GH therapy in PWS (& other endocrine problems) Dr. Shankar Kanumakala Consultant Paediatrician Brighton, UK
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1 GH therapy in PWS (& other endocrine problems) Dr. Shankar Kanumakala Consultant Paediatrician Brighton, UK
2 Overview GH therapy Indications Specific advantages Extra precautions Case scenarios without GH therapy with GH therapy Other Problems Hypogonadism Hypothyroidism Adrenal insufficiency Diabetes Questions
3 Life is... Mother Teresa An opportunity; avail it A beauty; admire it Bliss; taste it A dream; realise it Love; enjoy it A Challenge; meet it A duty; complete it A game; play it Costly; care for it A promise; fulfill it Sorrow; overcome it A song; sing it A struggle; accept it An adventure; dare it Too precious; do not destroy it
4 Child with PWS Life is a challenge meet it Mother Teresa Bigger challenge! More challenges!
5 Challenges Correct Diagnosis!! Hypotonia / Delayed motor milestones Weak suck / Poor feeding / Poor growth Endocrine abnormalities / short stature Obesity / Hyperphagia Scoliosis Sleep disordered breathing Cognitive difficulties
6 Hypothalamic dysfunction Hyperphagia High pain threshold Temperature instability Sleep disordered breathing Multiple endocrine abnormalities Variable pituitary hormone deficiencies
7 GH insufficiency Short stature Abnormal body composition Low IGF-1 levels Decreased GH levels on provocation tests Reported prevalence of % Decreased GH secretion with age US Growth failure; Europe improving body composition too Deal et al, 2013; Cohen et al, 2015
8 Indications for GH in UK Growth Hormone Deficiency Turner Syndrome Prader Willi Syndrome Chronic Renal Insufficiency Born SGA + growth failure at 4 years SHOX deficiency NICE guidelines (2010)
9 Specific advantages in PWS Promotes growth Improves body composition Helps with hypotonia Enhances muscle mass / strength Stabilises bones Improves cognitive / motor development And many more minor perks!
10 Linear Growth Increases Growth Velocity in short term Normalises final adult height in long term Response is unaffected by PWS genotype 21 GH (for 6 yrs) v 27 controls (age/sex matched) 131(+2) v 114(+2) cm Final Adult height -0.3 SD treated v -3.1 SD untreated Total height gain of approx cm Carrel et al, 2010; Angulo et al, 2007
11 Linear Growth - 2 Approximate cost 7,030/cm; (6,000 GHD, 16,000 TS & 15,000 CRI) Improved height leads to improved QoL More pronounced in the shortest patients In PWS, also due to improved body composition On-going GH treatment over 11 years Continued improvement in physical domain of QoL NICE Guidelines, 2010, Bakker et al, 2015
12 Body composition Lowers percentage of body fat 36% v 45 % Improves lean muscle mass 24 kg v 16 kg Improved physical function Jump 23 inches v 14 inches Sit ups 12 v 7 Some evidence of continued benefit in adults Body composition maintained in Del patients, treated with GH in childhood Carrel et al, JCEM 2010; Coupaye et al, JCEM 2016
13 Metabolic health Improves lipid profile Decreases Total & LDL cholesterol Increases HDL cholesterol Glucose tolerance & Diabetes Anabolic hormone increases insulin resistance Improved body composition increases insulin sensitivity Overall effect variable; seems a net benefit Angulo et al, 2007
14 Cognitive skills Children on GH Maintained & kept pace with development Did not catch up with peers Improvement in certain areas v baseline Controls, not on GH Deterioration in certain areas v baseline Children treated within 1 year Better Nonverbal IQ Perhaps reduces disparity with non-pws peers Merits further investigations Siemensma et al, 2012; Dykens et al, 2016
15 Potential adverse effects Transient headaches etc Scoliosis Sleep disordered breathing Sudden death
16 Scoliosis Very common 30 to 80%?Growth acceleration?hypotonia & poor posture?improved muscle mass helps reduce scoliosis No difference in incidence or progression of scoliosis in treated v untreated groups 43% v 39% in controls Careful screening at initiation Careful monitoring during treatment Angulo et al, 2007
