Congenital heart defects in the recurrent 2q13 deletion syndrome.

The recurrent 2q13 deletion syndrome is a rare genetic disorder associated with developmental delay, cardiac and urogenital malformations, and minor facial anomalies. Congenital heart defects (CHDs) are the most frequent malformations associated with del2q13. Experimental studies in zebrafish suggest that two genes mapping within the 2q13 critical region (FBLN7 and TMEM87B) could confer susceptibility to congenital heart defects in affected individuals. We reviewed the cardiac characteristics in four patients with 2q13 deletion admitted to our hospitals, and in published patients. Two of our patients had congenital heart defects, consisting in partial anomalous pulmonary venous connection, ostium secundum atrial septal defect ostium secundum, and small muscular ventricular septal defect in one of them, and aortic valve insufficiency with partial fusion of two commissures (incomplete bicuspid aortic valve) and mitral valve insufficiency due to trivial mitral valve prolapse in the other. The anatomic types of CHD in del2q13 syndrome are highly variable and distributed widely, including laterality defects, complex atrioventricular septal defect, septal anomalies, and cardiomyopathies. Cardiac evaluation should be part of the clinical workup at diagnosis of 2q13 deletion.

Echocardiographic long-term follow-up of adult survivors of pediatric cancer treated with Dexrazoxane-Anthracyclines association.

AIMS: Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer treated with anthracyclines. Co-administration of Dexrazoxane has been shown to significantly reduce short-term and mid-term cardiotoxicity. Aim of this study was to assess cardiac function in long-term (>10 years) survivors of childhood tumors treated with dexrazoxane/anthracycline association. METHODS AND RESULTS: Twenty cancer survivors previously treated with co-administration of anthracyclines-dexrazoxane for childhood renal tumors or sarcoma and a control group of 20 healthy subjects were enrolled in the study. Echocardiographic measurements included 3D left ventricular (LV) ejection fraction (LVEF) and LV and right ventricular (RV) global longitudinal strain (GLS). Among cancer survivors group the median age at diagnosis was 5 years (1-17) and they were evaluated at median follow-up time of 21.5 years (10-26). No evidence of cardiac toxicity, as defined by current guidelines, was reported in all survivors. No significant differences in standard and deformation imaging parameters were observed between survivors and controls (3D LVEF 58 ±â€¯3% vs 60 ±â€¯5% p = NS; LV GLS -21 ±â€¯1% vs -21 ±â€¯2% p = NS; RV GLS -23 ±â€¯2% vs -23 ±â€¯5% p = NS). No second tumor was registered in dexrazoxane-treated survivors. CONCLUSIONS: Our findings may support the role of dexrazoxane as a useful strategy for cardio-protection in children undergoing anthracycline based treatment. However, large randomized trials are needed to confirm the cardio-protective role of dexrazoxane in pediatric setting at long-term follow-up.

Atrioventricular canal defect and genetic syndromes: The unifying role of sonic hedgehog.

The atrioventricular canal defect (AVCD) is a congenital heart defect (CHD) frequently associated with extracardiac anomalies (75%). Previous observations from a personal series of patients with AVCD and "polydactyly syndromes" showed that the distinct morphology and combination of AVCD features in some of these syndromes is reminiscent of the cardiac phenotype found in heterotaxy, a malformation complex previously associated with functional cilia abnormalities and aberrant Hedgehog (Hh) signaling. Hh signaling coordinates multiple aspects of left-right lateralization and cardiovascular growth. Being active at the venous pole the secondary heart field (SHF) is essential for normal development of dorsal mesenchymal protrusion and AVCD formation and septation. Experimental data show that perturbations of different components of the Hh pathway can lead to developmental errors presenting with partially overlapping manifestations and AVCD as a common denominator. We review the potential role of Hh signaling in the pathogenesis of AVCD in different genetic disorders. AVCD can be viewed as part of a "developmental field," according to the concept that malformations can be due to defects in signal transduction cascades or pathways, as morphogenetic units which may be altered by Mendelian mutations, aneuploidies, and environmental causes.

Association of OPG-RANKL ratio with left ventricular hypertrophy and geometric remodeling in male overweight/obese youths.

PURPOSE: Receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) axis has been hypothesized as a potential mediator of left ventricular hypertrophy (LVH). The aim of the study was to assess whether circulating concentrations of RANKL, RANK, and OPG were associated with early signs of morphological cardiac changes in overweight/obese youths. METHODS: We determined serum levels of RANKL, RANK and OPG by enzyme-linked immunosorbent assays in 188 overweight/obese children and adolescents. LV mass index (LVMI) and relative wall thickness (RWT) were estimated using M-mode echocardiography. RESULTS: OPG and RANKL levels were higher among girls than among boys [1.73 (1.64-1.86) and 3.28 (1.90-6.37) pmol/L, respectively, vs. 1.69 (1.59-1.82) and 2.12 (1.52-3.80) pmol/L; p = 0.02 and p = 0.0001, respectively], but the OPG/RANKL ratio was lower [0.52 (0.26-0.88) vs 0.77 (0.44-1.11); p = 0.001]. In gender-specific multivariate linear regression, OPG/RANKL ratio was associated with LVMI and RWT in boys but not in girls. In multiple logistic regression, after adjustment for clinical variables, OPG/RANKL ratio was associated with concentric remodeling, eccentric and concentric LVH in boys but not in girls. CONCLUSION: OPG/RANKL ratio is independently associated with LVH and patterns of LV structural remodeling in male overweight/obese children and adolescents.

