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Prevalence, mortality and socio-economic outcome in Turner syndrome Claus H. Gravholt Department of Endocrinology and Internal Medicine Department of.

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Presentation on theme: "Prevalence, mortality and socio-economic outcome in Turner syndrome Claus H. Gravholt Department of Endocrinology and Internal Medicine Department of."— Presentation transcript:

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2 Prevalence, mortality and socio-economic outcome in Turner syndrome Claus H. Gravholt Department of Endocrinology and Internal Medicine Department of Molecular Medicine Aarhus University Hospital Denmark

3 Who am I? I started working with Turner syndrome already in medschool in the last millenium I am an adult endocrinologist working with rarer endocrine conditions I have performed numerous studies in kids, adolescents and adults with Turner syndrome Also used epidemiology, genetics, cardiology, MR radiology and more I am also the father of 5 kids

4 What is Turner syndrome in 2014? Decreased final height, >95% Gonadal dysgenesis – no puberty – infertility – chronic estrogen insufficiency – androgen insufficiency Endocrine disturbances Psychosocial problems Physical abnormalities And much more………………………….

5 The heart? Socio-economic conditions? Diagnosis?Mortality and morbidity?

6 Genetics

7 SHOX – part of an explanation!  short 4th metacarpal  cubitus valgus  Madelung deformity  mesomelic growth  high arched palate  micrognathia  sensorineural deafness  dysproportionality of skeletal size Consequence:

8 Height, skeletal anomalies Height, gonads, lesser physical features Viability Gonadal dysgenesis SHOX (ZFX) (USP9X) (RPS4X) (DIAPH2) p q Gene (candidate)Phenotype Critical regions for TS phenotype on the X chromosome X

9 SHOX effects Ottesen et al, Am J Med Genet, 152A: , 2010 Marchini et al, Hum Mol Genet, 16: , 2007 SHOX – homeodomain transcription factor NPPB is a transcriptional target – encodes BNP, which is known as a cardiac and natriuretic hormone Involved in growth of hypertrophic chondrocytes Clement-Jones et al, Hum Mol Genet, 9: , 2000 SHOX2 SHOXSOX9

10 X chromosome inactivation (XCI) In each cell either the paternal or the maternal X is inactivated Initiation of XIC is controlled by Xist X chromosome: ~1100 genes Y chromosome: ~100 genes Heard and Disteche, Genes Dev 20:1848, 2006

11 Early letality – placental factor Urbach et al, PloS ONE 4:e4175, 2009 CSF2RA Colony-stimulating factor 2 receptor alpha Encodes the α subunit of the receptor of the granulocyte-macrophage colony-stimulating factor Essential for normal placental development

12 When are patients diagnosed? And how many are eligible for GH? Delay in diagnosis / years Range = 0-86 years Median = 15 years N = 746 Number Stochholm et al, J Clin Endocrinol Metab, 2006

13 Age at diagnosis – effect of karyotype Stochholm et al, J Clin Endocrinol Metab, 2006

14 Prevalence of TS – closing the gap? Stochholm et al, J Clin Endocrinol Metab, 2006

15 How good are we at diagnosis? Median age : 15.1 years ( )range Median age : 15.1 years ( )range Stochholm et al, J Clin Endocrinol Metab, 2006 Stochholm et al, unpublished data

16 Swedish data on diagnosis Age at diagnosis Stigmata 45,X ,X/46,XX Isochromosome X-marker Y-marker Ring chromosome N=126 El-Mansoury et al, Clin Endocrinol, 66: , 2007

17 How many suffer from TS? 50 per 100,000 females About 1300 in Denmark 125,500 in EU 78,000 in USA 5500 in Australia – about 1300 in Sydney

18 Europe Denmark: 900/5,400,000, expected 1350 – relative percentage: 67% Sweden: 900/9,000,000, expected 2250 – relative percentage: 40% UK: 5000/62,000,000, expected – relative percentage: 32%

19 Rate of abortion 2008: 28 prenatally diagnosed / 20 abortions 2009: 15 prenatally diagnosed / 13 abortions 2010: 20 prenatally diagnosed / 18 abortions 2011: 26 prenatally diagnosed / 20 abortions : 89 / 71 = 80% abortion rate Viuff et al., unpublished data

20 Prenatal conditons Viuff et al., unpublished data

21 Mortality in TS  British registry study of 400 TS and 62 deaths  RR: 4.2 (95% CI 3.2 – 5.4)  Causes: nervous, cardiovascular, digestive and genitourinary systems  Specific causes: epilepsy, IHD, aortic dissection, pneumonia, cong. heart disease  No gonadoblastoma deaths  Bias: ascertainment, cause of mortality Swerdlow et al., Ann Hum Genet, 65: , 2001