17 Sleep disordered breathing Hypothalamic dysfunction Autonomic instability, endocrine deficiencies, reduced sensitivity to hypoxia & hypercapnia Restrictive lung disease Poor muscle tone, morbid obesity, scoliosis Lack of association with obesity per se Improves respiratory muscle strength, nocturnal coupling of HR & BP Improved cardiovascular & autonomic function Follow up study on hgh (2 years) 2 developed OSA & 13 remained well (n=15) Katz-Salamon et al, 2012; Al-Saleh et al, 2013, Pavone et al, 2015
18 Sudden death Case report year old boy, started hgh 4 months ago Review of 64 deaths in PWS children Actual causes of death did not differ However for 21/28 deaths, hgh started within 9 months Is this clustering significant? important? No clear answer at present Sleep study before GH and 6 months after GH Eiholzer et al, 2002; Tauber et al, 2008
19 Initiation & monitoring Experienced professionals Clinical monitoring Scoliosis Biochemical monitoring IGF-1, TFTs Auxological monitoring Ht, Wt, BMI, BIA Radiological moniotring Bone age, Dexa scan, Spine Xray Other Sleep study
20 When to start hgh Pro-active decision; but not in isolation Definitely prior to the onset of obesity In UK, reluctance to start before 2 years Earlier start - Potential risks v benefits Dietary input Balanced diet with calorie limitation Avoid excess weight gain Physiotherapy Promote motor skills and development
21 When to stop GH Linear Growth GV <50% from baseline in 1 st year GV <2cm in any year Final Height attained Re-test for GH deficiency at final height or 18 years Worsening scoliosis, morbid obesity Worsening obstructive sleep apnoea Uncontrolled diabetes Active malignancy or psychosis Insurmountable problems with adherence
22 Patient without GH Non identical twin Mid-parental height: 50 th centile At 2 yrs PWS twin Ht 2 nd, Wt 9 th Other twin Ht 50 th, Wt 50 th Very pro-active parents Happy with progress No hgh
23 Patient without GH Plenty of physical activities PWS twin 7000 steps, 1150 cals Other twin steps, 1900 cals Diet Calorie controlled (64%) At 9 yrs PWS twin Ht 2 nd, Wt 9 th Other twin Ht >50 th, Wt >50 th Without hgh Good progress With hgh perhaps more progress?
24 Patient on hgh Significant Hypotonia hgh from 4.0 yrs Completed 1 year Ht: 0.4 th to >2 nd centile Wt: 9 th to 25 th centile First Sports day He tried all the activities. He is a different boy now; really transformed in the last year. I am so proud of him.
25 hgh therapy - summary Extremely important An important part But not the complete plan! Actively Promote physical activities Limit unnecessary calories Prevent excess weight gain Support development
26
27 Hypogonadism Small genitalia, undescended testes, delayed or incomplete puberty & infertility Combined Hypothalamic dysfunction & gonadal failure Occasional Precocious puberty (4%) or adrenarche (15%) Hormone Replacement therapy For induction, promotion or maintenance of puberty Positive effects on bone, muscle & general well being No paternity reported; but 4 pregnancies documented
28 Hypothyroidism Central suspected 20 to 30% reported abnormalities in tests Adult prevalence 2% With GH therapy TFTs annually; especially if on GH Butler et al, 2007
29 Adrenal Insufficiency Central suspected due to hypothalamic dysfunction Autopsy in 4 Children with unexpected death 3 had small adrenals by weight Prevalence around 15% ITT test only 4% Stress-dose steroids when unwell v major surgery Weight gain Connell et al, Clin Endo 2010
30 Diabetes Type 2 in 25% adults Obesity (mean BMI 37) Infrequent in children None in 74 children at age 10 Check for diabetes if obese >12 yrs Check if starting on GH treatment Diene et al, Hor Res Paed 2010
31 Challenges Life is a challenge meet it Life is an opportunity avail it Life is an adventure dare it Life is a dream realise it Life is too precious protect it Mother Teresa
32 Any questions... Thank you
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