Aortic Arch Abnormalities Research Articles

Aortic dissection in Turner syndrome

Turner syndrome is a relatively common disorder of female development with cardinal features of short stature and congenital cardiovascular defects (CHD). Turner syndrome is the most common established cause of aortic dissection in young women, but has received little attention outside pediatric literature. This review focuses on emerging knowledge of the characteristics of aortic disease in Turner syndrome in comparison with Marfan-like syndromes and isolated aortic valve disease. The incidence of aortic dissection is significantly increased in individuals with Turner syndrome at all ages, highest during young adult years and in pregnancy. Pediatric patients with dissection have known congenital cardiovascular defects (CHD), but adults often have aortic valve and arch abnormalities detected only by screening cardiac magnetic resonance. Thoracic aortic dilation in Turner syndrome must be evaluated in relation to body surface area. Dilation is most prominent at the ascending aorta, similar to the pattern seen in nonsyndromic bicuspid aortic valve, is equally prevalent (20-30%) in children and adults, and does not seem to be rapidly progressive. Cardiovascular anomalies and risk for aortic dissection in Turner syndrome are strongly linked to a history of fetal lymphedema, evidenced by the presence of neck webbing and shield chest. Risk for acute aortic dissection is increased by more than 100-fold in young and middle-aged women with Turner syndrome. Monitoring frequency and treatment modalities are decided on an individual basis until more information on outcomes becomes available.

OP08.07: Three‐dimensional ultrasound with STIC in the prenatal definition of aortic arch abnormalities

scan and fetal echocardiogram exam were routinely made. In one case mild aortic valve stenosis was found confirmed postnatally. Results: In about 60% of fetuses the complete fetal echocardiography including the examination of four-chamber and three-vessel view was obtained. Age-dependent rise of velocities at semilunar and AV valves was observed. Tricuspid flow velocities were higher than mitral valve flow velocities. Tei Index for right and left ventricle did not vary between examined gestational weeks. Heart/chest area ratio ranged between 0.23-0.24 at all examined gestational weeks. Conclusions: Standard echocardiographic views of the fetal heart were obtained at first trimester scan in about 60%. No abnormal heart anatomy was found in the group. The increase of velocities at semilunar and AV valves relative to estimated gestational age may be dependent on the fetal growth and the volume of blood entering ventricles. Higher velocities at tricuspid valve reflect right ventricle stroke volume and output as well as the right ventricle predominance, which is normally observed later in pregnancy. The gestational increase of E/A ratio at AV valves may be connected with the shift of blood from late diastole to early diastole and increased ventricular compliance and relaxation rate.

PHACES Association: A Vasculocutaneous Syndrome

PHACES association is a spectrum of anomalies that might occur in infants with large facial hemangiomas. Most infants with PHACES association have segmental hemangiomas of the head or neck. Cardiac and cerebrovascular anomalies might be the most important association, as they carry a significant risk of complications. This article summarizes the dermatologic, cardiac, and cerebral vascular findings in a cohort of infants diagnosed with PHACES association. All had large segmental facial hemangiomas and aortic arch abnormalities. Four of the five were not suspected of having arch obstruction prior to imaging studies because of the aberrant origin of both subclavian arteries, and 4/5 required either interventional or surgical repair for arch obstruction. In contrast to classic aortic coarctation, the aortic anomalies found in the cohort had unusually complex and unpredictable anatomic involvement. Cerebral vascular anomalies were identified in 5/5, and 2/5 had neurologic complications secondary to abnormal cerebral vascular supply. It is important for care providers to recognize this association that presents with a cutaneous stigma, as it is associated with potentially lethal and often unrecognized vascular anomalies. Earlier recognition of the associated vascular pathologies might enable preemptive treatments before potentially devastating and irreversible sequelae.

Abstract 939: Galpha-i Signaling in Neural Crest Cells is Required for Normal Migration of Cardiac Neural Crest Cells, Cardiac Development, and Survival

G protein coupled receptors (GPCRs) have long been known to play crucial roles in transducing environmental signals to the adult cardiovascular system. In recent years, the roles of G protein-mediated signaling pathways in orchestrating the interactions of different tissues during cardiovascular development have become increasingly evident. To analyze the role of G protein signaling pathways in vivo we have generated mice where the function of the heterotrimeric G alpha subunit Gai can be ablated in a cell type specific manner utilizing the Cre-loxP system. We have mated these mice to two different neural crest-specific Cre lines in order to probe the effects of loss of Gai mediated signaling on the ability of neural crest cells (NCC) to contribute to the developing outflow tract and aortic arch arteries. METHODS: We have generated mice that express the Gai-inhibiting pertussis toxin S1 subunit (PTX) from the ROSA26 locus in a Cre recombination dependent manner (ROSA-PTX mice). These were mated to mice expressing either the Wnt1 Cre or P0 Cre transgene. Wnt1Cre is active in both premigratory and migratory NCC, whereas P0Cre is active only in migratory NCC and their derivatives. RESULTS: P0Cre-ROSA-PTX mice were normal at birth and demonstrated no structural heart defects. In contrast, Wnt1Cre-ROSA-PTX mice were present in normal numbers at late gestation but died perinatally due in part to cardiac outflow tract defects. Excision reporter and in situ hybridization studies suggest this is secondary to a delay/blockage of cardiac NCC migration into the developing outflow tract. NCC migration into the pharyngeal arches was unaffected in these mice and no craniofacial, thymic, or aortic arch abnormalities were observed. CONCLUSIONS: These results indicate that Gai-mediated signaling is required in premigratory or early migratory cardiac NCC for normal development of the outflow tract. In contrast, endothelin A receptor knockout mice (currently the only GPCR knock out with a neural crest phenotype) are thought to exhibit defects of postmigratory NCC function. RNA profiling of NCC for GPCRs involved in this Gai-dependent pathway has revealed several potential candidate receptors, including orphan receptors. Further analysis of these receptors is underway.

