2013 Update on Endocrine Complications in

Prader-Willi syndrome

October 18, 2013 NM PWS Gathering

Carol Clericuzio,MDUNM Medical Genetics/PediatricsMedical Advisor NM PWS Project

Outline for Today’s Discussion Brief overview of features of

PWS Hypothalamic dysfunction in

PWS Diagnosis and management of

endocrine abnormalities

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

Prader-Willi Syndrome at Different Ages

Infancy: hypotonia,feeding problems, cryptorchidism, apnea,check adrenals

Childhood: obesity, apneaoppositional behaviors,learning problems,short stature Rx GH andthyroid, check adrenals

Adulthood: type 2DM, obstructive sleepapnea, hypogonadismRx hormone replacement

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

•

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)

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

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

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

Risks of GH therapy

Contraindications per pharmaceutical industry and clinical experts:

Severe obesity Untreated severe obstructive sleep

apnea Uncontrolled diabetes Active cancer Active psychosis

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

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 SyndromeNixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)

Risks of GH therapy

Sleep disordered breathing may increase with GH therapy in some studies

May be improved on other studies

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

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

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

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

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

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)

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.

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

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

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)

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

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

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

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

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)

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

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)

Questions?

Endocrine manifestations and management of Prader-Willi syndrome. Emerick JE, Vogt KS. Int J Pediatr Endocrinol. 2013 Aug 21;2013(1):14.

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 hypercapniaSleep and Breathing in Prader-Willi Syndrome

Nixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)