1. 2013 Update on Endocrine Complications in Prader-Willi syndrome 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 Infancy: hypotonia, feeding problems, cryptorchidism, apnea, check adrenals Childhood: obesity, apnea oppositional behaviors, learning problems, short stature Rx GH and thyroid, 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 PWS patients 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. Emerick JE, Vogt KS. Int J Pediatr Endocrinol. 2013 Aug 21;2013(1):14.

32. Sleep disorders in PWS Main feature Associated 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)