Relazione Dott. Federico Prefumo

Translucenza nucale
aumentata in feti con cariotipo
normale: sindromi correlate
Federico Prefumo
Dipartimento di Ostetricia e Ginecologia
Università di Brescia
A.O. Spedali Civili di Brescia
NT aumentata e cariotipo normale: MEF
95% 99%
5
Rischio MEF (%)
MEF <24 sett
4
3
MEF >24 sett
2
1
0
-0.5
0.5
1.5
2.5
3.5
Delta NT (mm)
MEF (background): <24w 0.5%
>24w 0.5%
Spencer et al 2006
4.5
Rischio di morte endouterina fetale
54722 gravidanze singole: MEF 0.5% <24 sett. e 0.5% >24 sett.
20
7
6
15
5
MEF <24 sett.
4
Rischio MEF (%)
Rischio MEF (%)
MEF >24 sett.
MEF >24 sett.
3
2
10
MEF <24 sett.
5
1
0
0
0
0.20.30.4
0.6
0.8
1.0
1.2
Free ß-hCG (MoM)
ß-hCG <5* (0.4MoM) – DR MEF <24 sett 12%
Spencer et al 2006
MEF >24 sett 12%
0
0.20.3 0.4
0.6
0.8
1.0
1.2
PAPP-A MoM
PAPPPAPP-A <5° (0.4MoM) – DR MEF <24 s 15%
MEF >24 s 8%
NT aumentata e cariotipo normale: anomalie fetali
Cariotipo alterato
%
Translucenza
nucale
Cariotipo normale
<95° percentile
1.6%
95°-99° percentile
2.5%
3.5-4.4 mm
10.0%
4.5-5.4 mm
18.5%
5.5-6.4 mm
24.2%
>6.5 mm
46.2%
100
90
80
70%
70
60
50
45%
50%
40
30
20%
20
10
0
5%
NT 3
4
5
6
>7
Malformazioni
fetali
NT aumentata è associata con:
• tutte le principlai anomalie
cromosomiche
• > 50 malformazioni e sindromi
genetiche
• il R aumenta all’aumentare dell’NT
NT aumentata - fisiopatologia
Malformazioni cardiache
congenite
Compressione intratoracica
Anomalie del sistema linfatico
Patologie neuromuscolari
Anomalie di composizione del
derma
Anomalie associate con NT aumentata
Cardiache
Cardiache
Musculoscheletriche
acondrogenesi
osteogenesi imperfetta
distrofia toracica di Jeune
displasia campomelica
fetal akinesia deformation sequence
Strutturali
ernia diaframmatica
onfalocele
body stalk anomaly
Screening per malformazioni fetali a 11-13+6 sett.
Anatomia normale
Screening per malformazioni a 11-13+6 sett.
Diagnosi di malformazioni fetali
Anomalie associate con NT aumentata
Cardiache
Cardiache
Musculoscheletriche
acondrogenesi
osteogenesi imperfetta
distrofia toracica di Jeune
displasia campomelica
fetal akinesia deformation sequence
Strutturali
ernia diaframmatica
onfalocele
body stalk anomaly
Clur SA et al. Prenat Diagn 2009; 29: 739–748
Screening delle cardiopatie congenite
Fattori di rischio
Anamnesi
Madre
Padre
6%
2%
Un fratello
Due fratelli
2%
10%
Diabete Mellito
2%
Teratogeni
Talidomide
10%
Litio
5%
Antiepilettici
1%
First‐trimester ductus venosus screening for cardiac defects:
a meta‐analysis
BJOG: An International Journal of Obstetrics & Gynaecology
Volume 118, Issue 12, pages 1438-1445, 14 JUN 2011 DOI: 10.1111/j.1471-0528.2011.03029.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2011.03029.x/full#f2
First‐trimester ductus venosus screening for cardiac defects:
a meta‐analysis
BJOG: An International Journal of Obstetrics & Gynaecology
Volume 118, Issue 12, pages 1438-1445, 14 JUN 2011 DOI: 10.1111/j.1471-0528.2011.03029.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2011.03029.x/full#f4
NT aumentata e cariotipo normale
Craniosynostosis
Iniencephaly
Agnathia/micrognathia
Cardiac defects
Diaphragmatic hernia
Exomphalos
Megacystis
Renal agenesis
Polycystic kidneys
Multicystic kidneys
Nephrotic syndrome
Body stalk anomaly
Congenital lymphedema
Akinesia deformation sequence
Myotonic dystrophy
