Mocaisism, growth, and IGF-1 mitigates ear and hearing problems in Turner Syndrome introducing the cell cycle delay hypothesis.

Transkript

1 Mocaisism, growth, and IGF-1 mitigates ear and hearing problems in Turner Syndrome introducing the cell cycle delay hypothesis. Marie-Louise Barrenäs, docent Centrum för Pediatrisk Tillväxtforskning, Drottning Silvias Barn och Ungdomssjukhus Institutionen för Kliniska vetenskaper, avd för pediatrik Göteborgs Universitet

2 Turners syndrom: Genetik: Medfödd avsaknad av eller defekt på X-kromosomen i alla eller vissa celler. Stigmata: Kortvuxenhet Utebliven pubertet Infertilitet Webbed neck Cubiti valgi Hjärtmissbildning Kärlmissbildning Tunnformad thorax Synnedsättning Öron- hörsel problem mm

3 FISH

4 Örats anatomi Marie-Louise Barrenäs, 23 March, 2013,

5 Conventional classification Monosomy 45,X Mosaics 45,X/46,XX Deleted X chromosomes 45,X/46,X,der(X) 45,X/46,X,del(X)(p11.2p21. 2) Marker chromosomes 45,X/46,X,+mar Isochromosomes 45,X/46,X,i(X)(q10) 45,X/46,XX/46,X,i(X)(q11q2 8) Ring chromosomes 45,X/46,X,r(X) 45,X/46,XX/46,X,r(X) 45,X/46,X,r(X)/47,X,r(X)x2 Y-chromosomal material 45,X/46,X,der(Y) 45,X/46,XY 45,X/46,X,i(Y)(p10) Non-mosaic 46,X,der(X) 46,X,i(X)(q10) 46,X,inv,dup,dic(X)(qter q27:: p11 q27::q27 p11::q27 qter) 46,X,der(X) Marie-Louise Barrenäs, 23 March, 2013,

6 Conventional paradigm Compare monosomics versus non-monosomics

7 One hypothesis That loss of the SHOX-gene plays an important role in Turner syndrome (Short-stature-HOmeoboX gene, which is located one the p-arm in the Pseudo-Autosomal Region, PAR, of the X-chromosome) Marie-Louise Barrenäs, 23 March, 2013,

8 Göteborg Classification Barrenäs et al., 2007 Monosomy 45,X Mosaics 45,X/46,XX Others Dvs underskott av genetiskt material i alla celler Dvs underskott av genetiskt material i vissa celler, men en frisk 46,XX linje Dvs överskott av genetiskt material i alla celler

9 Our hypothesis: geno- phenotype that the occurrence/severity of clinical symptoms depends on the degree of chromosomal damage, i.e. that subjects with a total deletion of the p-arm exhibit a higher occurrence of more severe ear and hearing problems compared to them who have a partial deletion i.e. monosomy 45,X or isochromosomy 46,X,i(Xq) worse than 46,XX mocaisism and structural deletions) Marie-Louise Barrenäs, 23 March, 2013,

10 Ear and hearing disorders are common in Turner Syndrome % recurrent otitis media during childhood % sensorineural hearing loss as adults % minor auricular malformations Lindsten, 1963 Watkin, 1989 Hultcrantz et al., 1994 Barrenäs et al., 1999 Marie-Louise Barrenäs, 23 March, 2013,

11 Mer TS studier Ukraina: Zelinska et al., 2018 Japan: Hanew et al., 2018 Albanien: Hoxha et al., 2015 Iran: Bakhshaee et al., 2015 Taiwan: Chan et al., 2012 Holland: Verver et al., 2011 Italien: Bergamaschi et al., 2008

12 Ear and Hearing in Relation to genotype and growth in Turner syndrome Marie-Louise Barrenäs, MD, PhD, Dept of Audiology Olle Nylén, MD, PhD, Dept of oto-rhino-laryngology Kerstin Landin-Wilhelmsen, Dept of Endocrinology Charles Hanson, PhD, Dept of Obstetrics and Gynaecology Sahlgrenska University Hospital, Sweden Marie-Louise Barrenäs, 23 March, 2013,

