dana david recommendations for the management of prader-willi 2

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11/7/2010

Recommendations for the Management of Prader-Willi Syndrome. Effects of growthhormone therapy in children and adults

Dana David, Raluca Dumache

UMFVB- Timisoara

The 2nd Eastern European Conference on Prader

Willi Syndrom

29- 30 october 2010,

Zalu



11/7/20102

PWS / Growth and GH status - Prenatal

Mild prenatal growth hypotrophy is common with normal birth

weight

Premature and post-term deliveries are frequently observed, with

delivery more than 3 wk early or late reported in some studies in

around 1/3 of cases .



11/7/20103

PWS / Growth and GH status - Postnatal

Short stature:- always present,

- especially during the second year,

Serum levels - IGF-1

Spontaneous GH and GH peak during pharmacologicalstimulation test is < 10g/liter in 70% of children.



11/7/20104

PWS / Growth and GH status - Postnatal

Precise prevalence of severe GH deficiency is unclear because

reference ranges are unavailable in severe obesity Potential importance of knowing the GH status to evaluate

differential effects, depending on GH status.

Height velocity does not reflect GH status in children with PWS, particularly when they are obese.

Prior GH testing is not required before GH treatment but if available may be helpful.



11/7/20105

PWS / GH treatment in children - Aim

to improve growth during childhood, adult height andbody composition.

- adm sc, daily, g (or mg)/kg/day.

Pre-pubertal children - 25-50 g/kg/day in

- relationship in terms of height velocity in the first two years of

treatment has been clearly demonstrated within this range. Pubertal children - 100 g/kg/day



11/7/20106

PWS / GH treatment in children - Aim

1.0 mg/m2/day:

- significant increase in height, growth velocity

- decrease body fat during the first year of GH treatment

followed by stabilization during the second year.

- lean body mass increased significantly during the first two years

of GH treatment compared with untreated PWS children.



11/7/20107

PWS / GH treatment in children

After the initial 2 yr, GH therapy for two additional years had

continued beneficial effects on body composition when doses of

1.0 and 1.5 mg/m2/day were administered but not with a

dose reduction to 0.3 mg/m2/day.

Maintenance of improved body composition requires at least GH

dose of 1.0mg/m2/day

Bone mineral density continued to improve at all doses of GH.



11/7/20108


Kabi International Growth Study, 33 patients (21 boys and 12 girls)

reached adult height, and 2/3 of them were above _2 SDS; themedian adult height was _1 SDS for height after a mean durationof 8.4 yr.

Recent report - 21 adults (13 boys, eight girls), the mean adultheight was_0.3 SDS for height after a mean duration of 7.9 yr of GH treatment.



11/7/201010


Starting GH treatment as early as 2 yr are well established, Increasing evidence of additional benefit in starting therapy

between 6 and 12 months of age, particularly in terms of motor

development, muscle, head circumference, and possibly cognition.



11/7/201011


GH treatment should be started at a low dose,

- 0.25 ² 0.30 mg/m2/day or 0.009 ² 0.012 mg/kg/day,

increasing during the first weeks and months to reach a standardreplacement GH dosage

1.0mg/m2/day or 0.035 mg/kg/day,

- monitoring clinical effects, sleep apnea,

- avoiding high IGF-I levels, over treatment (edema, snoring,

headache, acromegalic clinical features)



11/7/201012


Results of control trials involving ¿ 100 patients

Respiratory disfunction improved during 6²9 months of GHtreatment, decrease in apnea - after 6 months of GH treatment.

Improved body composition, increased lean body mass,

Lipolytic effect

Improved motor skills, strength, agility and endurance

Improved in hand and foot size, more normal facial appearance Increased ultimate stature and cognitive function



11/7/201013

Management monitoring

Before starting GH treatment

Genetic confirmation of PWS

Evaluation of IGF-I and GH status Nutritional evaluation and advice and body composition if

available (DXA)

Prior control of food environment, especially in obese children

Complete clinical evaluation:

- sleep and breathing studies (sleep-disordered breathing,

snoring, or enlarged tonsils and adenoids are present, ENTassessment and polysomnography are mandatory).



11/7/201014

Management monitoringBefore starting GH treatment

OGTT, particularly if obese and/or older than 2 yr and family

history of diabetes Family instruction on GH treatment including benefits and risks

of the treatment and importance of careful monitoring

Scoliosis evaluation including X-ray

Evaluation of hypothyroidism (TSH,FT4,FT3) and

commencement of replacement if needed



11/7/201015


On GH treatment

Assessment of height, weight, BMI, body composition, pubertalstatus, scoliosis, IGF-I, and side effects every 3²6 months

Ideally ENT assessment and within the first 6 months

- If development or worsening of sleep-disordered breathing,snoring, or enlargement of tonsils and adenoids.



