patients being able of integra-
ders, and sleep disorders in perinatal period (5). tion into the community, having a good social
During childhood and adolescence, short stature, efficiency in small working groups and vocational
reduced bone density, small hands and feet, narrow programs (10).
temples, prominent nose, facial obesity, almond For our particular case, the diagnosis was settled
eyes, soft pale skin can be observed. After a tran- late; therefore treatment with growth hormone may
sient period of malnutrition, obesity installs, Prad- have low efficiency. Our patient will further need
er-Willi Syndrome being the most common cause multidisciplinary follow up, comprising family im-
of morbid obesity in children. Children with Prader plication and monitoring by physicians, pediatri-
Willi Syndrome may develop type II diabetes mel- cians, endocrinologists and neurologists.
litus, cardiopulmonary disease, thrombophlebitis,
210 REVISTA ROMN DE PEDIATRIE VOLUMUL LXII, NR. 2, AN 2013

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