PEDIATRICS Vol. 117 No. 5 May 2006, pp. e924-e927 (doi:10.1542/peds.2005-1012)
Cri du Chat Syndrome and Congenital Heart Disease: A Review of Previously Reported Cases and Presentation of an Additional 21 Cases From the Pediatric Cardiac Care Consortium
a Departments of Pediatrics
b Pediatric Cardiology
d Pediatric Genetics and Metabolism, University of Minnesota, Minneapolis, Minnesota
c Center for Care Innovation and Research, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. To analyze the cases submitted to the Pediatric Cardiac Care Consortium (PCCC) database from 1982 to 2002 to determine the frequency and distribution of congenital heart disease (CHD) found in this population, to review the literature for previously published accounts of CHD in this population, and to review current genotype-phenotype associations for cri du chat (CDC) syndrome with CHD.
METHODS. We performed a retrospective review of the 98422 CHD cases submitted to the PCCC between 1982 and 2002, to find patients who had a noncardiac diagnosis of CDC syndrome.
RESULTS. A total of 21 patients (15 female and 6 male patients) were identified. Although some patients had multiple cardiac anomalies, they were categorized according to primary diagnoses on the basis of the most hemodynamically significant component. The patient groups were ventricular septal defect (n = 6), patent ductus arteriosus (n = 6), tetralogy of Fallot (n = 5), pulmonary valve atresia with ventricular septal defect (n = 2), pulmonary valve stenosis (n = 1), and double-outlet right ventricle (n = 1). Eighteen of the 21 patients underwent surgical repair of their defects. There was 1 late operative death. To determine whether the observed frequency of these cardiac defects among patients with CDC syndrome was comparable to that of the general population of patients with CHD, data for all cases submitted to the PCCC from 1982 to 2002 were used. Use of these numbers to determine expected frequencies for these defects showed significantly greater proportions of patients with these specific lesions among the patients with CDC syndrome.
CONCLUSIONS. Currently there is no clear understanding of the genomic cause of the prevalence of these defects in the population with CDC syndrome, although CHD has been noted among patients with other deletion syndromes.
Key Words: congenital heart disease • genotype-phenotype correlation • genetics
Abbreviations: CDC—cri du chat • CHD—congenital heart disease • PCCC—Pediatric Cardiac Care Consortium • VSD—ventricular septal defect • PDA—patent ductus arteriosus • TOF—tetralogy of Fallot • ASD—atrial septal defect
Cri du chat (CDC) syndrome, also known as 5p– syndrome, is a rare genetic syndrome that was first described in 1963 by Lejeune et al.1 The French name of this syndrome translates to "cry of the cat"; the syndrome was named for the characteristic high-pitched cry that is usually heard during early infancy among affected neonates. CDC syndrome affects 1 of 15000 to 45000 live births and may be one of the most common deletion syndromes.2,3 Newer diagnostic testing with 5p-specific DNA probes and comparative genomic delineation may increase the number of cases diagnosed. Patients with CDC syndrome may have multiple nonspecific characteristics, including low birth weight, poor muscle tone, microcephaly, language difficulties, developmental delays, and profound retardation. Facial characteristics are generally most prominent in the first year of life and may include a round face, hypertelorism, low-set ears, micrognathia, a prominent nasal bridge, epicanthal folds, and facial hypotonia.2,4
CDC syndrome results from the variable loss of chromosomal material from spans as small as only the 5p15.2 region to the entire short arm of chromosome 5.5 Evidence shows that the size of the deletion may be correlated with phenotypic features.6 Studies by Overhauser and colleagues5,7 in 1994 and 1995 determined that deletions of 5p15.2 were correlated with facial dysmorphism and developmental delays and that deletion of 5p15.3 was related to the presence of the characteristic cat-like cry.5,7 Additional analyses published by Zhang et al8 in 2005 localized the region of the cat-like cry to 5p15.31, speech delay to 5p15.32 to 5p15.33, and facial dysmorphism to 5p15.2 to 5p15.31.
Cardiac anomalies have been estimated to affect 15% to 20% of patients with this syndrome.9 Detailed cardiac diagnoses were published previously for 41 patients with CDC syndrome (Table 1).