11/7/201016

Management monitoringOn GH treatment

IGF-I measurement are mandatory

X-ray _ orthopedic assessment if concern or doubt about scoliosis

Regular bone age determination, particularly during pubertal

age range

Monitoring for hypothyroidism



11/7/201017


Cessation of GH treatment

Uncontrolled progression of obesity

Continued worsening of glycemic control despite weightcontrol, diabetic medication, and normal IGF-I

Continued worsening of sleep-disordered breathingdespite weight control, tonsillectomy and adenoidectomy andnormal IGF-I

Attainment of final height ??!!



11/7/201018

GH Replacment: Possible Problems/ AdverseEffects associated

Daily injection

Concern about worsening scoliosis?

Edema Dose ² dependent increase in insulin levels ² occasional one set of

hyperglicemia

Increased strength in those with severe behavioral problems

Intracranial hypertension

Slipped capital femoral epiphysis

Gynecomastia



11/7/201019

GH Treatment / Benefits

Increase in bone mineral density (BMD), Increased height andgrowth rate

Increase of hand and foot sizes to normal proportions Decrease in body fat

Decrease in body mass index (BMI)

Increase in muscle development

Improvement in cholesterol levels

Improved respiratory function

Improved physical and cognitive performance

prevention of cardiovascular morbidity

Improvement in well-being and quality of life andreduced depression.

)



11/7/201020

Transition into adult life

The potential benefits of continuing, starting, or restarting GH

treatment after completion of growth are achievements National circumstances often dictate cessation of GH treatment

and reevaluation of GH status at final height.

- Body composition can rapidly worsen

- Persistence of GH deficiency (70% partial, 30% severe)

- IGF-I low

Modest benefits reported with short-term GH treatment of usingthe lower conventional GH dosage (0.53 mg/d).



11/7/201021

GH Treatment of Persons who have AchievedFinal Height and Adults with PWS

Dosages:

- substantially lower (6 - 25g/kg/day )

- side effects are more common,

- IGF-1 levels - normal range for age and sex.

The prevalence of GH deficiency in adults with PWS is not well-documented.



11/7/201022

Mortality during rhGH therapy

Studies of natural mortality rates in PWS are absent

Most of the reported deaths occurred with doses at or below thelabeled recommendation of 0.25 mg/kg/day.

No apparent reason to limit the rhGH dose in relation to preventing morbidity or mortality.

Reported deaths occurred within the first 18 months of treatment;

82% within the first year. special in the first 9 months of GHtreatment

Clinical follow-up should be especially attentive during the first 12- 18 months.



11/7/201023

Mortality during rhGH therapy

October 2002, several reports of unexpected death in have been

published, patients +/- GH treatment, were related to a

complicated course of the syndrom

Death by respiratory disfunction - airway obstruction, pre-

existing compromised respiratory system and sleep disturbance

Death related to obesity

- 17 reports of death worldwide (june 2006)- most obese (12) with pre-existing respiratory problems

- sudden death, acute pneumonia, respiratory failure, aspiration

pneumonia, sleep apnea.



11/7/201024

Major recommendations for the management of PWS

Early diagnosis of PWS

Multidisciplinary teams

Family education and support

Control of the food environment and regular exercise is essentialto manage hyperphagia and obesity

GH therapy should be started early in childhood, taking into

account cautions and relative contraindications Appropriate monitoring of GH replacement is essential



11/7/201025

Major recommendations for the management of PWS

Management of the transition from adolescence to adulthood

requires specific attention and care,

Increased availability of group homes with experience in themanagement of PWS.

Recognition of the distinction between the underlying behaviour

problems seen in PWS and acute psychiatric illness is essential.



11/7/201026

Conclusions

New management strategies

- to reduce morbidity and mortality

- improving quality of life.

Requiring further study

- best age at which to start GH therapy in infancy or

childhood- role for GH therapy in transition and adulthood



11/7/201027

References

1. Hoybye et al, 2005 J Intellect Disabil Res 49:245²252

2. Goldstoneet al.

J Clin Endocrinol Metab, November 2008, 93(11):4183² 4197

3. Angulo MA et al. 2007, Am J Med Genet A 143:1456²1461

4. Myers S, Carrel A, Whitman B, Allen B 2000 . J Pediatr 137:42²49

5. Harriette R. Mogul, Phillip D. K. Lee, Barbara Y. Whitman, William B.Zipf, Michael Frey,et al, J Clin Endocrinol Metab, April 2008,93(4):1238²1245

6. Carrel et al . Benefits of Long-Term GH Therapy, J Clin EndocrinolMetab, April 2002, 87(4):1581²1585

7. Tauber M, et al, 2008,Areview, Am J Med Genet A 46:881²887

8. Festen DAM,et al. 2008 Clin Endocrinol (Oxf), 68:919²925)



11/7/201028

Thank you

dana david recommendations for the management of prader-willi 2

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