Difficult diagnosis of atypical kawasaki disease in an infant younger than six months: a case report.

BACKGROUND: Kawasaki disease (KD) is an acute inflammatory vasculitis of unknown origin. CASE PRESENTATION: We report the case of a 5-month-old child with an atypical form of KD, characterized by undulating symptoms, who developed an aneurysm of the right coronary artery and an ectasia of the left anterior descending coronary artery. CONCLUSION: This case report underlines the difficulties in recognizing incomplete forms of the illness in young infants, who are at higher risk of cardiac complications.

A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Very little information is available on whether docosahexaenoic acid (DHA) supplementation has a beneficial effect on liver fat and cardiovascular disease (CVD) risk factors in children with nonalcoholic fatty liver disease (NAFLD). In a double-blind, placebo-controlled randomized trial we investigated whether 6-month treatment with DHA improves hepatic fat and other fat depots, and their associated CVD risk factors in children with biopsy-proven NAFLD. METHODS AND RESULTS: Of 58 randomized children, 51 (25 DHA, 26 placebo) completed the study. The main outcome was the change in hepatic fat fraction as estimated by magnetic resonance imaging. Secondary outcomes were changes in visceral adipose tissue (VAT), epicardial adipose tissue (EAT), and left ventricular (LV) function, as well as alanine aminotransferase (ALT), triglycerides, body mass index-standard deviation score (BMI-SDS), and insulin sensitivity. At 6 months, the liver fat was reduced by 53.4% (95% CI, 33.4-73.4) in the DHA group, as compared with 22.6% (6.2-39.0) in the placebo group (P = 0.040 for the comparison between the two groups). Likewise, in the DHA group VAT and EAT were reduced by 7.8% (0-18.3) and 14.2% (0-28.2%), as compared with 2.2% (0-8.1) and 1.7% (0-6.8%) in the placebo group, respectively (P = 0.01 for both comparisons). There were no significant between-group changes for LV function as well as BMI-SDS and ALT, while fasting insulin and triglycerides significantly decreased in the DHA-treated children (P = 0.028 and P = 0.041, respectively). CONCLUSIONS: DHA supplementation decreases liver and visceral fat, and ameliorates metabolic abnormalities in children with NAFLD.

Syndromic non-compaction of the left ventricle: associated chromosomal anomalies.

Non-compaction of the left ventricle (NCLV) is a cardiomyopathy characterized by prominent left ventricular trabeculae and deep intertrabecular recesses. Associated extracardiac anomalies occur in 14-66% of patients of different series, while chromosomal anomalies were reported in sporadic cases. We investigated the prevalence of chromosomal imbalances in 25 syndromic patients with NCLV, using standard cytogenetic, subtelomeric fluorescent in situ hybridization, and array-comparative genomic hybridization (CGH) analyses. Standard chromosome analysis disclosed an abnormality in three (12%) patients, including a 45,X/46,XX mosaic, a 45,X/46,X,i(Y)(p11) mosaic, and a de novo Robertsonian 13;14 translocation in a child affected by hypomelanosis of Ito. Cryptic chromosome anomalies were found in six (24%) cases, including 1p36 deletion in two patients, 7p14.3p14.1 deletion, 18p subtelomeric deletion, 22q11.2 deletion associated with velo-cardio-facial syndrome, and distal 22q11.2 deletion, each in one case. These results recommend accurate clinical evaluation of patients with NCLV, and suggest that chromosome anomalies occur in about one third of syndromic NCLV individuals, without metabolic/neuromuscular disorder. Array-CGH analysis should be included in the diagnostic protocol of these patients, because different submicroscopic imbalances are causally associated with this disorder and can pinpoint candidate genes for this cardiomyopathy.

RASopathies: Clinical Diagnosis in the First Year of Life.

