1. Xs & Os of Turner Syndrome Karine Khatchadourian MD, MSc, FRCPC Pediatric Endocrinologist CHEO May 7, 2016

2. Objectives Diagnosis of Turner Syndrome To review the major health issues that are associated with Turner’s Syndrome and the general screening necessary for these issues To understand the main hormonal heath issues that we screen for in Turner’s Syndrome and to discuss how they are managed

3. Turner Syndrome (TS) Common condition present in 1 in 2000 to 1 in 2500 newborn girls We talk about syndrome when doctors see several clinical features that tend to occur together The diagnosis of TS requires the presence of these features + absence of all or part of second X chromosome in some or all cells of the body

4. Features of Turner Syndrome and Frequency Very frequent (>50%) Growth deficiency Absent pubertal development Infertility Recurrent ear infections Lymphedema of hands and feet (swelling) Tendency towards obesity High arched palate, small lower jaw, dental crowding Some learning disability

5. Features of Turner Syndrome and Frequency Frequent 25-50% Short 4 th finger in hand Eyes: ptosis (droopy eyes) and strabismus (eyes misaligned) Feeding problems Sensorineural hearing loss Kidney malformation Hypertension (high blood pressure) Increased birth marks (naevi)

6. Features of Turner Syndrome and Frequency Less Frequent 10-25% Scoliosis Heart issues: stenosis (coarctation) of aorta, bicuspid aortic valve Thyroid: hypothyroidism and even less frequent is hyperthyroidism Increased liver enzymes Diabetes Mellitus

7. Features of Turner Syndrome and Frequency Uncommon (<10%) Patellar dislocation Congenital hip dislocation Celiac Disease Inflammatory Bowel disease Osteoporosis Aortic dissection Juvenile Rheumatoid Arthritis

8. Genetics ~ ~ 50% 45X Mosaicism Structural abnormalities of the X chromosome Small percentage have some Y chromosome material

9. All patients Cardiovascular evaluation by specialist Renal ultrasound Hearing evaluation by an audiologist Evaluation for scoliosis/kyphosis Evaluation for knowledge of TS; referral to support groups Evaluation for growth and pubertal development Ages 0–4 yr Evaluation for hip dislocation Eye exam by pediatric ophthalmologist (if age > 1) Ages 4–10 yr Thyroid function tests (T 4, TSH) and celiac screen (TTG Ab) Educational/ psychosocial evaluations Orthodontic evaluation (if age > 7) Age > 10 Thyroid function tests (T 4, TSH) and celiac screen (TTG Ab) Educational and psychosocial evaluations Orthodontic evaluation Evaluation of ovarian function/estrogen replacement LFTs, FBG, lipids, CBC, Cr, BUN BMD (if age >18 yr) Screening at diagnosis of TS Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007

10. Ongoing Monitoring in TS Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007 All ages Cardiological evaluation as indicated Blood pressure annually ENT and audiology every 1–5 yr Girls <5 yr Growth Rate Annually School age Liver and thyroid screening annually Celiac screen every 2–5 yr Educational and social progress annually Dental and orthodontic as needed Older girls and adults Fasting lipids and blood sugar annually Liver and thyroid screening annually Celiac screen as indicated Age-appropriate evaluation of pubertal development and psychosexual adjustment

11. Growth At least 95% of girls with Turner Syndrome (TS) have short stature The cause of short stature is likely related to a complex interaction of various hormonal and genetic effects Growth can be affected in all stages of life in an individual with TS

12. Growth Intrauterine growth restriction (IUGR) has been reported to occur in newborns with TS Studies have revealed that newborns with TS are born in the low normal range for length compared to newborns without TS -an average length 2.8cm below the mean Poor growth may be noticed in infancy

13. Growth The poor growth that occurs in childhood in girls with TS is felt to be composed of 2 main features -delay in the onset of the childhood component of growth -decreased growth velocity throughout childhood and adolescence Absent pubertal growth spurt

14. Growth in girls with TS: missing one copy of SHOX gene found on X chromosome http://www.medscape.org/viewarticle/445555

15. Short Stature: Combination 2 Main Factors TS girls growth hormone levels are typically normal -There is however impaired response at the level of the growth plates to their own growth hormone Missing one copy of SHOX

