Conotruncal heart defects and chromosome 22q11microdeletion
1997; Elsevier BV; Volume: 130; Issue: 4 Linguagem: Inglês
10.1016/s0022-3476(97)70260-9
ISSN1097-6833
AutoresM. Cristina Digilio, Bruno Marino, Aldo Giannotti, Giuseppe Novelli, Bruno Dallapiccola,
Tópico(s)Coronary Artery Anomalies
ResumoTo the Editor:We read with interest, in a recent issue of The Journal, the article by Webber et al., 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar reporting the prevalence of 22q11 microdeletion (del22q11) in patients with conotruncal heart defects (CTHDs), and the related comments of Johnson et al., 2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar published in the Editor's Column section of the same issue. The authors pointed out the importance of del22q11 as a cause of specific cardiac malformations in the setting of DiGeorge or velocardiofacial syndrome, 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar whereas a low risk of deletion has been recognized in nonsyndromic patients. 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar These results support the experience of our group, documenting that classic or even “subtle” facial dysmorphisms are constantly present in patients with del22q11, and the occurrence of del22q11 in isolated patients with conotruncal cardiac defects is extremely low. 3Amati F Mari A Digilio MC Mingarelli R Marino B Giannotti A et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.Hum Genet. 1995; 95: 479-482Crossref PubMed Scopus (118) Google Scholar,4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar,5Digilio MC Marino B Mingarelli R Novelli G Amati F Mari A et al.Isolated conotruncal heart defects are really related to microdeletion of chromosome 22q11? [Abstract].J Am Coll Cardiol. 1996; 27: 93AGoogle Scholar We report our up-to-date results, with inclusion in the study of del22q11 by fluorescent in situ hybridization (FISH) of patients with other types of CTHDs. On the whole, we have hitherto analyzed 315 children with CTHDs. All patients underwent accurate clinical and phenotypical examination by two geneticists at the time of first observation and blood sampling, and again after 6 months. In particular, mild dysmorphic features were searched, including lateral displacement of inner canthi, narrow up-slanting palpebral fissures, prominent nose, small mouth, dysmorphic ears, and slender fingers. Clinical analysis revealed that 205 patients were nonsyndromic, including 105 patients with classic tetralogy of Fallot (TF), 20 with TF plus pulmonary atresia, 41 with transposition of the great arteries, 30 with congenitally corrected transposition, 10 with double-outlet right ventricle, and 7 with truncus arteriosus. The microdeletion del22q11 has been detected in only one of these patients, a girl with transposition of the great arteries 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar who was no longer alive at the time of revaluation for mild anomalies. Considering our cases as a whole, del22q11 has been identified in 12% (38/315) of all the patients, in 33% (37/111) of the syndromic patients, and in 74% (37/50) of the patients with a clinical diagnosis of DiGeorge or velocardiofacial syndrome. In our series the prevalence of patients with a phenotypic appearance consistent with CATCH-22 syndrome ( c ardiac defects, a bnormal facies, t hymic hypoplasia, c left palate, and h ypocalcemia), but lacking del22q11 (26%), is lower than that reported by Webber et al., 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar nevertheless indicating that such a subgroup of children does exist. 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar,7Lindsay EA Greenberg F Shaffer LG Shapira SK Scambler PJ Baldini A Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region.Am J Med Genet. 1995; 56: 191-197Crossref PubMed Scopus (107) Google Scholar We have suggested that the syndrome in these patients be called “CATCH-non-22 syndrome.” 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar In addition, we completely agree with Webber et al. that certain cardiac defects are associated with a higher incidence of del22q11. We have compared the occurrence of genetic syndromes in patients with classic TF and in those with TF and pulmonary atresia. 8Digilio MC Marino B Grazioli S Agostino D Giannotti A Dallapiccola B Comparison of occurrence of genetic syndromes in ventricular septal defect with pulmonic stenosis (classic tetralogy of Fallot) versus ventricular septal defect with pulmonic atresia.Am J Cardiol. 