Multidisciplinary approach in the Multidisciplinary approach in the management of PWSmanagement of PWS

11stst East European Conference East European Conference

Assoc. Prof. Corin Badiu

&Maria Picu, Madalina Vintila, Simona Verzea

Endocrine approach in PWS patientEndocrine approach in PWS patient

Prader-Willi Syndrome...Prader-Willi Syndrome...

• described in 1956• prevalence = 1:10,000 to 12,000• multisystemic disorder • genetic background• endocrine impact (development, puberty, metabolic)

Diagnosis…Diagnosis…

• Prenatal reduced fetal movement /

polyhydramnios amniocentesis genetic testing (chorionic villous

sampling) • Postnatal clinical features

(Holms’ criteria 1993)

behavior !! confirmed by genetic testing

Genetic testing….Genetic testing….

• Deletion / breakpoints in PW Critical Region

chromosome 15 bands q11.2-q13 = 50 - 70% (paternal deletion)

• two maternal chromosome 15s and no paternal 15 and impriting defect = 30 % (maternal uniparental disomy = UPD)

Doornbos M, et al. in press Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioral disturbances. Eur J Med Gen (2009),doi:10.1016/j.ejmg. 2009.03.010Breaking news!!Breaking news!!

Etiology ofendocrine disorders

in PWS?

▼

Endocrine disorders suggest hypothalamic-pituitary dysfunction

• genetic abnormalities in chromosome 15 disrupt the normal functioning of the hypothalamo-pituitary system

• no organic defect of the hypothalamus has been discovered on post mortem investigation (Skryabin BV, Gubar LV, Seeger B, et al (2007). )

• Hypothalamic autopsies: the PVN nucleus = reduced in size fewer oxytocin-expressing neurons reduction in GHRH-releasing neurons in the nc. arcuatus

deficiency in vasopressin

• Pituitary hypoplasia frequently observed

• IRM - abnormal bright spot

in the posterior pituitary

Endocrine changesin PWS

• short stature• hypogonadism → osteoporosis• delayed puberty• excessive appetite → morbid obesity• central hypocorticism

Dysfunctions of hypothalamo – pituitary axis in PWS

? ? ?

GH - What can go wrong?

GH deficiency (GHD)

• low spontaneous GH secretion

• low peak GH response to stimulation tests

• low serum IGF-I levels

• low levels of IGF-BP3

GHD- What can go wrong?Clinical features support the presence of GHD in PWS

• short stature• abnormal body composition• obesity with extra fat deposits over the abdomen• reduced muscle mass• decreased bone density• retarded bone age

The degree of GHD may vary from mild to severe

Stature in PWS

53 /1,10BMI=19

80 /1,59BMI=32

123/1,58BMI=50

23 ys110/1,49BMI=51

27ys135/1,53BMI=59

56 /1,06BMI=50

111/1,55BMI=47

41/1,32BMI=24

What should we do?• start GH treatment as early as 2 yr• benefit in starting therapy between 6 and 12 months of

age (Festen DAM et all, Clin Endocrinol 2008)

Recommended dose = 1.0 mg/m2/d

▼• increases longitudinal growth• increases muscle mass• decreases in percent body fat• improves bone mineral density

Restrictions: Sleep apnea, age (more than 18), local regulations

The Hypothalamic-Pituitary-Gonadal Axis Hypogonadism:

► GnRH deficiency (low LH) (central – hypothalamic)

► primary gonadal damage (peripheral) (low inhibin B and high FSH)

▼Retarded / incompletesexual development

▼Estrogen and androgen status should be monitored yearly during adolescenceand adulthood BMD assessed by DXA

Hypogonadism in PWSHypogonadism in PWS

♂ ♀Genital hypoplasia

• small penis

• small, poorly rugated, poorly pigmented, hypoplastic scrotum

• cryptorchidism (80%-90%)

• often overlooked

• small labia minora

• small clitoris

Disordered pubertal development

No / delayed/ incomplete puberty

Precocious puberty (4%)

Isolated premature pubarche(14%)

• primary/ secondary amenorrhea

oligomenorrhea

Infertility is the rule few reports of pregnancy

! aware of the possible need for contraceptives

Gonadal values in our PWS patientsGonadal values in our PWS patients

Sex Age LH/FSH (mIU/mL)

E2/testost(pg/mL)/(ng/mL)

M 13 nd/0,01 0,39

F 19 1,63/5,68 33,51

M 3 nd/1,48 0,15

F 19 nd/0,16 2,2

F 9 nd/0,72 10,75

M 20 1,19/2,27 0,55

M 11 nd/1,1 0,37

F 27 nd/1,25 42,4

F 23 0,08/1,94 57,47

What should we do?What should we do? • Cryptorchidism → orchidopexy

• Puberty induction• Sex hormone steroid replacement therapy

1. Sexual infantilism

2. Development of secondary sexual characteristics

3. Amenorrhea / oligomenorrhea (♀)

4. Low-normal BMD (♀)

5. Reduced estradiol levels (♀)

► known benefits to bone health/muscle mass

► metabolic protection

► possible benefits to mental, emotional, and physical well-being

Food intake - What can go wrong?

• Significant decrease in the number of OXT neurons of the PVN nucleus which inhibit food intake should play a physiological role in ingestive behavior

▼

Hyperphagia and Obesity

• hypocaloric diet• regular exercise• appetite suppressant drugs*:

Diethylpropion Phendimetrazin

Sibutramine• fat blockers drugs:

Xenical (Orlistat)

• Bariatric surgery ?

WARNING!!! Diabetes, metabolic disorders

*not recommended before 12 years

CRH/ACTH - What can go wrong?

▼CENTRAL ADRENAL INSUFFICIENCY (CAI)

• 60% of PWS patients have CAI during stressful conditions

• measure basal cortisol levels• perform dynamic tests

• more research is required, but at this moment, it is important to consider hydrocortisone treatment for PWS patients during stressful conditions

Adrenal axis in PWSAdrenal axis in PWSObesity Hypercortisolism

PWS Central hypocorticism

0

5

10

15

20

25

Cor

tiso

l ug%

1 2 3 4 5 6 7

basal DXM

0

5

10

15

20

25

Cor

tiso

l ug%

1 2 3 4 5 6 7

basal DXM

TRH/TSH - What can go wrong?

• Hypothyroidism has been reported

• it may be of central or peripheral origin

• screening with TSH, free T4, and free T3

• LT4 replacement therapy if necessary

Clinically significant thyroid dysfunction has not been reported in PWS

In conclusion...

• Prader-Willi syndrome is associated with endocrine disorders that are often untreated

• a more active approach to correction of these hormone deficiencies would benefit individuals with this condition

• Multidisciplinary approach(neonatologist/ pediatricianclinical genetics, nutrition,endocrinologist,psychology/family support)