22 Mortality in TS  SMR – 2.86 (95% CI 2.26 – 3.62)  Endocrine diseases, SMR: 5.68  Coronary diseases, SMR: 3.47  Congenital anomalies, SMR:  No increased cancer mortality  , SMR: 4.68  , SMR: 2.86  , SMR: 2.49, test for trend p=0.08 Stochholm et al, J Clin Endocrinol Metab, 2006

23 Mortality in TS 45,X Isochromosomes Other karyotypes Background population Stochholm et al, J Clin Endocrinol Metab, 2006

24 Mortality Schoemaker et al, JCEM (2008).

25 Mortality Schoemaker et al, JCEM (2008).

26 Quality of life and socio-economy

27 TS persons – Quality of lifeNormal – Higher education Increased – MarriedFewer – Health problemsIncreased – Children ? – Income? – Retirement? Turner syndrome - questionnaires Carel 2005, Verlinde 2004, Naess 2009, Bannink 2006, Cunnif 1995

28 Material and methods Danish Cytogenetic Central Registry 997 Turner syndrome persons identified controls (age and gender) Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

29 Materials and methods Statistics Denmark – Cohabitation – Income – Education – Children – Retirement – Mortality Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

30 Statistical approach Hazard ratios – Total – Before the diagnosis Turner syndrome – After the diagnosis Turner syndrome Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

31 Cohabitation First partner Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

32 Cohabitation Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

33 Children First child Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

34 Children Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

35 Income Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

36 Income Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

37 Retirement Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

38 Retirement Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

39 Retirement Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

40 Education Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

41 Education Hazard ratios – Total1.0 ( ) – Before the diagnosis0.9 ( ) – After the diagnosis1.1 ( ) ControlsTurner syndrome p-value controls compared to all TS Number with at least one higher education (%) 16,018 (32.5) 193 (34.5) 0.98

42 Mortality Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

43 Mortality Hazard ratios – Total3.2 ( ) – Adjusted education and retirement 2.9 ( ) Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

44 Conclusion Divergent socio-economic profile with little impact on the increased mortality No major differences between karyotype groups The reason for the reported high quality of life may be due to a ”coping” mechanism Note: number of mothers Noteincome Noteeducation Stochholm et al, Eur J Endorcrinol, 166:1013, 2012

45 US Turner syndrome women N=240 females Gould et al, J Women Health, 22:230, 2013

46 The heart in TS Mortensen et al, Endocrine Reviews, 33: , 2012

47 Congenital malformations 70-80% of a given Turner syndrome population will have a congenital malformation! Matura et al, Circulation, 116:1663, 2007; Mortensen et al, Cardiol Young, 20:191, 2010

48 Summary Epidemiology tells us a lot about Turner syndrome However, only scant data on GH and HRT and long term outcome How to interfere with hypertension, heart disease and other disease? Continued studies are necessary

49 Turner syndrome clinics oDedicated oMulti disciplinary oAnchored in one department oImplementation of international guidelines on a national basis o… but a still a need for further research on a number of issues!

50 Recommendation Screening – everybody at diagnosis – Evaluation by cardiologist – Full investigation including blood pressure – Echocardiography, especially in younger girls – MRI and Echo in older girls and adults Continuous monitoring – follow-up dependent of clinical situation – Re-evaluation at transition, before pregnancy, hypertension, etc. – Or every 5-10 year Clinical Practice Guideline, J Clin Endocrinol Metab, 92:10-25, 2007

51 Pregnancy work-up Pre-pregnancy screening: – MRI af the heart and great vessels – Hypertension – Hypothyreosis, diabetes, vitamin D, celiac disease During pregnancy: – Echocardiography in first and last trimester, MRI if necessary, hypothyreosis, diabetes, vitamin D After pregnancy: – hypothyreosis, diabetes, vitamin D

52 Adult medical follow-up oBlood pressure, heart auskultation and echocardiography, MRI oThyroid status, coeliac screen oBody composition status (BMI<25), including physical exercise and diet instruction oBlood sugar, lipid profile, and liver enzymes oOsteoporosis surveillance oOtological examination oUrinary screening

53 Treatment oFemale sex steroid substitution with natural estrogens (17β-estradiol) and gestagens oMale sex steroid substitution ? oGH substitution ? oTight control of blood pressure (beta-blocker or other drugs?) oPrevention of obesity and other lifestyle diseases oRegular visits in outpatient clinics (internal medicine, gynaecology or other specialists with an interest in the syndrome)

54 Information book Available on the internet –

55 Take-home message  Turner syndrome is often diagnosed late (or never)  Metabolic disease is frequent  Hypothyroidism is seen in 50%  Type 2 diabetes is frequent  HRT can prevent osteoporosis  Heart disease is frequent  The natural history is still not unravelled  Morbidity and mortality is clearly increased


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