Alessandra Toscano

Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factors

Atrial septal defect (ASD) is a common cardiovascular malformation, affecting over 1 in 1000 live births, accounting for 10% of congenital heart defects (CHD).1 ASD refers to a communication between the right and left atria, anatomically classified into the deficient atrial septum structure. ASD ostium secundum (ASDos) is the prevalent defect, representing 85% of all ASDs.2 ASD may be isolated or associated with other CHDs, such as pulmonary valve stenosis (PVS), ventricular septal defect (VSD), or conduction defects. In addition, persistent left to right blood shunt may result in atrial and ventricular dysfunctions and atrial arrhythmias, in the absence of surgical or catheter based repair. The atrial septum is one of the cardiac structures most sensitive to environmental or genetic factors. Several lines of evidence have highlighted a role for different proteins and transcription factors in the septogenesis process;3 however, only two genes, encoding for the transcription factors NKX2.5 and GATA4, have been implicated so far in non-syndromic ASDs.4,5 Clinical and molecular analyses have shown that mutations in these two genes are responsible for ASDs in association with distinct cardiac features.4–15 Mutations in NKX2.5 , a member of the NK-2 class of homeobox genes, have been described in autosomal dominant ASDos with progressive atrioventricular (AV) block, and in 1–4% of sporadic ASD patients.4,6–12 Most of these mutations occur within the homeodomain, a critical protein domain that interacts specifically with DNA, and are associated with conduction anomalies. Low penetrance NKX2.5 gene mutations, mainly outside the homeodomain, have been found in 5% of patients with tetralogy of Fallot, and in a number of individuals with other CHDs and normal conduction.4,6,9–13 Recently, heterozygous mutations in the GATA4 zinc finger transcription factor gene have been identified in three families with …

Anatomic patterns of conotruncal defects associated with deletion 22q11

Purpose: Patients with cardiovascular malformations (CVMs) and deletion 22q11 from our series were studied in order to (1) analyze the association with dysmorphic features and noncardiac anomalies, (2) identify specific cardiac patterns and the distinctive association with additional CVMs.Methods: From 1993 to 2000, 931 patients with CVM (95 with a clinical diagnosis of DiGeorge/velocardiofacial syndrome (DG/VCFS), 208 with different genetic syndromes, 628 without dysmorphic features) underwent accurate cardiac assessment, clinical and phenotypical examination, and screening for deletion 22q11 by fluorescence in situ hybridization (FISH).Results: Deletion 22q11 was detected in 88 of the total patients, and in 87 of the 95 patients with a clinical diagnosis of DG/VCFS. Only one patient among the 628 without dysmorphic features had deletion 22q11. Conotruncal heart defects were the most common CVMs, often presenting in association with additional anomalies in four areas of the cardiovascular system: (1) the aortic arch can be right sided, cervical, double, and the subclavian artery can be aberrant, (2) the pulmonary arteries can present discontinuity, diffuse hypoplasia, discrete stenosis, defect of arborization and major aortopulmonary collateral arteries (MAPCA), (3) the infundibular septum can be malaligned, hypoplastic, or absent, (4) the semilunar valves can be bicuspid, severely dysplastic, insufficient, or stenotic.Conclusion: In subjects with deletion 22q11 CVM is virtually always associated with one or more noncardiac anomalies. Deletion 22q11 is exceptionally rare in children with nonsyndromic CVMs. Specific patterns of CVMs are observed in patients with deletion 22q11, including (1) anomalies of the aortic arch, (2) anomalies of the pulmonary arteries and of the pulmonary blood supply, (3) defects of the infundibular septum, (4) malformations of the semilunar valves. These additional CVMs may influence the surgical treatment of these patients.

Atrioventricular canal defect without down syndrome : A heterogeneous malformation

