Slide 1

Challenges, successes and pitfalls of

growth and development and GH therapy

in Turner Syndrome Case presentations that underscore some of the variance of growth

response and growth trajectory in TS. PENS Conference May 7, 2015, Savannah, Georgia, USA

Irena Hozjan RN (EC), BScN, MN, NP-Pediatrics

SickKids, The Hospital for Sick Children

Toronto, Ontario Canada

Disclosures

Over the last 2 years I have:

• Received honoria for pharmaceutical Nursing Advisory Board meetings (one-off) for

Pfizer, Sandoz, Merck EMD-Serono, Hoffman La Roche.

• I have been an invited speaker for Merck EMD Serono International IMAGE European

Nursing Conference (October 2014).

• Using Hoffman La Roche/Genentech/CDC TS /regular growth charts in this presentation.

Objectives

1. Describe general Canadian practice in the treatment and management of growth in

Turner Syndrome (TS).

2. Identify and review predictors of good growth hormone (GH) response in TS.

3. Identify and review predictors of poor GH therapy response in TS.

4. Compare and contrast literature findings of GH and growth response in TS.

Slide 2

Turner Syndrome (TS):

• About 1 in 2500 live female births is

affected by TS.

• Implicated in 15-20% of all miscarriages.

• One of the more common genetic conditions.

• Complete or partial loss of one X chromosome.

• Short stature caused by haploinsufficiency of the short-stature homeobox-containing gene (SHOX) located within the Xp-terminal, pseudoautosomal region of the X chromosome. It affects virtually all individuals with TS.

Short Stature Growth in TS

Linear growth is attenuated in utero.

Linear growth lags during childhood and

adolescence resulting in mean final adult

heights of 143cm (4 feet 8 inches) + 20 cm (8

inches) below the mean for the population

Turner Percentiles from Lyon AJ, Preece, MA, Granti DB. Growth curve for girls with

Turner Syndrome. Arch Dis Childhood. 1985; 60: 932-35

Slide 3

Phenotypic features and conditions associated with TS

Very Frequent >50% Short Stature Gonadal dysgenesis Recurrent otitis media Lymphedema of hands and feet Hyperconvex nails Unusual shape/rotation of ears Narrow maxilla, dental crowding Micrognathia Low posterior hair line Broad chest, wide spaced nipples Wide carrying angle Short fourth metacarpals Obesity

Misinformation of effects of GH in TS

“Human growth hormone is a standard part of treatment of Turner Syndrome (TS)…”

“Today, it is considered a safe and effective way to reverse some of the signs of Turner Syndrome”.

“The primary purpose of growth hormone is to regain height in girls with TS. Without growth

hormone treatment, the average height of an adult woman with Turner Syndrome is 4 ft 8 in. In

fact, girls who do not receive growth hormone are typically about 8 inches shorter than their

predicted height would be with growth hormone.”

“Growth hormone not only treats delayed physical growth but also delayed sexual development

(another main fixture of Turner Syndrome…”)

Slide 4

Cochrane Systemic Reviews of GH tx in TS • 4 RCTs (n=211)

• Recombinant human growth hormone (hGH) doses between 0.3 - 0.375 mg/kg/wk

• Increase short-term growth in girls with Turner Syndrome (TS)

• approximately 3 cm in the first year of treatment

• and by approximately 2 cm in the 2nd year of treatment.

• the FAH of treated women was still outside the normal range (more than -2SD below the normal population mean).

Cave CB, Bryant J, Milne R.

Cochrane Database Syst Rev. 2003;(3):CD003887.

Subsequent review in 2007 noted similar results with 4 RCT’s (n=365)

• (same findings as above)

• It does appear that initial growth improvements decline over longer treatment periods

• FAH of treated women was still outside the normal range.

• Recommended additional trials to be carried out with control groups until FAH to allow better informed decisions about

whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost

L, Bryant J, Cave CB, Milne R.

Cochrane Database Syst Rev.(2007). Jan 24;(1):CD003887.