13 115 girls and women with TS 56 monosomy (45,X) 22 mocaisism 9 isochromosomy (46,X,i,(Xq) 11 structural deletion q q Marie-Louise Barrenäs, 23 March, 2013,

14 Auricular anomalies Auricular anomaly Yes No Total deletion 30% 35% Partial deletion 8% 27% Girl/women with TS are twice as likely to have auricular anomalies if she has a total deletion of the p-armen than if she has a partial deletion (95% confidence limits for RR: ; p<0.05)

15 Recurrent otitis media Otitis media Yes No Total deletion Partial deletion 49% 17% 21% 13% Girl/women with TS are 1,2 times more likely to have otitis media problems if she has a total deletion of the p-arm than if she has a partial deletion (95% confidens limits for RR: ; p<0.10)

16 Conductive Hearing Loss Cond HL Yes No Total deletion Partial deletion 22% 44% 2% 32% Girl/women with TS are 5,6 times more likely to have a conductive HL if she has a total deletion of the p-arm than if she has a partial deletion (95% konfidence intervall for RR: )

17 Samband mellan TS genotyp och fenotyp avseende såväl inner-, mellan- som ytteröra innebärande att total förlust av p-armen ger högre prevalens av ytteröreanomalier högre prevalens av ledningsfel svårare hörselnedsättning med avseende på ålder jämfört med fall där p-armsfragment finns kvar i alla celler (strukturella) p-armen finns kvar i vissa celler (mosaik) Marie-Louise Barrenäs, 23 March, 2013,

18 Öron- och Hörsel problem vid TS Beroende på p-arm (totalt/partiellt bortfall) Genetik Ju gravare kromosom-skada (karyotype / FISH) Desto högre förekomst av ytteröron anomalier Desto högre andel av öronbarn / ledningsfel pga otosalpingit Tillväxt Ju kortare Ju lägre IGF-1 nivå Desto gravare SNHL

19 Ett litet antal TS har cochlea implantat

20 Ingen effekt av GH eller östrogen på hörsel, otiter Oxandrolone GH (Davenport et al., 2010; Ko et al., 2010; ) Estrogen (Hedenstierna et al., 2009)

21 Finmotorik Ring, Iso, Trisomi, Y (others, n=14) Age - ** Faktorer inom Metabola Syndromet (Abdominal Fat, glucos, BP) - ** Bentäthet **

22 Balans Ring, Iso, Trisomi, Y (others, n=14) Age - ** Faktorer inom Metabola Syndromet - ** (Abdominal Fat, BP) Benvariabler ** (BMD, IGF-1)

23 Signifikanta skillnader mellan mosaiker och others BMI 0,043 Waist 0,013 Hip 0,026 Body fat 0,074 Cholest 0,029 ApoA 0,067 Insulin 0,079 Fibrinogen 0,071 IBG-1 0,031 IGFBP 0,081 Antal stigmata 0,038

24 Growth promoting treatment normalizes speech frequency in Turner syndrome Andersson-Wallgren Gunnel, speech pathologist, 1 Ohlsson Ann-Christine, speech pathologist, PhD 2 Albertsson-Wikland Kerstin, MD, professor 1 Barrenäs Marie-Louise, MD associate professor 1 Laryngoscope, 2008