1996; 77: 1375-1376Abstract Full Text PDF PubMed Scopus (70) Google Scholar It is evident that classic TF can be associated with many genetic conditions, del22q11 having been diagnosed in 6% of the patients, but most cases are nonsyndromic. Patients with TF and pulmonary atresia, on the contrary, have a high incidence of genetic syndromes, del22q11 representing 32% of the total in our series. Considering that truncus arteriosus and interruption of the aortic arch are classically considered CTHDs in which there is a particular risk of del22q11, with a prevalence of del22q11 estimated around 30% and 55%, respectively, 9Goldmuntz E Emanuel BS Molecular genetic defects and cardiac morphogenesis.Progress in Pediatric Cardiology. 1996; 5: 113-121Abstract Full Text PDF Scopus (1) Google Scholar TF with pulmonary atresia must also be included among the defects strongly related to monosomy 22q11.However, the detection of del22q11 in CTHDs rarely associated with the DiGeorge and velocardiofacial syndromes 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar implies the need of an accurate phenotypical examination of all patients with a CTHD not only those affected by specific cardiac malformations. It is obvious that clinical evaluation can be subjective, but we believe that the support of experience and familiarity with the specific dysmorphisms makes phenotypic examination the first required screening to identify patients with CTHDs at risk of del22q11. Our experience is based on a numerically representative sample of patients with CTHDs, and the prevalence of del22q11 in nonsyndromic patients is effectively very low, as further corroborated by the results of other research groups. 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,10Takahashi K Kido S Hoshino K Ogawa K Ohashi H Fukushima Y Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: a prospective study.Eur J Pediatr. 1995; 154: 878-881Crossref PubMed Scopus (80) Google Scholar,11Debrus S Berger G de Meeus A Sauer U Guillaumont S Voisin M et al.Familial nonsyndromic conotruncal defects are not associated with a 22q11 microdeletion.Hum Genet. 1996; 97: 138-144Crossref PubMed Scopus (51) Google Scholar In addition, the absence of del22q11 in our series of patients with nonsyndromic cleft palate, 12Mingarelli R Digilio MC Mari A Amati F Standoli L Giannotti A et al.The search for hemizygosity at 22q11 in patients with isolated cleft palate.J Craniofac Genet Dev Biol. 1996; 16: 118-121PubMed Google Scholar another characteristic sign of velocardiofacial syndrome, supports the evidence that a single isolated dysmorphic feature in a nonsyndromic patient is probably related to etiologic factors different from del22q11. 3Amati F Mari A Digilio MC Mingarelli R Marino B Giannotti A et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.Hum Genet. 1995; 95: 479-482Crossref PubMed Scopus (118) Google Scholar, 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar, 5Digilio MC Marino B Mingarelli R Novelli G Amati F Mari A et al.Isolated conotruncal heart defects are really related to microdeletion of chromosome 22q11? [Abstract].J Am Coll Cardiol. 1996; 27: 93AGoogle Scholar, 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar Furthermore, the relatively high prevalence of del22q11 previously reported by Goldmuntz et al., 13Goldmuntz E Driscoll D Budarf ML Zackai EH McDonald-McGinn DM Biegel JA et al.Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects.J Med Genet. 1993; 30: 807-812Crossref PubMed Scopus (198) Google Scholar in their series of apparently isolated CTHD patients, has recently been modified because of the demonstration of mild dysmorphisms in the studied cases. 9Goldmuntz E Emanuel BS Molecular genetic defects and cardiac morphogenesis.Progress in Pediatric Cardiology. 1996; 5: 113-121Abstract Full Text PDF Scopus (1) Google Scholar We agree that “early identification of patients with the CATCH-22 syndrome may be of critical importance,” 2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar but we suggest that an accurate phenotypic analysis, including cardiac phenotype, 14Marino B Digilio MC Grazioli S Formigari R Mingarelli R Giannotti A et al.Associated cardiac anomalies in isolated and syndromic patients with tetralogy of Fallot.Am J Cardiol. 1996; 77: 505-508Abstract Full Text PDF PubMed Scopus (58) Google Scholar can identify patients at risk of having del22q11.In conclusion, we believe that routine FISH analysis for definition of the precise prevalence of del22q11 in all types of syndromic and isolated congenital heart defects could be reserved to selected research groups, whereas in clinical practice the screening by clinical and phenotypic analysis is sufficient for selection of patients at risk of having del22q11. FISH analysis must be performed in patients with CTHDs and one or more additional phenotypic sign of CATCH-22 and related syndromes. In our opinion, this selection makes it possible to avoid the indiscriminate use of expensive genetic techniques and the unjustified anxiety that can be generated in the parents of an affected child. To the Editor:We read with interest, in a recent issue of The Journal, the article by Webber et al., 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar reporting the prevalence of 22q11 microdeletion (del22q11) in patients with conotruncal heart defects (CTHDs), and the related comments of Johnson et al., 2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar published in the Editor's Column section of the same issue. The authors pointed out the importance of del22q11 as a cause of specific cardiac malformations in the setting of DiGeorge or velocardiofacial syndrome, 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar whereas a low risk of deletion has been recognized in nonsyndromic patients. 