16. TS Growth Curve Untreated girls with TS Average height 144 cm (4 foot 9 inches) Around 20 cm lower (8 inches) shorter than women without TS ←164 cm ←144 cm

17. Treatment with Growth Hormone Synthetic growth hormone (made in the lab) used as treatment for over 25 years Growth hormone given by injection 6-7 times a week until growth completed Growth expected with growth hormone: 2-4 inches (5-10 cm) above expected final height without GH treatment

18. Treatment with Growth Hormone Treatment monitored every 4-6 months by pediatric endocrinologist Adjustments based on weight, growth velocity and value of IGF-1 (blood test indirectly looks at GH) Treatment continued until: Growth slows down to <2 cm per year Bone age of 14 years (tells us growth plates have closed)

19. Better Response to Growth Hormone 1. Longer duration of treatment (started younger) 2. Taller parents leading to taller mean parental height 3. Taller height at start of treatment 4. Compliance (taking the medication) 5. Higher dose of growth hormone

20. Growth Hormone Treatment It is estimated that girls with TS can reach an average adult height of 150cm with GH therapy A Canadian Study showed an average height gain of 7.3cm over girls who were not treated 1 1 Canadian Growth Hormone Advisory Committee. Impact of Growth Hormone Supplementation on Adult Height in Turner Syndrome: Results of the Canadian RCT. 2005 J Clin Endocrinol Metab 90: 3360

21. Growth Hormone Side Effects Generally very safe Side effects rare: 1.Fluid retention (swelling hands/legs) 2.Elevated fluid pressure in brain: benign intracranial hypertension 3. Displacement of growth plate of femur: Slipped capital femoral epiphyses (SCFE) 4. May lead to higher blood sugars 5. Curvature of spine (scoliosis)

22. Key Points Short stature key feature in TS Treatment with growth hormone has shown to improve final height in girls with TS

23. Let’s talk about Puberty! Period of time during which sexual development occurs Usually starts between ages 8 -13 in girls Tanner staging: the physical changes of puberty on a scale of 1 to 5

24. Tanner Staging Carel JC and Leger J, N Eng J Med 2008

25. Normal Puberty (ages on average) Breast: 10 ½ - 11 yrs Pubic Hair: 11 ½ yrs Peak Growth Spurt: 12 yrs Menarche (first period): 12 ½ yrs Bone growth stops within 2 years after menarche Rosen DS. Pediatric in Review 2004

26. Babic B and Kives S, Turner Syndrome: Across the Lifespan

27. Androgens from Adrenals (Adrenarche) is normal in girls with TS Androgens: pubic hair, body odour

28. Girls with Turner syndrome Genes on X chromosome important for ovarian development and function Egg loss accelerated leading to ovarian failure Most girls don’t enter spontaneous puberty (up to 30% will) 16% have first period spontaneously although will end prematurely in most

29. Goal and Benefits of Estrogen in Girls with TS Growth/Initiate puberty Improved self-esteem and quality of life May improve verbal and not verbal memory Improve risk for cardiovascular disease Bone strength/  osteoporosis

30. Estrogen Side Effects in Girls with TS Replace the estrogen that ovaries should normally be producing Side effects uncommon Nausea Fluid retention Irregular bleeding Mood swings

31. Estrogen Treatment in Girls with TS Follow patient to see if spontaneous puberty up to age 11-12 Doctor will order tests: FSH: Follicular Stimulating Hormone LH: Luteinizing hormone Estradiol Bone Age

32. Babic B and Kives S, Turner Syndrome: Across the Lifespan FSH  LH 

33. Timing of Treatment Depends on height Depends on age of diagnosis Depends on timing of growth hormone initiation Depends on bone age (usually start at bone age 11)

34. Treatment If no spontaneous puberty, estrogen started age 12-13 yrs If spontaneous puberty, follow progression, might need estrogen eventually Visit to endocrinologist every 6 months Dose gradually increased every 6 months over 2-3 years

35. Treatment Estrogen for growth: breast, uterine Estrogen for long-term Addition of progesterone After 2 yrs on estrogen or if there are signs of breakthrough bleeding

36. Addition of Progesterone Progesterone added first 10-12 days of each month to mimick normal menstrual cycle

37. Treatment After 2 years on estrogen treatment alone: 1.Estrogen 1 tablet daily (or patch) + Progesterone 1 tablet daily first 10-12 days of each month Or 2. Estrogen + Progesterone combined in Oral Contraceptive Pill (1 tablet daily) or Patch