Atrioventricular Septal Defect Recently Diagnosed by Fetal Echocardiography: Echocardiographic Features, Associated Anomalies, and Outcomes

We report our recent experience with atrioventricular septal defect (AVSD) diagnosed in utero. We reviewed fetal echocardiograms diagnosed with AVSD between November 2002 and November 2004, comparing fetuses with and without aneuploidy. We compared results with previous studies. Twenty (1.8%) fetuses had AVSD. Mean maternal age was 33 years (range 19-43). Mean gestational age was 26 weeks (range 18-38). Indications for fetal echocardiography were: abnormal obstetrical ultrasound (75%), chromosomal anomaly (15%), undetermined (10%). AVSD was an isolated cardiac defect in 5 (25%), associated with double-outlet right ventricle (9) or tetralogy of Fallot (3) in 12 (60%). Four had aortic arch anomalies. Atrioventricular valve regurgitation was mild in 7 (35%) and moderate in 4 (20%). Heart block existed in 2 (10%). Five (25%) with trisomy had Rastelli type A AVSD as a single lesion (odds ratio 24, P < .01). Extracardiac anomalies existed in 6, with and without aneuploidy. Pregnancy was terminated in 4 (20%), neonatal death in 4 (20%), and reparative surgery in 6 (30%), not ascertained in 6. Atrioventricular septal defect is usually an isolated cardiac lesion in fetuses with aneuploidy. In the absence of aneuploidy, fetal AVSD is often associated with conotruncal and aortic arch abnormalities, which are important in determining outcomes. Pregnancy termination and neonatal death continue to be prevalent.

Upper Gastrointestinal Bleeding Secondary to an Aberrant Right Subclavian Artery-Esophageal Fistula: A Case Report and Review of the Literature

An aberrant right subclavian artery (ARSA) is a common aortic arch abnormality. A case of a 57-year-old man presenting with melena and hypotension secondary to an ARSA-esophageal fistula is reported. The current report is unique because it is the first reported case of ARSA-esophageal fistula associated with prior esophagectomy and gastric pull-up. A MedLine search was performed for ARSA-esophageal fistula cases, which were then compared with the present case. Because this patient had no vascular conduits, nasogastric or endotracheal tubes, the fistula likely occurred secondary to the previous surgery. This case is unusual because the patient survived the original hemorrhage associated with the ARSA-esophageal fistula. An ARSA-esophageal fistula is a rare, but potentially fatal cause of upper gastrointestinal bleeding. A high index of suspicion is needed to make the diagnosis. This condition should be considered in patients with risk factors combined with hemodynamically significant gastrointestinal bleeding.

Postnatal lethality and cardiac anomalies in the Ts65Dn Down Syndrome mouse model

The Ts65Dn mouse is a well-studied model for Down syndrome (DS). The presence of the translocation chromosome T17 16 (referred to as T65Dn) produces a trisomic dosage imbalance for over 100 genes on the distal region of mouse Chromosome 16. This dosage imbalance, with more than half of the orthologs of human Chromosome 21 (Hsa21), causes several phenotypes in the trisomic mice that are reminiscent of DS. Careful examination of neonates in a newly established Ts65Dn colony indicated high rates of postnatal lethality. Although the transmission rate for the T65Dn chromosome has been previously reported as 20%-40%, genotyping of all progeny indicates transmission at birth is near the 50% expected with Mendelian transmission and survival. Remarkably, in litters with maternal care that allowed survival of some pups, postnatal lethality occurred primarily in pups that inherited the T65Dn marker chromosome. This selective loss within 48 h of birth reduced the transmission of the marker chromosome from 49% at birth to 34% at weaning. Gross morphologic examination revealed cardiovascular anomalies, i.e., right aortic arch accompanied by septal defects, in 8.3% of the trisomic newborn cadavers examined. This is an intriguing finding because the orthologs of the DiGeorge region of HSA22, which are posited to contribute to the aortic arch abnormalities seen in trisomy 16 mice, are not triplicated in Ts65Dn mice. These new observations suggest that the Ts65Dn mouse models DS not only in its previously described phenotypes but also with elevated postnatal lethality and congenital heart malformations that may contribute to mortality.