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar These results support the experience of our group, documenting that classic or even “subtle” facial dysmorphisms are constantly present in patients with del22q11, and the occurrence of del22q11 in isolated patients with conotruncal cardiac defects is extremely low. 3Amati F Mari A Digilio MC Mingarelli R Marino B Giannotti A et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.Hum Genet. 1995; 95: 479-482Crossref PubMed Scopus (118) Google Scholar,4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar,5Digilio MC Marino B Mingarelli R Novelli G Amati F Mari A et al.Isolated conotruncal heart defects are really related to microdeletion of chromosome 22q11? [Abstract].J Am Coll Cardiol. 1996; 27: 93AGoogle Scholar We report our up-to-date results, with inclusion in the study of del22q11 by fluorescent in situ hybridization (FISH) of patients with other types of CTHDs. On the whole, we have hitherto analyzed 315 children with CTHDs. All patients underwent accurate clinical and phenotypical examination by two geneticists at the time of first observation and blood sampling, and again after 6 months. In particular, mild dysmorphic features were searched, including lateral displacement of inner canthi, narrow up-slanting palpebral fissures, prominent nose, small mouth, dysmorphic ears, and slender fingers. Clinical analysis revealed that 205 patients were nonsyndromic, including 105 patients with classic tetralogy of Fallot (TF), 20 with TF plus pulmonary atresia, 41 with transposition of the great arteries, 30 with congenitally corrected transposition, 10 with double-outlet right ventricle, and 7 with truncus arteriosus. The microdeletion del22q11 has been detected in only one of these patients, a girl with transposition of the great arteries 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar who was no longer alive at the time of revaluation for mild anomalies. Considering our cases as a whole, del22q11 has been identified in 12% (38/315) of all the patients, in 33% (37/111) of the syndromic patients, and in 74% (37/50) of the patients with a clinical diagnosis of DiGeorge or velocardiofacial syndrome. In our series the prevalence of patients with a phenotypic appearance consistent with CATCH-22 syndrome ( c ardiac defects, a bnormal facies, t hymic hypoplasia, c left palate, and h ypocalcemia), but lacking del22q11 (26%), is lower than that reported by Webber et al., 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar nevertheless indicating that such a subgroup of children does exist. 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar,7Lindsay EA Greenberg F Shaffer LG Shapira SK Scambler PJ Baldini A Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region.Am J Med Genet. 1995; 56: 191-197Crossref PubMed Scopus (107) Google Scholar We have suggested that the syndrome in these patients be called “CATCH-non-22 syndrome.” 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar In addition, we completely agree with Webber et al. that certain cardiac defects are associated with a higher incidence of del22q11. We have compared the occurrence of genetic syndromes in patients with classic TF and in those with TF and pulmonary atresia. 8Digilio MC Marino B Grazioli S Agostino D Giannotti A Dallapiccola B Comparison of occurrence of genetic syndromes in ventricular septal defect with pulmonic stenosis (classic tetralogy of Fallot) versus ventricular septal defect with pulmonic atresia.Am J Cardiol. 1996; 77: 1375-1376Abstract Full Text PDF PubMed Scopus (70) Google Scholar It is evident that classic TF can be associated with many genetic conditions, del22q11 having been diagnosed in 6% of the patients, but most cases are nonsyndromic. Patients with TF and pulmonary atresia, on the contrary, have a high incidence of genetic syndromes, del22q11 representing 32% of the total in our series. Considering that truncus arteriosus and interruption of the aortic arch are classically considered CTHDs in which there is a particular risk of del22q11, with a prevalence of del22q11 estimated around 30% and 55%, respectively, 9Goldmuntz E Emanuel BS Molecular genetic defects and cardiac morphogenesis.Progress in Pediatric Cardiology. 