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In 1983, Wilkins et al10 reported an association with cardiac abnormalities for 29% of patients with an isolated deletion and 55% of those with an unbalanced translocation. Among patients with isolated deletions, 10 of 11 were found to have septal defects, such as a ventricular septal defect (VSD) or atrial septal defect (ASD). Unbalanced translocations were associated with more-complex diagnoses, such as tetralogy of Fallot (TOF) and endocardial cushion defect.
In 1978, Niebuhr2 reviewed data for 331 individuals with CDC syndrome and found 33 confirmed cases of an associated cardiac anomaly. Approximately one half of these defects were septal defects, with most of the remaining defects being patent ductus arteriosus (PDA). An additional 21 patients in that study were thought to have a PDA or septal defect but those findings were not confirmed.
In 1996, Iyer et al11 described 3 patients with CDC syndrome associated with congenital heart disease (CHD); the patients' diagnoses were coexistent perimembranous VSD and secundum ASD, partial atrioventricular canal, and multiple VSDs. Tullu et al12 reported a patient with a subaortic VSD and pulmonary hypertension who was a sibling of one of the patients described by Iyer et al.11
There have been 4 additional reports of patients with CDC syndrome and CHD. In 1965, McCracken and Gordon13 reported a case with a primary diagnosis of isolated PDA. In 1963, Lejeune et al1 reported on a patient with an atrioventricular canal, pulmonary stenosis, transposition, and partial anomalous pulmonary venous connection. A patient with in utero atrial flutter was described by Taylor and McIntosh14 in 1990. In 1991, Romano et al15 reported on a patient with a VSD that was repaired at 1 year of age.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Our study was undertaken to review the cases of CDC syndrome among the 98422 children with CHD submitted to the Pediatric Cardiac Care Consortium (PCCC) who underwent cardiac catheterization or surgery between January 1, 1982, and December 31, 2002. The registry has received data from 61 centers in the United States, Canada, Europe, and South America. Participating centers submit demographic and limited clinical data and procedure reports for each child who undergoes cardiac surgery or catheterization. For this study, the PCCC database was searched for patients with coexistent CDC syndrome. The genetic diagnosis was verified in all cases. Statistical analysis of these cases was performed with
2 analysis with continuity correction or Fisher's exact test, when the cell size did not meet the criteria for 2 analysis. P values of <.05 were considered significant. |
RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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A total of 21 patients (15 female patients and 6 male patients) were identified. Information on these patients was submitted by 14 different medical centers located in the United States and Canada. Although some patients had multiple cardiac anomalies, they were categorized according to primary diagnoses on the basis of the most hemodynamically significant component. Therefore, the patient groups were VSD (n = 6), PDA (n = 6), TOF (n = 5), pulmonary valve atresia with VSD (n = 2), pulmonary valve stenosis (n = 1), and double-outlet right ventricle (n = 1). Eighteen of the 21 patients underwent surgical repair of their defects. There was 1 late operative death, involving a patient with pulmonary valve atresia with VSD and tricuspid valve atresia who underwent a modified Blalock-Taussig shunt and atrial septectomy 39 days before death.
Of the 6 patients with a primary diagnosis of VSD, 4 underwent VSD repair between the ages of 10 months and 2.5 years. Each had pulmonary artery bands placed before definitive repair. The other 2 patients, who had pulmonary hypertension and pulmonary vascular disease, did not undergo surgical correction. Associated cardiac defects included ASD (n = 2), coarctation (n = 1), hypoplastic arch (n = 1), bicuspid aortic valve (n = 1), subpulmonary stenosis (n = 1), and mesocardia (n = 1). Associated noncardiac defects included subglottic narrowing (n = 1) and cleft lip and palate (n = 1).
For another 6 patients, an isolated PDA was the only cardiac lesion. Five of these patients underwent ductal ligation and the sixth underwent successful interventional coil occlusion between the ages of 2.5 months and 4 years. Associated noncardiac lesions included microcephaly (n = 1), intestinal malrotation (n = 1), and suspected neurofibromatosis (n = 1).
The 5 patients with TOF all underwent complete repair by the age of 3 years. Two patients had a right Blalock-Taussig shunt placed before definitive repair, whereas the remaining 3 patients had complete repair performed between 4 and 19 months of age. Associated cardiac diagnoses included ASD (n = 2), right aortic arch (n = 1), and PDA (n = 1). Associated noncardiac anomalies included tracheomalacia (n = 1) and omphalocele (n = 1).