Early diagnosis

Karyotype

Early and prolonged treatment, (with appropriate GH dosing)

Taller stature at GH start

Increased growth response in 1st year of therapy

Tall parents

Absence of other disease

Adherence to therapy Ranke MB et al (2000). J Clin Endocrinal Metab 85:4212-4218

Reiter EO et al (2001). J Clin Endocrinol Metab 86: 1936-1941

Carel, JC. Et al (1997). Horm Res 48: 31-34

Ranke, MB. (2000). J Clin Endocrinol Metab 85 4212-4218

Favourable GH growth response in TS is influenced by…

Slide 5

Current Canadian Practice:

Approved by Health Canada.

• GH stimulation testing-not required in Canada.

• GH offered to all TS girls.

• Initiation of tx at 2-6 years of age, or when GV declines, or at dx if older.

• Dosing: 0.05mg/kg/dose, 6 days /week (0.3mg/kg/week).

• Treated until FAH or BA of 14 years and/or GV actual or projected < 2 cm/year.

• Puberty induction ~ 12 years of age (oral/transdermal) for those that require it.

4 years of age ↓ GV Mom, 5’10”. Dad 5’9”’ MPH 5’7” Mother has hypothyroidism Hx of OM Sent to Pediatrician… Phenotypic stigmata of TS • epicanthal folds, • ptosis, • short webbed neck, low posterior

hairline, • outstanding and anomalous ears

(left anteriorly curved) , • wide spaced nipples (16 cm), and

moderate pectus excavatum, • grade 4 systolic ejection murmur, scoop nails. Clinical dx of TS made, confirmed with Karyotype • Normal Renal function and U/S,

TFT’s, • IGF-1 lowish • Large ASD secundum on Cardiac

assessment • Required cardiac sx • 6 mos after Cardiac surgery

initiated GH

Karyotype 45X

• Started GH at 4.5 yrs (2006)

following cardiac Surgery

• dose of .05 mg/kg/dose

(0.3mg/kg/week)

• Ht 97.1 cm and wt 14.1 kg.

First year on GH

9.9 cm of growth, excellent response

with catch up

• No SE

• TSH 3.16, Free T4 18.7,

anti-TPO <10, IGF-1 148 (48-130)

• 8 yrs of active (prepubertal)

• treatment with good adherence,

• crossed numerous centiles

• 25th centile regular growth curve

(8.3 cm, 7 cm, 5 cm, 6.2 cm, 6.3 cm,

5.1 cm, 4.1cm per year)

4.5 yrs SDS -2.37

12.5 yrs SDS -0.65

Slide 6

← Karyotype 45X/46XX-mosaic

Dx on amnio, confirmed postnatally

Followed by community ped endo.

Mom 5’1”, Dad 5’8” MPH 5’2”

No stigmata of TS

Fall off in GV

Started GH (0.05mg/kg/day) at 8.9yrs

(BA 6 yrs 10 mos)

N labs

Grew 8.8 cm in 1st year, IGF-1 312

Continues to respond well to tx, no SE,

BA at 12 years was 11years.

Now,

13 yrs, Spontaneous puberty

T3 for BD and PH

LH 2.0, FSH 1.7, Estradiol 60,

IGF-1 363 (82-467 ug/L)

8.5 yrs SDS -2.86

13.2 yrs SDS -1.35

↑

BMI 32.7 9.3yrs SDS -3.08

16 yrs SDS -3.15

45X/46Xi (X) (q(10)-Mosaic Karyotype Dx at 8.5 yrs re DD, SS, ↑ Anxiety,

?PDD, Hx of OM and M&T x2

MPH 5’6”

BAV

Family hx of autoimmune Thyroid

Disease

GH Started at 9 yrs

Ist yr of tx 7.5cm, no SE.

D/C’d tx 13.5 yrs

Started OHR 12 yrs (BA 13)

Menarche 14 yrs 8 months. BMI 32.7

Spontaneous Puberty in Turner Syndrome...

The incidence of spontaneous puberty in TS:

• Reported to be about 1/3 (12-40%) esp. in mosaic karyotypes.