1996; 5: 113-121Abstract Full Text PDF Scopus (1) Google Scholar TF with pulmonary atresia must also be included among the defects strongly related to monosomy 22q11.However, the detection of del22q11 in CTHDs rarely associated with the DiGeorge and velocardiofacial syndromes 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar implies the need of an accurate phenotypical examination of all patients with a CTHD not only those affected by specific cardiac malformations. It is obvious that clinical evaluation can be subjective, but we believe that the support of experience and familiarity with the specific dysmorphisms makes phenotypic examination the first required screening to identify patients with CTHDs at risk of del22q11. Our experience is based on a numerically representative sample of patients with CTHDs, and the prevalence of del22q11 in nonsyndromic patients is effectively very low, as further corroborated by the results of other research groups. 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,10Takahashi K Kido S Hoshino K Ogawa K Ohashi H Fukushima Y Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: a prospective study.Eur J Pediatr. 1995; 154: 878-881Crossref PubMed Scopus (80) Google Scholar,11Debrus S Berger G de Meeus A Sauer U Guillaumont S Voisin M et al.Familial nonsyndromic conotruncal defects are not associated with a 22q11 microdeletion.Hum Genet. 1996; 97: 138-144Crossref PubMed Scopus (51) Google Scholar In addition, the absence of del22q11 in our series of patients with nonsyndromic cleft palate, 12Mingarelli R Digilio MC Mari A Amati F Standoli L Giannotti A et al.The search for hemizygosity at 22q11 in patients with isolated cleft palate.J Craniofac Genet Dev Biol. 1996; 16: 118-121PubMed Google Scholar another characteristic sign of velocardiofacial syndrome, supports the evidence that a single isolated dysmorphic feature in a nonsyndromic patient is probably related to etiologic factors different from del22q11. 3Amati F Mari A Digilio MC Mingarelli R Marino B Giannotti A et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.Hum Genet. 1995; 95: 479-482Crossref PubMed Scopus (118) Google Scholar, 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar, 5Digilio MC Marino B Mingarelli R Novelli G Amati F Mari A et al.Isolated conotruncal heart defects are really related to microdeletion of chromosome 22q11? [Abstract].J Am Coll Cardiol. 1996; 27: 93AGoogle Scholar, 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar Furthermore, the relatively high prevalence of del22q11 previously reported by Goldmuntz et al., 13Goldmuntz E Driscoll D Budarf ML Zackai EH McDonald-McGinn DM Biegel JA et al.Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects.J Med Genet. 1993; 30: 807-812Crossref PubMed Scopus (198) Google Scholar in their series of apparently isolated CTHD patients, has recently been modified because of the demonstration of mild dysmorphisms in the studied cases. 9Goldmuntz E Emanuel BS Molecular genetic defects and cardiac morphogenesis.Progress in Pediatric Cardiology. 1996; 5: 113-121Abstract Full Text PDF Scopus (1) Google Scholar We agree that “early identification of patients with the CATCH-22 syndrome may be of critical importance,” 2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar but we suggest that an accurate phenotypic analysis, including cardiac phenotype, 14Marino B Digilio MC Grazioli S Formigari R Mingarelli R Giannotti A et al.Associated cardiac anomalies in isolated and syndromic patients with tetralogy of Fallot.Am J Cardiol. 1996; 77: 505-508Abstract Full Text PDF PubMed Scopus (58) Google Scholar can identify patients at risk of having del22q11.In conclusion, we believe that routine FISH analysis for definition of the precise prevalence of del22q11 in all types of syndromic and isolated congenital heart defects could be reserved to selected research groups, whereas in clinical practice the screening by clinical and phenotypic analysis is sufficient for selection of patients at risk of having del22q11. FISH analysis must be performed in patients with CTHDs and one or more additional phenotypic sign of CATCH-22 and related syndromes. In our opinion, this selection makes it possible to avoid the indiscriminate use of expensive genetic techniques and the unjustified anxiety that can be generated in the parents of an affected child. We read with interest, in a recent issue of The Journal, the article by Webber et al., 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar reporting the prevalence of 22q11 microdeletion (del22q11) in patients with conotruncal heart defects (CTHDs), and the related comments of Johnson et al., 2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar published in the Editor's Column section of the same issue. The authors pointed out the importance of del22q11 as a cause of specific cardiac malformations in the setting of DiGeorge or velocardiofacial syndrome, 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar whereas a low risk of deletion has been recognized in nonsyndromic patients. 