Giulio Calcagni

An unusual case of left aberrant innominate artery with right aortic arch: evaluation with high-resolution CT

A left aberrant innominate (brachiocephalic) artery is an angiographically well-known entity that may cause tracheal compression. We report a male newborn who was admitted for further investigation of a prenatally suspected major vessel anomaly. High-resolution CT was used to completely assess the abnormal anatomy and the relationship with the airway, as well as to guide the surgical approach for its correction.

Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results

BACKGROUND RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. METHODS A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. RESULTS Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. CONCLUSIONS The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death.

Congenital heart defects in Noonan syndrome and RIT1 mutation

To the Editor: We read with great interest the article by Kouz et al.1 reporting on genotype–phenotype correlations of patients with Noonan syndrome (NS) heterozygous for RIT1 mutations. The authors performed an exhaustive analysis of the features associated with mutations in this gene, which was recently described as a new causative gene for the syndrome and accounts for approximately 5–10% of the total cases of NS cases. Cardiac and extracardiac features of this new subset of patients were discussed by Kouz et al.,1 and clinical characteristics of patients with RIT1 mutation were compared to those found in patients with mutations in other genes known to be related to RASopathies. We report here a few additional details regarding the cardiac phenotype in this subgroup of patients. Among our series of 161 patients with a molecularly confirmed diagnosis of RASopathy, 9 patients (6%) with a clinical diagnosis of NS carrying a missense RIT1 mutation were recently identified. Congenital heart defects in this subgroup of patients are seen in 100% of patients, which is in line with the data reported by Kouz et al.1 Consistent with the published data, pulmonary valve stenosis, hypertrophic cardiomyopathy (HCM), atrial septal defect (ASD), and ventricular septal defect (VSD) were reported in our subjects with RIT1 mutations. One patient in our cohort had partial atrioventricular canal defect (pAVCD). Four patients in our series presented HCM. Two of them had an obstructive HCM (oHCM), which was associated with subaortic stenosis and pulmonary valve stenosis in one patient who required an orthotopic heart transplant during the first year of life due to the severity of the cardiac phenotype, which was unresponsive to extensive medical treatment. These data confirm what was previously reported by Colan et al.,2 as well as our unpublished data, documenting that patients with an early-onset HCM phenotype (younger than 2 years of age), particularly in cases of biventricular obstructions, have poor prognoses. Based on these considerations, HCM in NS subjects with a RIT1 gene mutation should be carefully evaluated, particularly if it occurs in early childhood. Four patients had pulmonary valve stenosis with a typical thickened and dysplastic valve. The supravalvular region was involved in the lesion in all of them, as generally reported in NS. To the best of our knowledge, our patient with pAVCD is the first diagnosed with RIT1 mutation. This observation confirms the high prevalence of AVCD previously noted in RASopathies and not only in association with PTPN11 and RAF1 mutations.3 Finally, lymphatic anomalies were present in three out of the nine patients in our cohort, including chylothorax in two subjects and lymphedema of the lower limbs in one. Chylothorax was persistent in both children and required postoperative drainage. These data confirm the relevant role of RIT1 mutations in early-onset and late-onset lymphatic complications, which could lead to significant postoperative morbidity in these subjects. In conclusion, the prevalence of congenital heart defects in patients carrying heterozygous RIT1 mutations is high and a great variety of anatomic types can be observed, including HCM, which can be particularly severe. Finally, complications due to lymphatic anomalies should also be taken into consideration.

Right superior vena cava draining into the left atrium

The right superior vena cava draining into the left atrium is a rare malformation causing cyanosis and clubbing in patients in whom no other signs of congenital heart defect are present. Diagnosis may be difficult as cyanosis may be mild and the anomaly is not always easily detectable by echocardiography. For this reason we report a 13-month-old male in whom we confirmed the clinical and echocardiographic suspicion of anomalous drainage of the right superior vena cava using multidetector CT. This allowed successful surgical reconnection of the right superior vena cava to the right atrium.

Coronary artery ectasia in Noonan syndrome: Report of an individual with SOS1 mutation and literature review.

Noonan syndrome (NS) is the second most frequent hereditary syndrome with cardiac involvement. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most prevalent cardiovascular abnormalities. We report on a 14‐year‐old girl with NS due to SOS1 mutation with pulmonary stenosis and idiopathic coronary ectasia. To the best of our knowledge, this is the first report describing coronary ectasia in a patient with NS secondary to a SOS1 mutation. We include a literature review of this rare association.

Some Isolated Cardiac Malformations Can Be Related to Laterality Defects

Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left–right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects.

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.

Congenital heart disease and genetic syndromes: new insights into molecular mechanisms

ABSTRACT Introduction: Advances in genetics allowed a better definition of the role of specific genetic background in the etiology of syndromic congenital heart defects (CHDs). The identification of a number of disease genes responsible for different syndromes have led to the identification of several transcriptional regulators and signaling transducers and modulators that are critical for heart morphogenesis. Understanding the genetic background of syndromic CHDs allowed a better characterization of the genetic basis of non-syndromic CHDs. In this sense, the well-known association of typical CHDs in Down syndrome, 22q11.2 microdeletion and Noonan syndrome represent paradigms as chromosomal aneuploidy, chromosomal microdeletion and intragenic mutation, respectively. Area covered: For each syndrome the anatomical features, distinctive cardiac phenotype and molecular mechanisms are discussed. Moreover, the authors include recent genetic findings that may shed light on some aspects of still unclear molecular mechanisms of these syndromes. Expert commentary: Further investigations are needed to enhance the translational approach in the field of genetics of CHDs. When there is a well-established definition of genotype-phenotype (reverse medicine) and genotype-prognosis (predictive and personalized medicine) correlations, hopefully preventive medicine will make its way in this field. Subsequently a reduction will be achieved in the morbidity and mortality of children with CHDs.

Paroxysmal atrioventricular block after heart transplantation in children: an early sign of rejection?

In OHT recipients, pathologic evaluation of the heart during acute rejection can show involvement of both the conduction system and the myocardium. We here describe the cases of a 9‐year‐old male with DCM and a 13‐year‐old female with RCM, who developed third‐degree PAVB associated with acute rejection 36 months and 24 months after OHT, respectively. We conclude that PAVB could be considered an early sign of acute rejection after OHT in children who exhibit post‐transplantation presyncope or syncope.

Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p.(Ala367Val)], an individual with AVSD and heterotaxy [p.(Val210Met)], and a subject with AVSD, heterotaxy, and oculo‐auriculo‐vertebral spectrum (OAVS) [p.(Ala696Thr)], respectively. The latter was also heterozygous for a missense change in TBX1 [p.(Pro86Leu)]. Targeted resequencing of genes associated with AVSD, heterotaxy, or OAVS excluded additional hits in the three mutation‐positive subjects. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity. When expressed in zebrafish, the three NFATC1 mutants caused cardiac looping defects and altered atrioventricular canal patterning, providing evidence of their functional relevance in vivo. Our findings support a role of defective NFATC1 function in the etiology of isolated and heterotaxy‐related AVSD.