• Streak gonad with

• Accelerated oocyte degeneration

• Increased stromal fibrosis

• Only a small percentage will have spontaneous menarche,

• Eventual gonadal failure in 90%

• Spontaneous pregnancies are rare (2–5%) Tarani et al. (1998). Gynecologic Endocrinol

Bannink EM, et al. (2009). Clin Endocrinol 70:265–273

Pasquino AM, et al. (1997). J Clin Endocrinol Metab 82:1810–1813

Mortensen KH et al. (2010).Obstet Gynecol 115:446–449

Slide 7

Spontaneous Puberty in Turner Syndrome...

Italian retrospective multicenter study:

• 522 girls with TS >12 yrs of age

• 84 (16.1%) had spontaneous onset of puberty with menarche at 13.2 +/-1.5 yr

• GH treatment does not seem to exert any influence on either the age of onset or the

prevalence of spontaneous puberty

Pasquino A M. (1997). JCEM. 82(6):1810-1813

Precocious Puberty in Turner Syndrome

• Precocious puberty in TS patients is rare.

• To date, only five cases have been reported in the literature, four of them showing mosaic

TS and one a karyotype with structural abnormality of one X chromosome.

Evanchec K.A., Rotenstein D. (2005). J Pediatr Endocrinol Metab,18, 819-822

Huseman C.A . (1983). Pediatr.102,892-894

Sabin M.A., Zacharin M.R J. (2007). Paediatr. Child. Health,43,776-778

Baek J.U.. Park H.K., Hwang I. (2012). J Pediatr Adolesc Gynecol., 2012,25, 113-114

Improdao, N et al. (2012). Ital J Pediatr, Oct 17;38:54

9.5 yrs SDS -3.08

16 yrs SDS -4.31

Karyotype 45 X (dx at 4 years of age)

MPH 4’11”

Started GH at 9 years of age BA: 7yrs 10

months-8 years 10 months

1st year on GH grew 9.3 cm

Seen at 10 .5 yrs (BA 10 yrs)

Labs (N) TFT’s, renal, ALT ↑ 71 (0-40), IGF-1

572 (80-446 ug/L)

LH 4.4, FSH 31.6, Estradiol 52 pmol/L

BD T2 Lt side

@ 11 years:

Grew 2.9 cm, and reported menarche 2 months

prior –had 2 cycles

• BD T3 (barely) bilaterally, PH T2

• Labs LH 15.5, FSH 68.4, Estradiol 84, ALT

AST and GGT ↑ (referral to GI)

• BA 11 yrs

• No exogenous E2 exposure and pelvic U/S

normal.

Subsequent visits N monthly cycling

Stopped GH at 12.5 years (BA 14 years)

FAH 136.9 cm

N monthly menses (BD T5, PH T4)

LH 20.1, FSH 57.3, Estradiol 88

Slide 8

Breast Development in TS

Shield / Broad Chest

Wide spaced nipples

Poor Breast Development

Hypoplastic and tubular breast development Normally:

•Breast bud responds to estrogen

•The action of estrogen depends upon the presence GH to

stimulate production IGF-I in the mammary gland. Kleinberg DL, Ruan W.J (2008). Mammary Gland Biol Neoplasia. 2008 Dec;13(4):353-60

•Skin envelope passively stretches in response to stimulated

growth

•Tanner staging

In tubular and or hypoplastic breasts:

•Tight fibrous mesenchymal layer resists growth in any or all of

the breast quadrants, except at the areola (an area of low

resistance)

• Attenuation of periareolar skin results in more stretching and

results in tubular shaped breast with a large areola.

Breast development in TS

• Paucity of medial and inferior skin

• Inner quadrant tightness (areolas face in)

Implications for TS:

• Poor breast development is not uncommon in TS

• May be problematic to use breast development to stage pubertal development with or

without use of ovarian hormone replacement.

• Breast and chest wall anatomy in TS may make it more difficult to differentiate

breast staging (Tanner).