The atrioventricular canal defect (AVCD) is one of the congenital heart defects most frequently associated with extracardiac anomalies. The association of AVCD with Down syndrome and heterotaxy has been studied extensively. However, little information is available about the prevalence of genetic syndromes and additional cardiac malformations in patients with AVCD and visceroatrial situs solitus without Down syndrome. This paper reviews the genetic and cardiologic characteristics of patients with non-Down AVCD and situs solitus in the literature and our series of 203 consecutive patients. In our experience, 132 (65%) of the patients have nonsyndromic AVCD, while 71 (35%) have non-Down syndromic AVCD. Chromosomal imbalances were detected in 7 cases (3%), Mendelian syndromes or associations in 44 (22%), and extracardiac anomalies without an identifiable syndrome in 20 (10%). Deletion 8p is prevalent among those with chromosomal imbalances. Noonan, Ellis-van Creveld, oro-faciodigital, Smith-Lemli-Opitz syndromes and VACTERL cases are frequent among patients with recognizable or identifiable nonchromosomal conditions. Based on this analysis of the type of AVCD and prevalence of associated cardiac anomalies in the different groups of patients, we found that: 1) the complete form is prevalent in patients with chromosomal imbalances; 2) the complete form is more frequently associated with additional cardiac defects, mainly left side obstructive lesions; and 3) additional cardiac anomalies are prevalent in syndromic patients. In conclusion, AVCD is a congenital heart defect with great variability in the anatomic patterns and heterogeneity of causes also in the subset without Down syndrome and without heterotaxy. The peculiar anatomic subtypes of this cardiac defect are associated with specific genetic conditions.

Prevalence and predictors of neoaortic regurgitation after arterial switch operation for transposition of the great arteries

BACKGROUND The fate of the native pulmonary valve after arterial switch operation is still unknown and may become a cause for a secondary aortic valve operation during adult life. We evaluated the prevalence and predictive factors associated with neoaortic valvular regurgitation by a retrospective study of children who underwent arterial switch operation for transposition of the great arteries. METHODS The onset of neoaortic valvular regurgitation was correlated with demographic data, cardiac anatomy, surgical technique, and postoperative ventricular function. The size of the neoaortic root and ascending aorta was measured in a selected subset of patients. RESULTS Among 253 survivors, 173 were eligible for the study. After a median follow-up time of 8.2 years, 61 patients showed echocardiographic or angiographic evidence of valvular incompetence, which was progressive in 14 cases; this led to surgical intervention in 2 patients, and there was 1 operative death. At multivariate analysis, the onset of valvular regurgitation was correlated with the trap-door technique for coronary reimplantation (P <.01). A smooth transition from the aortic sinus to the ascending aorta, with loss of the normal sinotubular junction geometry, may be associated with valvular incompetence. CONCLUSIONS After arterial switch operation, there is an increasing frequency of neoaortic regurgitation, which may lead to significant valvular dysfunction later in life. The trap-door type of coronary reimplantation is associated with an increased risk for valvular dysfunction, possibly because of a distortion of the sinotubular junction geometry. For this reason, we recommend the punch technique for repair in all but the most complicated coronary pattern.

Anomalous coronary artery origin from the pulmonary artery: correlation between surgical timing and left ventricular function recovery

BACKGROUND This study investigates the correlation between surgical timing and 15-year longitudinal left ventricular and mitral valve function, after repair of anomalous coronary artery origin from the pulmonary artery. METHODS Between 1987 and 2002, 31 patients (median age, 7.1 months) underwent repair for anomalous origin of the left (n = 28), right (n = 2), or both (n = 1) coronary arteries from the pulmonary artery. Repair was accomplished by subclavian interposition in 5 patients, intrapulmonary tunnel in 12, and direct aortic reimplantation in 14. Primary mitral valve repair was never associated with coronary revascularization. Total follow-up was 186.4 patient-years (mean, 77.2 months). RESULTS Fifteen-year actuarial survival was 92.9% +/- 4.9% for coronary transfer, 40.0% +/- 21.9% for subclavian interposition, and 89.9% +/- 7.5% for intrapulmonary tunnel (p = 0.019). Five patients required further intervention for supravalvular pulmonary stenosis (n = 3), baffle leak (n = 1), and mitral valve replacement (n = 1). Coronary transfer allowed best freedom from long-term reoperation (92.3% +/- 7.4%). Left ventricular shortening fraction increased from 17.3% +/- 6.3% before operation to 34.1% +/- 4.6% at last follow-up (p < 0.01). Regression analysis demonstrated a linear relationship between age at repair and shortening fraction recovery (r(2) = 0.573, p < 0.01). Patients younger than 6 months of age showed worse preoperative shortening fraction (15.9% +/- 5.2%) and best longitudinal shortening fraction recovery (36.4% +/- 5.1%; p < 0.001). Major improvement in mitral valve function was observed within 1 year from surgery in 90.4% of survivors. CONCLUSIONS Repair of anomalous coronary artery origin from the pulmonary artery in younger symptomatic infants offers the best potential for recovery of left ventricular function, despite a worse initial presentation. Coronary transfer is associated with superior long-term survival and freedom from reoperation. Most patients with patent two-coronary repair will recover normal mitral valve function; therefore, simultaneous mitral valve surgery seems unwarranted.

Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome)

The oculo–auriculo–vertebral spectrum (OAVS) is a non‐random association of microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations. Congenital heart defects (CHDs) have been reported in 5–58% of the patients. We analyze the frequency and anatomic features of CHD in a series of 87 patients with OAVS examined between January 1990 and February 2007 with normal chromosomes, ranging in age between 0.1 and 16.8 years. A twin pregnancy occurred in eight cases (dizygotic in six cases and monozygotic in two). CHDs were diagnosed in 28/87 (32%) patients, and classified into categories of postulated developmental mechanisms including 9 (32%) atrial and ventricular septal defects, 11 (39%) conotruncal defects, 4 (14%) targeted growth defects, two (7%) with situs and looping defects, one (4%) with a left‐sided obstructive lesion and one (4%) with patent ductus arteriosus. As noted in other series, the most common individual CHDs were ventricular septal defect (six patients) and tetralogy of Fallot (TOF) (classic or with pulmonary atresia) (six patients). Comparing the frequencies of CHDs groups observed in the OAVS patients with the findings of the Emilia‐Romagna Registry which ascertained CHDs prevalence in the general population, conotruncal defects, targeted growth defects, and heterotaxia were significantly associated with OAVS.

Deletion 22q11 in patients with interrupted aortic arch.

In our series of 27 children with various types of interruption of the aortic arch (IAA), deletion 22q11 is prevalent in patients with simple IAA type B, and is absent in patients with IAA type A and in those with associated additional major cardiac defects. Anomalies of the infundibular septum should be considered a characteristic aspect of children with IAA and deletion 22q11.

Recurrence risk figures for isolated tetralogy of Fallot after screening for 22q11 microdeletion.

Isolated tetralogy of Fallot (TF) has a multifactorial mode of inheritance in most cases, and recurrence risk rates of 2.5-3% have been attributed to first degree relatives of an affected child. In a subgroup of patients with a strong family history, the transmission of a monogenic trait has been suspected. Microdeletion 22q11 (del(22q11)) can cause TF in the setting of DiGeorge and velocardiofacial syndromes, and has also been related to familial conotruncal cardiac defects. Empirical risk figures in families after exclusion of del(22q11) have never been calculated. We have investigated the overall occurrence of congenital heart defect (CHD) in relatives of 102 patients with isolated non-syndromic TF previously screened for del(22q11). Our results show that the frequency of CHD is 3% in sibs, 0.5% in parents, 0.3% in grandparents, 0.2% in uncles or aunts, and 0.6% in first cousins. The recurrence risk rate for sibs in our series is the same as that previously estimated, indicating that after exclusion of patients with del(22q11) genetic counselling to patients with isolated TF should not be modified. A high concordance rate among our affected sibs has been documented. Gene(s) different from those located on chromosome 22q11 must be involved in causing familial aggregation of non-syndromic TF in these cases.

Noonan syndrome and aortic coarctation

Congenital heart defect (CHD) is present in half of the propositi with Noonan syndrome (NS). Aortic coarctation (AC) is rarely seen in NS, since only three male patients with NS and AC have been previously reported. On the other hand, AC is common in the Ull-rich-Turner syndrome, an aneuploidy disorder and not a mendelian syndrome. In order to evaluate if AC is truly rare in patients with NS, we reviewed our series of 184 propositi with NS and CHD. AC was diagnosed in 16 (8.7%) patients. There were 11 males and 5 females. All had normal chromosomes. Clinical characteristics of the patients are described. Familial occurrence was detected in one girl with NS and AC whose mother and sibs also had NS, but different form of CHDs. Thus, AC is more frequent in NS than previously reported.

Homozygous familial hypercholesterolaemia

A 5-year-old boy aff ected with homozygous familial hypercholesterolaemia, diagnosed aged 1 year, was referred to us after having an acute ischaemic cardiac event. He presented with an LDL-cholesterol concentration of 26 mmol/L, and tendon xanthomas at the wrists, knees, and achilles (fi gure A–C). He had been treated with colestyramine. Coronary angio graphy showed a complete obstruction of the left coronary artery (fi gure D; see also webvideo) and a partial obstruction of the right coronary artery, which required stent placement. After the