2013 Update on Endocrine Complications in Prader-Willi syndrome

1. 2013 Update on Endocrine Complications inPrader-Willisyndrome October 18, 2013 NM PWS Gathering Carol Clericuzio,MD UNM Medical Genetics/Pediatrics Medical Advisor NM PWS Project

2. Outline for Today’s Discussion • Brief overview of features of PWS • Hypothalamic dysfunction in PWS • Diagnosis and management of endocrine abnormalities

3. Prader-Willi Syndrome • 1/15,000 births • Neonatal hypotonia and cryptorchidism • Hypothalamic dysfunction: lack of satiety and subsequent obesity; low sex hormones and growth hormone • Cognitive and behavioral differences • Cause is lack of expression of paternal genes at 15q11-13

4. Prader-Willi Syndrome at Different Ages Childhood: obesity, apnea oppositional behaviors, learning problems, short stature Rx GH and thyroid, check adrenals Infancy: hypotonia, feeding problems, cryptorchidism, apnea, check adrenals Adulthood: type 2 DM, obstructive sleep apnea, hypogonadism Rx hormone replacement

5. Hypothalamus – part of the brain • One of the most important functions of the hypothalamus is to link the nervous system to the endocrine via the pituitary gland • The endocrine system is a system of glands, each of which secretes different types of hormones directly into the bloodstream

6. PWS: Problems with the hypothalamus • Body thermostat   • Regulation of appetite • Regulation of sleep  • Controls endocrine system • Growth hormone releasing factor • Corticotropin releasing factor (adrenal gland) • Pubertal hormone releasing factors • Thyrotropin releasing factor (thyroid gland)

7. PWS: Growth hormone deficiency in 40-100% of children • Effects of GH deficiency: • Short stature • Increased fat mass and decreased lean mass (abnormal body composition) – even toddlers • Low insulin-like growth factor (IGF-1: made by the liver in response to GH) • Decreased GH secretion on provocative tests

8. Benefits of GH therapy in children with PWS • Lower body fat; increased muscle mass • Better height • Better motor function • Possibly better cognition • Experts recommend starting GH prior to onset of obesity: ~ 2 yo

9. Benefits of GH therapy in adults with PWS • Benefits of childhood GH may persist into adulthood: lower fat • Prevalence of severe GH deficiency in adults is 40-50% • GH use associated with higher glucose • Currently no consensus on GH testing in adults, but GH is recommended

10. Risks of GH therapy • Contraindications per pharmaceutical industry and clinical experts: • Severe obesity • Untreated severe obstructive sleep apnea • Uncontrolled diabetes • Active cancer • Active psychosis

11. Risks of GH therapy • Concerns have been raised regarding: • Excessive elevations of IGF-1- may increase tonsils & theoretical risk of cancer • Sleep disordered breathing • Scoliosis • Alterations in glucose metabolism • Sudden death • Currently recommend monitor IGF-1 levels every 6-12 months

12. PWS: Sleep-disordered breathing • Obstructive sleep apnea • Sleep-related hypoxemia • Hypoventilation • Reduced ventilatory response to low oxygen and high CO2 Sleep and Breathing in Prader-Willi Syndrome Nixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)

13. Risks of GH therapy • Sleep disordered breathing may increase with GH therapy in some studies • May be improved on other studies

14. Current guidelines to evaluate sleep disordered breathing prior to starting GH therapy • Pulmonary evaluation and sleep studies on all patients • ENT referral if obstructive sleep apnea, snoring, enlarged tonsils/adenoids • Repeat sleep study within first 3-6 months of starting GH

15. PWS: Scoliosis and GH therapy • Scoliosis affects 30-80% • No effect of GH found on scoliosis • Consensus recommendation is that prior to GH therapy, have spine films and orthopedic referral if necessary • After start of GH therapy, spine film and/or orthopedic assessment should be considered if scoliosis progress a concern

16. PWS: Alteration in glucose metabolism with GH • Concern is GH can increase insulin resistance causing high blood glucose • Pediatric: no problem with GH therapy up to 4 years • Adult: minor increase in glucose/insulin • Consensus recommendation: monitor HgbA1C, glucose, insulin and consider oral glucose tolerance test for obesity, >12 yo, family history of diabetes

17. PWS: Association of sudden death with GH therapy • Has received a lot of attention: 2002-2006: 20 deaths reported in children on GH but cause not been proven to be GH • Respiratory disorders are the most common cause of death in PWS • When PWS deaths are looked at however, there is no increase in those on GH hormone