• Poor breast development has psycho-social implications for women.

• Breast augmentation-Plastic Surgery may be indicated, recommended and

covered in TS.

Slide 9

Karyotype 45X/46X Del 22.2.31 • Mom has TS, same Karyotype (4’11”) Required IVF, M obese, MPH 5’0” (?) Behavioural issues, DD, ADD/ADHD, ?Autism spectrum • Short webbed neck, • Low posterior hairline • Wide spaced nipples • Shortened arms-wide carrying angle Started GH just after 8yrs (0.05 mg/Kg/dose) IGF-1 135 (48-350)

BMI 45.5

8yrs SDS -1.25

15 yrs SDS -1.31

Excellent GV, first yr 10+cm (50centile) 9 yrs, BA 11 yrs IGF-1 596 (40-446ug/L) 10yrs 10 mos, BA 12-13 yrs IGF-1 780 (88-446/691ug/L) GH unchanged from start 2mg (0.05mg/kg/dose) Over time… ↑ Obesity ↑ IGF-1’s ↑ Disproportion (shortened arms, size 9.5 feet) Referrals to community Dietician, wt management programs, SW, psychiatrists. Spontaeous puberty Menarche 11.5 years LH 2.5, FSH 3.1, Estradiol 157 IGF-1 802 (120-691/1096ug/L) At 12 yrs 2 months BA 14yrs GH d/c’d at 12.5 years

Obesity…

What the literature says:

• Women with TS were more obese compared with women with a normal karyotype.

• Obese TS patients had higher serum triglyceride concentrations.

• More likely to be hypertensive.

• Hypertension was independent of obesity and may be under-recognized because of

failure to compare with age-matched normal ranges.

Elshaik M, Conway GS. (1998). Clin Endocrino. 49(4):447-50.

Slide 10

Supraphysiologic IGF-1 Levels

• IGF-1 is the major mediator of the anabolic and growth-promoting effects of growth

hormone (GH):

• Transported by IGF-binding proteins, in particular IGFBP-3

• Highly age dependent and results must always be interpreted within the context

of the patient's age.

• IGF- 1 is produced in large amounts in the liver as well as in adipose tissue

• The aim of both pediatric and adult GH replacement therapy is to achieve IGF-1

and IGFBP-3 levels within the reference range, ideally within the middle-to-upper

third. Wetterau L, Cohen P. (2000). J Ped Endocrinol Metab 13:1371-1376

Park P, Cohen P. (2004). Horm Res 62(Suppl 1):59–65

Supraphysiologic IGF-1 Levels

• Higher levels are rarely associated with any further therapeutic gains, but could

potentially lead to long-term problems of GH excess.

• When GH was given at the higher doses,

• IGF-I levels were often above the normal age and sex range

“Ideally, prolonged exposure to elevated IGF-I levels should

be avoided because of theoretical concern about potential

long-term adverse effects” Park P, Cohen P. 2004 Horm Res. 62 Suppl 1:59-65

Disproportionate Growth in TS

Body proportions of untreated girls with TS compared

to healthy girls, relative to height:

• More coarse and stocky body habitus

• Larger trunk, hands and feet

• Relatively short lower extremities

• Relatively broad shoulders and pelvis

Gerver WJM, et al. (1992). Acta Paediatr. 81:691–694

Neufeld ND, Lippe BM, Kaplan SA. (1978). Am J Dis Child. 132:296–298

Rongen-Westerlaken C, Rikken B. Vastrick P. (1993). Eur J Pediatr. 152:813–817.

Gravholt CH, Weis Naeraa R. (1997). Reference values for body proportions and

body composition in adult women with Ullrich-Turner syndrome. Am J Med

Genet 72:403–408

Slide 11

Disproportionate Growth in TS

The increase in height after long term GH treatment is accompanied

• By an even larger increase in foot size and

• A moderate improvement of the disproportion between height and sitting height.

• In the last phase of growth, some girls the study complained about big feet.

• The possibility of additional foot growth may have influenced their decision to discontinue GH treatment

before adult height was reached.