Diagnosis within Noonan syndrome and related disorders (RASopathies) still presents a challenge during the first months of life, since most clinical features used to differentiate these conditions become manifest later in childhood. Here, we retrospectively reviewed the clinical records referred to the first year of life of 57 subjects with molecularly confirmed diagnosis of RASopathy, to define the early clinical features characterizing these disorders and improve our knowledge on natural history. Mildly or markedly expressed facial features were invariably present. Congenital heart defects were the clinical issue leading to medical attention in patients with Noonan syndrome and LEOPARD syndrome. Feeding difficulties and developmental motor delay represented the most recurrent features occurring in subjects with cardiofaciocutaneous syndrome and Costello syndrome. Thin hair was prevalent among SHOC2 and BRAF mutation-positive infants. Café-au-lait spots were found in patients with LS and PTPN11 mutations, while keratosis pilaris was more common in individuals with SOS1, SHOC2 and BRAF mutations. In conclusion, some characteristics can be used as hints for suspecting a RASopathy during the first months of life, and individual RASopathies may be suspected by analysis of specific clinical signs. In the first year of life, these include congenital heart defects, severity of feeding difficulties and delay of developmental milestones, hair and skin anomalies, which may help to distinguish different entities, for their subsequent molecular confirmation and appropriate clinical management.

New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle.

Conotruncal defects (CTDs) represent 15-20% of all congenital heart defects. Mutations in a number of genes have been associated with CTD in humans and animal models. We investigated the occurrence and the prevalence of GATA4, NKX2.5, ZFPM2/FOG2, GDF1, and ISLET1 gene mutations in a large cohort of individuals with CTD, including tetralogy of Fallot with or without pulmonary atresia (TOF, 178 patients), double outlet right ventricle (DORV, 13 patients), and truncus arteriosus (11 patients). Denaturing high-performance liquid chromatography (DHPLC) analysis followed by bidirectional sequencing disclosed no putative pathogenic mutation in GATA4, ISLET1, and GDF1 genes. Two novel (Ile227Val, Met544Ile) and one previously reported (Glu30Gly) possibly pathogenic missense variants were identified in the ZFPM2/FOG2 gene in 3 sporadic patients of 202 (1.5%) with CTD, including 1 of 178 (0.6%) with TOF and 2 of 13 (15.4%) with DORV. Mutation analysis also detected one known missense change (Arg25Cys) in NKX2.5 gene in two (1.1%) sporadic patients with TOF. These sequence alterations were found to be absent in 500 population-matched controls. In conclusion, the present results (i) indicate and confirm that mutations in the GATA4, GDF1, and ISLET1 genes are not major determinants in the pathogenesis of TOF, (ii) provide supportive evidence of an association between ZFPM2/FOG2 gene and TOF/DORV, and (iii) provide additional examples of the possible contribution of the Arg25Cys change in the NKX2.5 to a small number of TOF cases.

Colour Doppler echocardiography in children with group A streptococcal infection related tic disorders.

BACKGROUND & OBJECTIVES: A possible relationship has been suggested between tic disorders and streptococcal infections. To understand the complex relationship between streptococcal infections and neuropsychiatric disorders in children the present study was done on colour Doppler echocardiography of patients with possible post-streptococcal tic disorders. METHODS: The patients were 23 children (22 males, 1 female) affected by tic disorders, who at the time of the observation presented (or had presented in the past) signs of streptococcal infections temporally related to the onset or recrudescence of tic disorders. Echocardiographic examination and laboratory tests were performed on these children. RESULTS: In 4 cases a mild mitral insufficiency and in 8 cases a minimal mitral insufficiency was seen, all haemodynamically not significant. Follow up studies (up to 1 yr) showed the consistency and persistence of these findings. Of the 12 patients with echocardiographic abnormalities, 10 displayed very high anti streptolysin O (ASO) titres, 5 showed positive cultures for GAS and 9 had abnormal ESR, even if no significant differences were found in respect to patients with tics and normal echocardiography. INTERPRETATION & CONCLUSION: With the caution due to the design of study and to low number of patients, our data seem to indicate that the pathophysiology of GAS-infection related tic disorders is similar to that SC, at least in some cases.

Use of ICRF-187 for prevention of anthracycline cardiotoxicity in children: preliminary results.

The objective of this study is to assess the efficacy of ICRF-187 as a protective agent against anthracycline cardiotoxicity. Cardiac function was evaluated by echocardiography before and after each cycle of anthracycline chemotherapy associated with ICRF-187 and compared with that of a second group receiving anthracycline chemotherapy without ICRF-187. The patients were a group of 15 consecutive children affected with various types of solid tumors who were treated with either doxorubicin-daunomycin or epirubicin (average doses 340 and 280 mg/m2, respectively), and treatment was associated with ICRF-187. A second group of 15 consecutive children affected with different malignancies were simultaneously treated with either doxorubicin-daunomycin or epirubicin (average doses 309 and 270 mg/m2, respectively), but without ICRF-187 association. None of the patients treated with anthracyclines and ICRF-187 association showed abnormalities on echocardiographic examination. In the second group of patients treated with anthracyclines but without ICRF-187 association, we observed a decrease in the left ventricular ejection fraction to < 55% and a decrease in the left ventricular fractional shortening to < 28% in two patients (13.3%). One of these (6.6%) showed a dilatative cardiomyopathy. Both groups of patients were treated with low doses of anthracyclines. Although this study was not randomized, in patients without ICRF-87 cardioprotection, there was a trend for a worse evolution with one case of clinical cardiomyopathy as well as subclinical cardiac abnormalities.