25 Differences in SFF <29 yy yy yy SFF (Hz) ,X0 vs mosaics 45,X0 vs controls Mosaics vs controls

26 SFF vs age Monosomy and Isochromosomy cases SFF Age Mosaics or structural deletions SFF Age

27 The Cell cycle delay hypothesis (Barrenäs, Nylén, Hanson, 1999) (Barrenäs, Landin-Wilhelmsen, Hanson, 2000)

28 Cell cycle delay hypothesis (Barrenäs et al., 2007) Tid

29 The cell cycle delay hypothesis The higher the frequency of chromosomally abnormal cells such as 45,X... Specific mechanisms:...the fewer growth regulating genes In vivo selection Fewer cells Growth disturbance Developmental delay Anomaly Dysplasia 1. Auricular malforamtion 2. Otitis media due to a poorly developed mastoid and a shortening of the cranial base, which in turn affects the Eustachian tube 3. Mid frequency SNHL due to fewer hair cells 4. High frequency SNHL Fewer hair cells from birth The age-related hair cells loss will cause hearing loss earlier in life General mechanisms:...the fewer cell cleavages due to cell cycle delay 5. The proportion of chromosomally abnormal cells declines with increased age

30 Mondini Bodet et al., 2012 Fish et al., 2009

31 Dentofacial morphology in Turner syndrome karyotypes. (Sara Rizell) Palatal height and dental arch dimensions in Turner syndrome karyotypes. 45,X/46,XX karyotype mitigates the aberrant craniofacial morphology in Turner syndrome. Select item Turner syndrome isochromosome karyotype correlates with decreased dental crown width.

32 Turner karyotype and childbirth Anna Hagman Morbidity and mortality after childbirth in women with Turnerkaryotype (2012). Obstetric outcomes in women with Turner karyotype (2011). Women who gave birth to girls with Turner syndrome: maternal and neonatal characteristics (2010)

33 Studier på normalpopulation: Hörselfunktion och tillväxt

34 Data Swedish Birth Register Swedish Conscripts Register conscripts born Odds Ratio

35 Birth size: an indirect marker for intrauterine growth retardation Small for Gestational Age SGA

36 Prevalence of SNHL 4.0% of the total study sample 5.7% among non-sga with a short adult stature 7.1% among those SGA with no catch-up and therefore a short adult stature (p<0,005)

37 Stature at conscription versus average if born non-sga 50% Risk increase born SGA-short 134% Risk increase Weight at conscription versus average if underweight 20-30% Risk increase overweight 20-30% Risk increase obese (BMI > 30) 99% Risk increase SGA light 30% SGA light + overweight at conscription 118%

38 Conventional classification Monosomy 45,X Mosaics 45,X/46,XX Deleted X chromosomes 45,X/46,X,der(X) 45,X/46,X,del(X)(p11.2p21. 2) Marker chromosomes 45,X/46,X,+mar Isochromosomes 45,X/46,X,i(X)(q10) 45,X/46,XX/46,X,i(X)(q11q2 8) Ring chromosomes 45,X/46,X,r(X) 45,X/46,XX/46,X,r(X) 45,X/46,X,r(X)/47,X,r(X)x2 Y-chromosomal material 45,X/46,X,der(Y) 45,X/46,XY 45,X/46,X,i(Y)(p10) Non-mosaic 46,X,der(X) 46,X,i(X)(q10) 46,X,inv,dup,dic(X)(qter q27:: p11 q27::q27 p11::q27 qter) 46,X,der(X)

39 Romberg + Tandem Romberg Öppna ögon < 6 sec: 0 points; 6-15 sec: 1 point; sec: 2 points; > 25 sec: 3 points. Slutna ögon: 1-5 sec: 1 point; 6-10 sec: 2 points; sec: 3 points; sec: 4 points; sec: 5 points; >25 seconds: 6 points.

40 Stå på ett ben Öppna ögon: < 5 sec: 0 points; 5-9 sec: 1 point; sec: 2 points; sec: 3 points; > 25 sec: 4 points. Slutna ögon: < 6 sec: 0 points; 6-9 sec: 1 point; sec: 2 points; sec: 3 points; sec: 4 points; sec: 5 points; sec: 6 points; > 27 sec: 7 points.

41 Dynamisk balans Walking forward on a balance beam using a normal stride: Crossing the first part (31 cm): 1 point. Crossing the second (62 cm): 2 points. Crossing the third part (92 cm): 3 points. Crossing the fourth part (124 cm): 4 points.