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar These results support the experience of our group, documenting that classic or even “subtle” facial dysmorphisms are constantly present in patients with del22q11, and the occurrence of del22q11 in isolated patients with conotruncal cardiac defects is extremely low. 3Amati F Mari A Digilio MC Mingarelli R Marino B Giannotti A et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.Hum Genet. 1995; 95: 479-482Crossref PubMed Scopus (118) Google Scholar,4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar,5Digilio MC Marino B Mingarelli R Novelli G Amati F Mari A et al.Isolated conotruncal heart defects are really related to microdeletion of chromosome 22q11? [Abstract].J Am Coll Cardiol. 1996; 27: 93AGoogle Scholar We report our up-to-date results, with inclusion in the study of del22q11 by fluorescent in situ hybridization (FISH) of patients with other types of CTHDs. On the whole, we have hitherto analyzed 315 children with CTHDs. All patients underwent accurate clinical and phenotypical examination by two geneticists at the time of first observation and blood sampling, and again after 6 months. In particular, mild dysmorphic features were searched, including lateral displacement of inner canthi, narrow up-slanting palpebral fissures, prominent nose, small mouth, dysmorphic ears, and slender fingers. Clinical analysis revealed that 205 patients were nonsyndromic, including 105 patients with classic tetralogy of Fallot (TF), 20 with TF plus pulmonary atresia, 41 with transposition of the great arteries, 30 with congenitally corrected transposition, 10 with double-outlet right ventricle, and 7 with truncus arteriosus. The microdeletion del22q11 has been detected in only one of these patients, a girl with transposition of the great arteries 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar who was no longer alive at the time of revaluation for mild anomalies. Considering our cases as a whole, del22q11 has been identified in 12% (38/315) of all the patients, in 33% (37/111) of the syndromic patients, and in 74% (37/50) of the patients with a clinical diagnosis of DiGeorge or velocardiofacial syndrome. In our series the prevalence of patients with a phenotypic appearance consistent with CATCH-22 syndrome ( c ardiac defects, a bnormal facies, t hymic hypoplasia, c left palate, and h ypocalcemia), but lacking del22q11 (26%), is lower than that reported by Webber et al., 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar nevertheless indicating that such a subgroup of children does exist. 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar,7Lindsay EA Greenberg F Shaffer LG Shapira SK Scambler PJ Baldini A Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region.Am J Med Genet. 1995; 56: 191-197Crossref PubMed Scopus (107) Google Scholar We have suggested that the syndrome in these patients be called “CATCH-non-22 syndrome.” 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar In addition, we completely agree with Webber et al. that certain cardiac defects are associated with a higher incidence of del22q11. We have compared the occurrence of genetic syndromes in patients with classic TF and in those with TF and pulmonary atresia. 8Digilio MC Marino B Grazioli S Agostino D Giannotti A Dallapiccola B Comparison of occurrence of genetic syndromes in ventricular septal defect with pulmonic stenosis (classic tetralogy of Fallot) versus ventricular septal defect with pulmonic atresia.Am J Cardiol. 1996; 77: 1375-1376Abstract Full Text PDF PubMed Scopus (70) Google Scholar It is evident that classic TF can be associated with many genetic conditions, del22q11 having been diagnosed in 6% of the patients, but most cases are nonsyndromic. Patients with TF and pulmonary atresia, on the contrary, have a high incidence of genetic syndromes, del22q11 representing 32% of the total in our series. Considering that truncus arteriosus and interruption of the aortic arch are classically considered CTHDs in which there is a particular risk of del22q11, with a prevalence of del22q11 estimated around 30% and 55%, respectively, 9Goldmuntz E Emanuel BS Molecular genetic defects and cardiac morphogenesis.Progress in Pediatric Cardiology. 