Spinal muscular atrophy
Souka et al. Am J Ob Gyn 2004
Beckwith-Wiedemman syndrome
GM1-gangliosidosis
Mucopolysaccharidosis type VII
Smith-Lemli-Opitz syndrome
Vitamin D resistant rickets
Zellweger syndrome
Brachmann-de Lange syndrome
Charge association
di George syndrome
EEC syndrome
Fryn syndrome
Noonan syndrome
Perlman syndrome
Stickler syndrome
Treacher-Collins syndrome
Trigonocephaly C syndrome
VACTER association
Achondrogenesis
Achondroplasia
Asphyxiating thoracic dystrophy
Blomstrand osteochondrodysplasia
Campomelic dysplasia
Hypophosphatasia
Jarcho-Levin syndrome
Nance-Sweeney syndrome
Osteogenesis imperfecta
Roberts syndrome
Short-rib-polydactily syndrome
Sirenomelia
Thanatophoric dysplasia
Blackfan Diamond anaemia
Dyserythropoietic anaemia
Thalassaemia-a
Parvovirus B19 infection
NT e malattie metaboliche
Disorder
Fetuses tested (n)
Affected (n)
NT measurement in
affected fetuses (mm)
Austin’s disease
Acid lipase deficiency
Fucosidosis
1
1
1
0
0
0
Galactosialidosis
1
0
Gangliosidosis GM1
Gaucher disease type II
Glycogenosis type I
4
6
1
0
3
0
Glycogenosis type II
Krabbe disease
Metachromatic leukodystrophy
Menkes disease
9
4
6
2
2
1
1
0
1.6, 1.4
1.4
1.8
Mucopolysaccharidosis type I
Mucopolysaccharidosis type II
Mucopolysaccharidosis type IIIA
5
5
4
2
1
0
1.2, 1.4
1.7
Mucopolysaccharidosis type IIIB
2
0
Mucopolysaccharidosis type IVB
2
0
Mucopolysaccharidosis type VI
2
0
Mucolipidosis type II
1
0
Niemann–Pick disease type A
Pelizaeus–Merzbacher
Sialidosis
Zellweger syndrome
Tay-Sachs disease
2
3
1
1
2
1
1
1
0
0
Total
66
13
0.6, 1.2, 1.4
1.5
1.2
1.1
De Biasio P et al. Prenat Diagn 2006; 26: 77–80
S. di Noonan
La sindrome di Noonan è caratterizzata da:
Prevalenza 1 su 1000-2500 nati
- Bassa statura, difetti della coagulazione,
- Ritardo psicomotorio (30%)
- Difetti oculari (95%)
- collo corto e tozzo
- Basso impianto delle orecchie
- Cardiopatia congenita (50-80%): stenosi della polmonare con displasia (40-50%)
cardiomiopatia ipertrofica congenita o infantile (20-30%) altri difetti
strutturali: difetti del setto interventricolare e interatriale, stenosi delle
arterie polmonari e tetralogia di Fallot
Genetica: Autosomica dominante, 30-50% forme familiari
penetranza completa, espressività variabile e
eterogeneità genetica:
- 50% mutazioni gene PTNP11,
PTNP11 stenosi polmonare
- 13% mutazioni gene SOS1
- 3-17% mutazioni gene RAF1 cardiomiopatia ipertrofica
- 5% mutazioni gene KRAS
Centri di Diagnosi Molecolare e/o Citogenetica della S. di Noonan
BOLOGNA Policlinico S. Orsola-Malpighi U.O. di Genetica Medica
ROMA Istituto CSS-Mendel Laboratorio di Biologia Molecolare e Citogenetica
ROMA Università Cattolica del Sacro Cuore Istituto di Genetica Medica
Segni prenatali e sindrome di Noonan
Prenatal findings in Noonan syndrome
Total cases
Increased NT/cystic Hygroma
Distended JLS
Increased NF/cystic hygroma second
trimester
Pleural effusion
Ascites
Scalp/skin edema
Brachycephaly
Hypertelorism
Low set ears
Broad nose
Full lips
Cardiac anomalies
Renal anomalies
Polyhydramnios
Oligohydramnios
Short femur
Other anomalies
N
42
15
7
21
%
100
35.7
16.7
50
17
6
14
3
2
7
4
4
16
10
21
1
4
5
40.5
14.3
33
7.1
4.8
16.7
9.5
9.5
38.1
23.8
50
2.4
9.5
11.9
Bakker M et al. Prenat Diagn 2011; 31: 833–840
Management dell’NT aumentata
11-13+6 sett.
