1. MALATTIE CARDIACHE CONGENITE
E
SINDROMI GENETICHE
Bruno Marino
Dipartimento di Pediatria
Università di Roma “La Sapienza”
bruno.marino@uniroma1.it
AGGIORNAMENTI DI
ECOCARDIOGRAFIA
FETALE. II edizione
18-19 APRILE 2015

2. Baltimore-Washington Infant Study 1981-1989
CASE-CONTROL DISTRIBUTION
OF NONCARDIAC MALFORMATIONS
CASES CONTROLS
Chrom 11.9%
Syndr 8.3%
Deform 2.2%
Org An 5.2%
Chrom 0.1%
Syndr 0.8%
Or An 1%
Deform 1.7%
Congenital Heart Diseases
Epidemiology
2011;159(1):70-78

3. Maria Victoria de la Cruz
AoS
RV
LV
Atria
RV
LV
CT
RV
LV
Atria
Embriology of the Heart
J Anat 1977;123:661
1916-1999

4. New Clinical Roles of Genetics
“REVERSE MEDICINE”
New Diagnostic Criteria
“PREDICTIVE MEDICINE”
Gene-Prognosis Correlation
“GENE THERAPY” ?
Stem Cells Therapy ?

5. Cardiovasc Pathol. 2000; 9(6):303-15
“REVERSE MEDICINE”
New Diagnostic Criteria

6. RA
LA
RV
LV
J Thorac Cardiov Surg 1986; 91: 467
Down Syndrome
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

7. Partial AVSD surgical experience
128 pts
< 1 Year
> 1 Year
Surgery before 1 yr
35 pts (27%)
Non-Down 80%
Mean age 5.0 mos
Mortality=31%
Surgery after 1 yr
93 pts (73%)
Mean age 5.5 yrs
Mortality=0%
Ann Thorac Surg 1996; 62: 151-4
Ann Thorac Surg 1996;62:151
Ann Thorac Surg 2004;78:666
AV Canal Defect
in Down Syndrome
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

8. Ann Thorac Surg 1995;59:573
ASD, VSD, TF repair
in Down Syndrome
Ann Thor Surg, 2006; 81: 968-75
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

9. Pediatrics, 2010;126:315-22
Postoperative
Complications
in Down Syndrome
J Pediatrics, 2011;158:319
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

10. Del22q11 Syndrome
DiGeorge/VCF Syndrome

11. Am J Cardiol 1996; 77: 505
Progress in Ped Cardiol 2002; 15: 9-17
Am J Cardiol 1999; 84: 360-1
Eur J Pediatr 2002; 161:11
Del22q11 Syndrome
- Cardiac Defects
“REVERSE MEDICINE”
New Diagnostic Criteria

12. 0
,2
,4
,6
,8
1
Cum.Survival
0 10 20 30 40 50 60
Time
Kaplan-M e ie r Cum . Survival Plot for f/up
Ce ns or Variable : s tatus
Grouping Variable : s nd type
vactrel
other
none
del22q11dow n
p= NS
Ann Thor Surg, 2006; 81: 968-75
JTCVS 2009;138:565-570
Del22q11 Syndrome -
Surgical Results
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

13. Del22q11 Syndrome
postoperative complications
J Thorac Cardiovasc Surg. 2014;148:1597-605
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

14. Del22q11 Syndrome -
Postoperative Care
Vasomotor instability
Hypertension
Hypotension
V Shashi, AJMG 2003;1211:231
Infections A Carotti, JTCVS 2003;126:1666
bacterial
fungal
Airways obstruction
Broncospasm
Vascular ring K Momma, JACC 1996;27:198
Laringeal web McElhinney, IJPO 2002;66:23
M Ackarman, JTCVS 2001;122:169
Hypocalcemia
Esophageal and GI anomalies
Renal defects
V Jatana,
Pediatr Crit Care Med 2007;8(5):459-63
Pediatr Crit Care Med 2007;8(5):459-63
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

15. J Pediatr 1999; 135:703
Nat Genet 2001; 29: 465-468
Noonan Syndrome
Nat Genet 2001; 29: 465-468
“REVERSE MEDICINE”
New Diagnostic Criteria

16. Am J Hum Genet 2002; 71: 389-394
LEOPARD Syndrome
Am J Hum Genet 2002; 71: 389-394
“REVERSE MEDICINE”
New Diagnostic Criteria

17. Am J Med Genet A 2008; 146A: 620-628
Am J Cardiol 2007; 100:736-41
Noonan-LEOPARD Syndromes
Genotype – Prognosis Correlations
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

18. Noonan-LEOPARD
Syndromes
Post-Operative Outcome
Overall
(n=15)
Early
(n=28)
Midterm
(n=43 )
Overall
(n=6)
Early
(n=3)
Midterm
(n=3)
MORTALITY REINTERVENTION
Multicenter study among 384 pts with Noonan or related
syndromes
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

19. Pediatrics 2014; In press
Noonan-LEOPARD Syndromes
Post-Operative Complications
Additional extracardiac anomalies
• Gastrointestinal
• Genitourinary
• Cerebrovascular
• Lymphatic
• Haematologic
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

20. Eur J Cardiothorac Surg 2009;35(4):606-14
Turner SyndromeMarfan Syndrome
Williams Syndrome Alagille Syndrome
“PREDICTIVE MEDICINE”
Gene-prognosis correlation

21. Science 2004; 306: 247-251
“GENE THERAPY” ?
Stem Cells Therapy ?

22. Cardiol Young 2012;22:558-563
“GENE THERAPY” ?
Stem Cells Therapy ?

23. Future Cardiol 2012; 8(2):161-169
“GENE THERAPY” ?
Stem Cells Therapy ?

24. Ann Thor Surg, 2006; 81: 968-75
0
,2
,4
,6
,8
1Cum.Survival
0 10 20 30 40 50 60
Time
Kaplan-Meier Cum. Survival Plot for f/up
Censor Variable: status
Grouping Variable: snd type
vactrel
other
none
del22q11dow n
p= NS
Ann Surg. 1955; 142: 418–442
TETRALOGY OF FALLOT
Surgical Outcome

25. “Ho quasi undici anni e mezzo, mi piace leggere, prima la
matematica mi sembrava difficile ma adesso va meglio.
Suono il clarinetto nella banda della scuola e faccio parte
degli scout. Mi piace essere organizzata e per questo la
mia stanza è molto pulita. Sono fortunata a poter fare così
tante cose. Voglio che sappiate che anche se ho la
sindrome di Down sto bene.”
Sarah Itah – The New York Time 2007
…io sto bene…