18. PWS: Association of sudden death with GH therapy • However, 75% of deaths in GH group occurred within 9 months of start of GH • Need close surveillance for any worsening of sleep related breathing disorders during first year of GH therapy • Sudden death may also be related to central adrenal insufficiency – we published a study showing small adrenals

19. PWS: Problems with the hypothalamus • Body thermostat   • Regulation of appetite  • Controls endocrine system • Growth hormone releasing factor • Corticotropin releasing factor (adrenal gland) • Pubertal hormone releasing factors • Thyrotropin releasing factor (thyroid gland)

20. Adrenal Gland Function • Adrenal glands sit on top of the kidneys. They are chiefly responsible for regulating the stress response through the synthesis of cortisol. • Cortisol increases blood pressure and blood sugar, and reduces immune responses • Cortisol deficiency can lead to death if an individual is stressed by surgery, infection, dehydration, etc.

21. PWS and adrenal insufficiency • Frequency is unknown but it does occur • Due to problems with the hypothalamus • While deaths may be associated with adrenal problems, especially during an acute illness or after surgery, none of the individuals were on GH • GH interferes with cortisol production so in theory could contribute to a death

22. PWS and adrenal insufficiency • No consensus on appropriate evaluation and management of PWS-associated adrenal insufficiency • In New Mexico our pediatric endocrinologists have recommended low-dose ACTH stimulation testing • Some experts recommend giving families hydrocortisone to use at home in case of severe illness and for surgeries

23. PWS: Problems with the hypothalamus • Body thermostat   • Regulation of appetite  • Controls endocrine system • Growth hormone releasing factor • Corticotropin releasing factor (adrenal gland) • Pubertal hormone releasing factors • Thyrotropin releasing factor (thyroid gland)

24. PWS: Hypogonadism • Decreased function of ovaries and testes due to hypothalamic and pituitary understimulation • Underdevelopment of genitals, delayed or incomplete puberty and infertility in the vast majority • Most males have undescended testes and should have surgery by 1-2 yo

25. PWS: Replacement hormone treatment for hypogonadism • Many individuals require hormonal treatment for induction, promotion or maintenance of puberty • Benefits include improved bone health, muscle mass and possibly general well-being • Timing should reflect normal puberty

26. PWS: Replacement hormone treatment for hypogonadism • Sex hormone deficiency contributes to low bone density in adults • Female sex hormones are taken orally • Male sex hormones can be delivered by injection or patches and gels • PWSpatients may have difficulty with topical treatment due to skin irritation and skin picking behaviors

27. PWS: Reproduction • No instances of paternity • Four cases of pregnancies and therefore potential of fertility in females necessitates discussion of sexuality and birth control at the appropriate age • 2 of the babies had Angelman syndrome, a severe neurologic disorder

28. PWS: Problems with the hypothalamus • Body thermostat   • Regulation of appetite  • Controls endocrine system • Growth hormone releasing factor • Corticotropin releasing factor (adrenal gland) • Pubertal hormone releasing factors • Thyrotropin releasing factor (thyroid gland)

29. PWS: Hypothyroidism • Reported in 20-30% of children • Adult frequency is 2% = general population • Experts recommend that freeT4 and TSH be screened in the first 3 months of life and annually thereafter, especially if receiving GH therapy

30. SUMMARY: PWS is characterized by problems with the hypothalamus • Body thermostat   • Regulation of appetite • Regulation of sleep  • Controls endocrine system • Growth hormone releasing factor • Corticotropin releasing factor (adrenal gland) • Pubertal hormone releasing factors • Thyrotropin releasing factor (thyroid gland)

31. Questions? Endocrine manifestations and management of Prader-Willi syndrome. EmerickJE, Vogt KS. IntJ PediatrEndocrinol. 2013 Aug 21;2013(1):14.

32. Sleep disorders in PWS Main featureAssociated features • Excessive daytime sleepiness Increased nocturnal sleep Behavioral problems Issues related to learning and safety • Abnormalities of arousal Reduced arousal to hypoxic and hypercapnic stimuli during sleep • Sleep-disordered breathing Obstructive sleep apnea Sleep-related hypoxemia Hypoventilation Reduced ventilatory response to hypoxia and hypercapnia Sleep and Breathing in Prader-Willi Syndrome Nixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)