For each of the 4 remaining patients, right ventricular outflow tract obstruction was present. Three of these patients had cardiac malformations that could be considered variants of TOF. For 2, there was pulmonary atresia; the other defect was diagnosed as double-outlet right ventricle with pulmonary stenosis. Three of these patients underwent corrective surgery and 2 survived. Associated cardiac anomalies included left superior vena cava (n = 1), ASD (n = 1), right aortic arch (n = 1), complete heart block (n = 1), and tricuspid atresia (n = 1).
To determine whether the observed frequency of these cardiac defects among patients with CDC syndrome was comparable to that of the general population of patients with CHD, data for all cases submitted to the PCCC between 1982 and 2002 were used. For the 98422 cases reported, distributions of primary diagnoses were as follows: VSD, 10.1%; TOF, 6.5%; PDA, 7.0%; pulmonary atresia plus VSD, 2.5%; pulmonary stenosis plus intact ventricular septum, 4.4%; doubleoutlet right ventricle, 1.6%. Use of these numbers to determine expected frequencies for these defects showed significantly greater proportions of patients with these specific lesions among the patients with CDC syndrome (Table 2).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Cardiac anomalies occur among significant proportions of patients with CDC syndrome. Diagnostic advances in the detection of chromosomal deletions suggest that the number of cases of genetically confirmed CDC syndrome is likely to increase. The distribution of CHD within this population has been reported sporadically. Our study presents information about an additional 21 children with coexisting CDC syndrome and CHD. VSD, PDA, and right ventricular outflow tract obstructive anomalies, including TOF and pulmonary atresia, were found to be the predominant lesions present in our patient group. The distribution of these lesions is greater for patients with CDC syndrome than for other patients with CHD, but the surgical mortality rate does not seem to be elevated.
An association between deletion syndromes and CHD was reported previously. McElhinney et al16 described the association between chromosome 22q11 deletions and VSD in 2003. In that study, 10% of 125 patients with VSD who were treated at the Children's Hospital of Philadelphia between November 1991 and December 2001 were found to have a chromosomal 22q11 deletion when their chromosomes were analyzed with fluorescence in situ hybridization.
There are multiple genes with some known cardiac expression on the short arm of chromosome 5, including DNAH5 on 5p15.33, NDUFS6 on 5p15.33, IRX4 on 5p15.33, and ADAMTS16 on 5p15.32. Of these, IRX4 may be the most likely contributor to cardiac malformations in the developing fetus. The IRX4 member of the Iroquois gene family was found to have ventricle-specific cardiac expression.17 Bruneau et al18 reported the development of cardiomyopathy among Irx4-deficient mice, which suggests that patients with this syndrome may have a propensity for cardiomyopathic conditions later in life.
The frequency of CDC syndrome itself is likely attributable to the propensity for deletions. Notably, when this region of 5p is compared with the syntenic region of the mouse genome, there is a change in synteny from mouse chromosome 16 to a region of unknown mouse synteny at 15.31. This change in synteny has been observed for other genomic deletions, notably del10q23.19,20
The subjects of this study were patients enrolled in the PCCC database. Patients were enrolled in this database only if they underwent a catheterization or operative procedure at one of the participating centers. Therefore, the exact incidence of cardiac malformations among patients with CDC syndrome cannot be determined from this study. It is also possible that patients who were diagnosed subsequently as having CDC syndrome might have been reported to the PCCC as having an unknown chromosomal abnormality; such patients would have been missed for the purposes of this study. In addition, children are not reported to the PCCC database unless they have undergone a catheterization or operative procedure or have died while admitted to the hospital. Therefore, it is possible that this study missed patients who did not undergo these procedures or died outside the hospital setting. Nonetheless, this study describes the distribution of CHD among this population of patients with this syndrome.
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ACKNOWLEDGMENTS |
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We thank the PCCC and its participating hospitals for the effort and time spent by untold contributors to establish and to maintain this database. Special thanks go to E. Virgil Larson for his database research assistance and to Sarah Larson, Program Director of the PCCC.
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FOOTNOTES |
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Accepted Dec 13, 2005.
Address correspondence to Christine Hills, MD, Department of Pediatrics, MMC 391, 420 Delaware St S.E., Minneapolis, MN 55455. E-mail: christin{at}umn.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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