cariotipo
ecografia
Anomalie cromosomiche
Malformazioni fetali precoci
Cariotipo normale
Nessuna anomalia rilevabile all’ecografia del I trimestre
Malformazioni fetali
16 sett.
Morfologica precoce
Morfologica normale
NT ancora aumentata
Screening
infettivologico
Nessuna anomalia
Resolving nuchal
Malformazioni fetali
20 sett.
Morfologica
Ecocardio
Morfo normale
NT aumentata
Nessuna anomalia
Ripetiz. screening
infettivologico
Consul. genetica
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Results
337
studies
included
181 studies: excluded on title and abstract
156 studies
132 studies: excluded for lack of outcome data on
postnatal neurodevelopmental delay
7 studies: excluded for specifically assessing fetuses
with ↑ NT for a genetic syndrome
17 studies
included in the systematic review
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Fetuses with ↑ NT and normal at birth
NT
cut-off
Number
of studies
Pooled rate of neurodevelopmental
delay (N, 95% CI)
Total
17
1.14%
(28/2458, 0.79–1.64)
99th centile
8
0.96%
(15/1567, 0.58–1.58)
95th centile
4
1.05%
(7/669, 0.51–4.88)
3 mm
5
2.70%
(6/222, 1.24–5.77)
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Fetuses with ↑ NT and normal 2nd trimester anomaly scan
NT
cut-off
Number
of studies
Pooled rate of neurodevelopmental
delay (N, 95% CI)
99th centile
8
1.08%
(15/1666, 95% CI 0.76–1.56)
95th centile
4
1.01%
(7/691, 0.49–2.07)
3 mm
5
2.47%
(6/243, 1.14–5.28)
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Presence of nuchal edema at the second trimester scan (4 studies)
NT>99th centile
AND
Pooled rate of neurodevelopmental
delay (N, 95% CI)
Normal nuchal fold
0.66%
(10/1494, 0.36–1.21)
Persistent nuchal edema
1.06%
(1/94, 0.19–5.78)
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Discussion
• Neurodevelopmental delay in fetuses with ↑ NT, normal fetal
karyotype and lack of structural defects or identifiable syndromes is
about 1%
• Rates of neurodevelopmental delay reported for the general population is
approximately 3%
• The low rate for developmental delay did not differ across the various
subgroup analyses
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Limitations
• Absence of firm consensus on the definition of developmental delay
• Possible sources of bias:
1.Screening bias: most studies used telephone interviews (parents may
under- or over-estimate child’s development)
2.Ascertainment bias: most studies did not offer sufficient information
about the steps which followed identification of high-risk infants at
screening
•
Syndromes are not always reliably identified (5/28 cases had an
unidentified genetic syndrome)
Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Conclusion
The risk for developmental delay in fetuses with increased firsttrimester NT is not increased compared to the general population, after
exclusion of chromosomal abnormalities, structural defects and genetic
syndromes.