1996; 5: 113-121Abstract Full Text PDF Scopus (1) Google Scholar TF with pulmonary atresia must also be included among the defects strongly related to monosomy 22q11. However, the detection of del22q11 in CTHDs rarely associated with the DiGeorge and velocardiofacial syndromes 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar implies the need of an accurate phenotypical examination of all patients with a CTHD not only those affected by specific cardiac malformations. It is obvious that clinical evaluation can be subjective, but we believe that the support of experience and familiarity with the specific dysmorphisms makes phenotypic examination the first required screening to identify patients with CTHDs at risk of del22q11. Our experience is based on a numerically representative sample of patients with CTHDs, and the prevalence of del22q11 in nonsyndromic patients is effectively very low, as further corroborated by the results of other research groups. 1Webber SA Hatchwell E Barber JCK Daubeney PEF Crolla JA Salmon AP et al.Importance of microdeletion of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.J Pediatr. 1996; 129: 26-32Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,10Takahashi K Kido S Hoshino K Ogawa K Ohashi H Fukushima Y Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: a prospective study.Eur J Pediatr. 1995; 154: 878-881Crossref PubMed Scopus (80) Google Scholar,11Debrus S Berger G de Meeus A Sauer U Guillaumont S Voisin M et al.Familial nonsyndromic conotruncal defects are not associated with a 22q11 microdeletion.Hum Genet. 1996; 97: 138-144Crossref PubMed Scopus (51) Google Scholar In addition, the absence of del22q11 in our series of patients with nonsyndromic cleft palate, 12Mingarelli R Digilio MC Mari A Amati F Standoli L Giannotti A et al.The search for hemizygosity at 22q11 in patients with isolated cleft palate.J Craniofac Genet Dev Biol. 1996; 16: 118-121PubMed Google Scholar another characteristic sign of velocardiofacial syndrome, supports the evidence that a single isolated dysmorphic feature in a nonsyndromic patient is probably related to etiologic factors different from del22q11. 3Amati F Mari A Digilio MC Mingarelli R Marino B Giannotti A et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.Hum Genet. 1995; 95: 479-482Crossref PubMed Scopus (118) Google Scholar, 4Melchionda S Digilio MC Mingarelli R Novelli G Scambler P Marino B et al.Transposition of the great arteries associated with deletion of chromosome 22q11.Am J Cardiol. 1995; 75: 95-98Abstract Full Text PDF PubMed Scopus (45) Google Scholar, 5Digilio MC Marino B Mingarelli R Novelli G Amati F Mari A et al.Isolated conotruncal heart defects are really related to microdeletion of chromosome 22q11? [Abstract].J Am Coll Cardiol. 1996; 27: 93AGoogle Scholar, 6Dallapiccola B Marino B Digilio MC Mingarelli R Novelli G Giannotti A The mendelian basis of congenital heart defects [Editorial].Cardiology in the Young. 1996; 6: 264-271Crossref Google Scholar Furthermore, the relatively high prevalence of del22q11 previously reported by Goldmuntz et al., 13Goldmuntz E Driscoll D Budarf ML Zackai EH McDonald-McGinn DM Biegel JA et al.Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects.J Med Genet. 1993; 30: 807-812Crossref PubMed Scopus (198) Google Scholar in their series of apparently isolated CTHD patients, has recently been modified because of the demonstration of mild dysmorphisms in the studied cases. 9Goldmuntz E Emanuel BS Molecular genetic defects and cardiac morphogenesis.Progress in Pediatric Cardiology. 1996; 5: 113-121Abstract Full Text PDF Scopus (1) Google Scholar We agree that “early identification of patients with the CATCH-22 syndrome may be of critical importance,” 2Johnson MC Watson MS Strauss AW Chromosome 22q11 monosomy and the genetic basis of congenital heart disease [Editorial].J Pediatr. 1996; 129: 1-3Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar but we suggest that an accurate phenotypic analysis, including cardiac phenotype, 14Marino B Digilio MC Grazioli S Formigari R Mingarelli R Giannotti A et al.Associated cardiac anomalies in isolated and syndromic patients with tetralogy of Fallot.Am J Cardiol. 1996; 77: 505-508Abstract Full Text PDF PubMed Scopus (58) Google Scholar can identify patients at risk of having del22q11. In conclusion, we believe that routine FISH analysis for definition of the precise prevalence of del22q11 in all types of syndromic and isolated congenital heart defects could be reserved to selected research groups, whereas in clinical practice the screening by clinical and phenotypic analysis is sufficient for selection of patients at risk of having del22q11. FISH analysis must be performed in patients with CTHDs and one or more additional phenotypic sign of CATCH-22 and related syndromes. In our opinion, this selection makes it possible to avoid the indiscriminate use of expensive genetic techniques and the unjustified anxiety that can be generated in the parents of an affected child.
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