Mocaisism, growth, and IGF-1 mitigates ear and hearing ... · •Cubiti valgi •Hjärtmissbildning •Kärlmissbildning ... Marie-Louise Barrenäs, 22 maj, 2008 FISH. Örats anatomi

Marie-Louise Barrenäs, 22 maj, 2008

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


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


FISH

Örats anatomi

Marie-Louise Barrenäs, 23 March, 2013, Hurghada, Egypt


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)(q11q28)

– 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)(qterq27::p11q27::q27p11::q27qter)

•46,X,der(X)


Conventional paradigm

• Compare monosomics

versus non-monosomics

One hypothesis

That loss of the

SHOX-geneplays 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)



Göteborg ClassificationBarrenäs et al., 2007

• Monosomy

– 45,X

Dvs underskott av

genetiskt material

i alla celler

•Mosaics

– 45,X/46,XX

Dvs underskott av

genetiskt material

i vissa celler, men en frisk 46,XX linje

•Others

Dvs överskott av

genetiskt material

i alla celler

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)


Ear and hearing disorders

are common in Turner Syndrome

50-80 % recurrent otitis media during childhood

70-90 % sensorineural hearing loss as adults

30-60 % minor auricular malformations

Lindsten, 1963

Watkin, 1989

Hultcrantz et al., 1994

Barrenäs et al., 1999


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


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


115 girls and women with TS

56 monosomy (45,X)

9 isochromosomy

(46,X,i,(Xq)

22 mocaisism

11 structural deletion

q

q


Auricular anomalies

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: 1.0-3.8; p<0.05)

Auricularanomaly

Yes No

Totaldeletion

30% 35%

Partialdeletion

8% 27%

Recurrent otitis media

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: 0.9-1.7; p<0.10)

Otitismedia Yes No

Totaldeletion

49% 17%

Partialdeletion

21% 13%

Conductive Hearing Loss

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: 1.0 - 7.6)

Cond HL Yes No

Totaldeletion

22% 44%

Partialdeletion

2% 32%

Samband mellan TS genotyp ochfenotyp 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)



Öron- och Hörsel problem vid TSBeroende på p-arm (totalt/partiellt bortfall)

Genetik

Ju gravare kromosom-skada (karyotype / FISH)

Desto högre förekomst av ytteröron anomalier

Tillväxt

Ju kortare

Ju lägre IGF-1 nivå

Desto högre andel av öronbarn / ledningsfel pga otosalpingit

Desto gravare SNHL

Ett litet antal TS har cochlea implantat


https://sv.wikipedia.org/wiki/Cochleaimplantat

Ingen effekt av GH eller östrogen på hörsel, otiter

• Oxandrolone

• GH (Davenport et al., 2010; Ko et al., 2010; )

• Estrogen (Hedenstierna et al., 2009)



FinmotorikRing, Iso, Trisomi, Y (others, n=14)

• Age - **• Faktorer inom

Metabola Syndromet

(Abdominal Fat, glucos, BP) - **

• Bentäthet **


BalansRing, Iso, Trisomi, Y (others, n=14)

• Age - **• Faktorer inom

Metabola Syndromet - **(Abdominal Fat, BP)

• Benvariabler **(BMD, IGF-1)


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


Growth promoting treatment normalizes speech frequency in Turner syndrome

Andersson-Wallgren Gunnel, speech pathologist, 1

Ohlsson Ann-Christine, speech pathologist, PhD2

Albertsson-Wikland Kerstin, MD, professor1

Barrenäs Marie-Louise, MD associate professor1

Laryngoscope, 2008


Differences in SFF

-40

-20

0

20

40

60

80

100S

FF

(H

z)

<29 yy 30-39 yy 40-59 yy

45,X0 vs mosaics 45,X0 vs controls Mosaics vs controls


SFF vs age

Monosomy and Isochromosomy cases

0

100

200

300

400

10 20 30 40 50 60

Age

SF

F

Mosaics or structural deletions

0

100

200

300

400

10 20 30 40 50 60

Age

SF

F


The Cell cycle delay hypothesis

(Barrenäs, Nylén, Hanson, 1999)

(Barrenäs, Landin-Wilhelmsen, Hanson, 2000)


Tid

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


The higher thefrequency of

chromosomallyabnormal cells

such as 45,X...

Specificmechanisms:

...the fewer growthregulating genes

General mechanisms:...the fewer cellcleavages due to cellcycle delay

In vivo selection

Fewer cellsGrowth disturbance

”Developmental delay””Anomaly”

”Dysplasia”

1. Auricular malforamtion2. Otitis media

due to a poorly developed

mastoid and a shorteningof the cranial base, whichin turn affects theEustachian tube

3. Mid frequency SNHLdue to fewer hair cells

4. High frequency SNHL

Fewer hair cells from birthThe age-related hair cellsloss will cause hearingloss earlier in life

5. The proportionof chromosomallyabnormal cellsdeclines with

increased age

The cell cycle delay hypothesis

Mondini

• Bodet et al., 2012

• Fish et al., 2009


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 213038124.

Turner syndrome isochromosome karyotype

correlates with decreased dental crown width.


https://www.ncbi.nlm.nih.gov/pubmed/22834215




Turner karyotype and childbirthAnna 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)


http://www.gu.se/english/research/publication?publicationId=175655

http://www.gu.se/omuniversitetet/vara-fakulteter/omdirigering-person?userId=xhannt&userName=Anna+Hagman&languageCode=en


Studier på normalpopulation: Hörselfunktion och tillväxt


Data

• Swedish Birth Register

• Swedish Conscripts Register

• 245.092 conscripts born 1973-1978.

• Odds Ratio


Birth size: an indirect marker for

intrauterine growth retardation

Small for Gestational Age

SGA


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)


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%


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)(q11q28)

– 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)(qterq27::p11q27::q27p11::q27qter)

•46,X,der(X)


Romberg + Tandem Romberg

Öppna ögon

< 6 sec: 0 points; 6-15 sec: 1 point; 16-25 sec: 2 points; > 25 sec: 3 points.

Slutna ögon:

1-5 sec: 1 point; 6-10 sec: 2 points; 11-15 sec: 3 points; 16-20 sec: 4 points;

21-25 sec: 5 points; >25 seconds: 6 points.


Stå på ett ben

Öppna ögon:

< 5 sec: 0 points; 5-9 sec: 1 point; 10-17 sec: 2 points; 18-25 sec: 3 points;> 25 sec: 4 points.

Slutna ögon:

< 6 sec: 0 points; 6-9 sec: 1 point; 10-13 sec: 2 points; 14-16 sec: 3 points;

17-20 sec: 4 points; 21-24 sec: 5 points; 25-27 sec: 6 points; > 27 sec: 7 points.


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.

Documents

Mocaisism, growth, and IGF-1 mitigates ear and hearing ... · •Cubiti valgi •Hjärtmissbildning •Kärlmissbildning ... Marie-Louise Barrenäs, 22 maj, 2008 FISH. Örats anatomi