38. Forms of Estrogen Tablet Estrace Transdermal Patch Estraderm, Estradot Patch to be cut (1/6-1/8 initially) Changed once or twice weekly

39. Forms of Estrogen Both oral tablet and Patch similar results for: Breast growth Linear growth Lipid profile One study found increase in bone mineral density and uterine growth with transdermal patch Cost similar Question of preference and compliance

40. Oral Progesterone (added once we see breakthrough bleeding) Provera (medroxyprogesterone acetate)

41. Combination estrogen + progesterone Oral contraceptive pill -Different brand names (Alesse, Marvelon) Transdermal patch -Ortho Evra

42. Other treatments not standard of care Androgen (testosterone treatment) Estrogen started earlier (infancy and childhood)

43. Key Points Most girls with TS have ovarian failure Need help with treatment to enter/progress through spontaneous puberty Estrogen treatment usually initiated age 12-13 and then progesterone added later on

44. Autoimmune Disease Increased Risk for autoimmune disease Hypothyroidism most common -5-40% of girls/women with TS Celiac Disease -4-6% of girls/women with TS

45. Screening: all pts at time of Dx evaluation by a cardiologist with expertise in CHD comprehensive exam including blood pressure in all extremities all require clear imaging of the heart, aortic valve, aortic arch, pulmonary veins echo for infants and young girls MRI and echo for older girls and adults ECG Monitoring: follow-up depends on clinical situation For pts with apparently normal CVS and age-appropriate BP reevaluation with imaging at timely occasions: transition, before attempting pregnancy; appearance of HTN. Girls who have only had an echo should have an MRI when old enough otherwise imaging q5-10 yrs For pts with pathology: as per cardio Cardiovascular Screening Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007

46. Cardiovascular risk factors Increased risk of obesity Hypertension 50% Impaired glucose tolerance in 10-34% Type 2 diabetes 4x more common / also earlier than the general population Increased cholesterol levels

47. All patients Cardiovascular evaluation by specialist Renal ultrasound Hearing evaluation by an audiologist Evaluation for scoliosis/kyphosis Evaluation for knowledge of TS; referral to support groups Evaluation for growth and pubertal development Ages 0–4 yr Evaluation for hip dislocation Eye exam by pediatric ophthalmologist (if age > 1) Ages 4–10 yr Thyroid function tests (T 4, TSH) and celiac screen (TTG Ab) Educational/ psychosocial evaluations Orthodontic evaluation (if age > 7) Age > 10 Thyroid function tests (T 4, TSH) and celiac screen (TTG Ab) Educational and psychosocial evaluations Orthodontic evaluation Evaluation of ovarian function/estrogen replacement LFTs, FBG, lipids, CBC, Cr, BUN BMD (if age >18 yr) Screening at diagnosis of TS Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007

48. Ears & Eyes Ear -Middle Ear Infections common -conductive hearing loss -sensorineural hearing loss -speech Eyes -Amblyopia/ Strabismus -farsightedness -Red-green color deficiency

49. Bones Increased risk of decreased BMD Risk Factors: -estrogen non-compliance -vitamin D deficiency -smoking / alcohol -celiac disease Ensure good Calcium and Vitamin D intake Weight bearing exercise

50. Other Skeletal System -Increased risk of congenital hip dislocation -Scoliosis and kyphosis Learning -Impairment of nonverbal skill math, direction sense -Increased rate of ADD (24%) -Excel at verbal skills, many adults University level education

51. Other Urinary tract -Congenital malformations 30- 40% Liver disease -elevated liver enzymes -usually not associated with true disease

52. Transition At time of completion of growth and puberty Gradual shifting from parent to adolescent Transition of focus from growth to puberty and sexual development Healthy eating and active living Adult care plan with new health care provider Bondy et al. Care of Girls and Women with Turner Syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endo Metab: 92 (1) :10-25

53. Conclusions Girls and women with TS face different health challenges at different ages and stages A health check-list (or screening program) facilitates the medical care of girls and women with TS By maintaining a regular follow-up with your health care team and a healthy lifestyle you can ensure ongoing optimal health!

54. THANK YOU FOR YOUR ATTENTION! Special thanks to Dr Ahmet for help with slides