Theo C. J. et al. (1999). JCEM 84:12, 4622-4628.

3.1 years SDS -2.53

9 yrs SDS -2.19

Karyotype 45X/46X i(X) (q10)-mosiac Dx amnio, confirmed post natally BAV, Wide spaced nipples Later: SNHL-bilaterally-hearing aids DD Started GH: 3yrs Issues with adherence from 5-6 yrs of age. Normal range IGF-1’s Over the last 2 years no GH

Adherence

• Poor adherence to GH is common (5-80%)

• Efficacy of GH tx is based on adherence.

• Adherence rates not generally associated with:

• Age

• Cause of GH treatment

• Socioeconomic status

• Person who administered the injections

• Type of injection device

• GH product Aydin BK, et al. (2014). Endocr Pract. Jan-Feb;20(1):46-51.

Slide 12

Factors Affecting Adherence to GH Therapy

Barriers to GH therapy adherence in paediatric patients may include:

• Medication issues (e.g. apparent ineffectiveness, inadequate supply and side

effects)

• Scheduling issues (social convenience)

• Cognitive/emotional issues (e.g. forgetfulness, preoccupation, lack of

understanding of condition or instructions, lack of symptoms, fear of needles,

poor tolerability and inadequate family support).

• Additional barriers in adolescence may include: denial, peer pressure and

reluctance to seek medical advice

Haverkamp F, et al. (2008). Clin Ther. 30:307-316

Factors Associated and Not Associated with Adherence

“Factors specifically associated with poor adherence to GH therapy in observational studies are listed in

table; notably, several factors have been associated with poor adherence in some studies but not in others”.

Fisher BJ. (2013). Horm Res Paediatr .79:189-196

**Do not want to continue

tx

Scoliosis

• General incidence of scoliosis in general population is 2-3%.

• Girls with TS have higher risks for scoliosis and kyphosis

• 10–20%of girls with TS develop scoliosis, and kyphosis

Australian study:

• The 30% incidence in Turner syndrome was noted to be much higher than previously

reported (11–12%).

G.A. Day, I.B. McPhee, and J. Batch. (2004). J Bone Joint Surg Br, 86-B:(SUPP IV) 455

Lippe B. (1991). Endocrinology and Metabolism Clinics of North America, 20:121-152

Kim J, Rosenfeld S, Keyak J. (2001). J Ped Orthop, 21:765-766

Slide 13

Thoracic dextroscoliosis with a Cobb angle measuring 66° from T5 to L1 Lumbar levoscoliosis with a Cobb angle measuring 23° from L2 to L5.

3 years later. Again seen is a short segment dextroscoliosis of the thoracic spine measuring 79 degrees from the superior

T6 endplate through the inferior T12 endplate

8.2 yrs SDS -4.78 17 yrs SDS -5.37

Karyotype 45X dx at birth MPH unknown Foster Care TS stigmata ++ Coarctation, repaired Horseshoe Kidney-vesicoureteral reflux Congenital diaphragmatic hernia Lymphedema (hands and feet) Lt ptosis DD, SLP, OT, PT Scoliosis @ 7 yrs: (N) GH stimulation test (25.6 ug/L Arginine, 12ug/L Clonidine)

Started GH @ 8.1 years BA 6 yrs 10 mos Initiated OHR at 14 yrs BA 11 yrs Menarche 15.5 GH d/c’d 15 yrs. Posterior spinal fusion @ 15.5 yrs

Slide 14

Summary

• TS is a complex mix of complete and mosaic karyotypes that all have very

individual phenotypic expression.

• Growth and development in TS is an unfolding story.

• GH potentially provides 1 additional cm of growth for every year of use.

• Adverse events are minimally reported.

• Not all growth is a result of GH tx, when used.

• Poor pubertal growth velocity has a significant impact on FAH in TS

• Clinicians need to be keenly aware of the many factors that impact growth and

development in TS.

• Be conservative in growth predictions prior to and while on GH therapy.

Thank you!