Clinical, anatomopathological and genetic pattern of 10 patients with cervical aortic arch

Cervical aortic arch (CAA) is a rare congenital abnormality in which the aortic arch is situated cranially to its usual position, often associated with complex developmental alteration of aortic laterality and branching. More recently, some authors reported deletion of chromosome 22q11 (del22q11) in few patients with CAA. The aim of this study was to describe the clinical, anatomopathological and genetic pattern of 10 new cases of CAA. From 1975 to 2003, 10 patients with CAA (4 female, mean age 12.4+11.1 years) underwent complete cardiovascular evaluation and screening for del22q11 using fluorescence in situ hybridization. Six patients underwent CAA surgical repair with histological analysis of aorta samples. Six patients were asymptomatic; one patient had syncope on effort, 2 patients had dyspnea on effort and 1 had cyanosis and dyspnea (tricuspid atresia). A murmur and/or a pulsatile mass of the neck was present in all patients. Femoral pulses were weak or absent in 6 patients. Four patients had right and 6 left CAA; kinking or true obstruction of the aortic arch was present in 9/10. Abnormal aortic arch branching pattern was found in 8/10 (mainly aberrant subclavian artery). Two patients had del22q11 with dysmorphic features, multiorgan anomalies and degenerative mediocystic necrosis of aortic wall. Our data confirm clinical polymorphism and anatomic complexity of CAA as well as the association between del22q11 and CCA in 2 syndromic patients.

Aortic Arch Abnormality in a Patient with Klippel-Feil Syndrome

We present a case of a 43-year-old female with headaches, progressive paresthesias of the upper extremities, and vertigo. Ultrasonography could not visualize the left internal carotid artery (ICA). Magnetic resonance imaging (MRI) showed complete fusion of the C5, C6, and C7 levels, representing Klippel-Feil deformity. Angiography showed a unique abnormality of the aortic arch with complete absence of the left ICA. An embryologic defect associated with this type of abnormality is proposed, with defects of development of the third aortic arch and the aortic sac secondarily.

Images in anesthesia: transesophageal echocardiography during cesarean section in a marfan’s patient with aortic dissection

with Marfan’s syndrome presented to the emergency room with chest, back, and epigastric pain. Echocardiography three months earlier had shown mild aortic dilatation (37 mm) and mitral valve prolapse. Both transesophageal echocardiography (TEE) and computer tomography confirmed aortic dissection from the take-off of the left subclavian artery that extended past the bifurcation and to the iliac arteries. The patient was hospitalized in the intensive care unit (ICU) near the cardiothoracic surgery department for invasive monitoring that confirmed acute (Stanford) type B aortic dissection.1 Antihypertensive, sedative, and steroid therapy were administered immediately. Three days later, because of exacerbation of pain, the patient was scheduled for Cesarean section with preparation for aortic replacement in case of expansion of the dissection into the aortic arch or other unexpected and untoward complications. General anesthesia was induced with fentanyl, propofol, and rocuronium to minimize cardiovascular response to tracheal intubation, and the TEE probe was immediately positioned to monitor the condition of the dissection (video available at www.cja-jca.org). The patient remained hemodynamically stable throughout delivery and was returned to the ICU for continuous conservative treatment. Two weeks later she was discharged in good health. The baby suffered from bilateral hydronephrosis (no genetic information available to date) and mild aortic arch abnormalities compatible with Marfan’s syndrome. In the past, women with Marfan’s syndrome were counseled to avoid the risk of pregnancy and delivery. Today, with improved means of identifying patients that facilitate better care, increased longevity, and improved quality of life, more women with Marfan’s syndrome are attempting to have babies, despite the high risk of aortic dissection even in the absence of aortic root dilatation prior to pregnancy. For this reason, intraoperative TEE observation ensures an extra measure of real-time control during Cesarean section, particularly in case of acute or chronic aortic dissection, and risk factors such as aortic diameter $ 40 OBSTETRICAL AND PEDIATRIC ANESTHESIA 737

Diagnosis of fetal ductus arteriosus aneurysm: importance of the three-vessel view

To present four cases of ductus arteriosus aneurysm (DAA) detected by fetal echocardiography and highlight the value of the three-vessel view in the diagnosis of DAA. In addition to the standard fetal echocardiographic views, we examined the three-vessel view in four cases of DAA. The three-vessel view was achieved by sliding the transducer cranially from the four-chamber plane toward the fetal upper mediastinum to demonstrate cross-sections of the main pulmonary artery, the ascending aorta and superior vena cava arranged in a straight line from the left anterior to the right posterior aspect of the mediastinum. DAA was diagnosed when there was a tortuous ductus arteriosus with a dilation that protruded leftward of the aortic arch. In the first case, an insulin-dependent diabetic woman underwent fetal ultrasound examination at 36 weeks' gestation showing right-to-left cardiac disproportion and bidirectional flow in the aorta and main pulmonary artery (PA). The three-vessel view showed a dilated ductus arteriosus (DA) which was stenosed at its distal end. In the second case, a woman had fetal ultrasound scans at 38 and 39 weeks' gestation for suspected intrauterine growth restriction and oligohydramnios. The scans identified an abnormal aortic arch and the three-vessel view showed an elongated vascular structure at the distal end of the PA, which was the DAA. In the third case, a woman with a high-risk obstetric history had multiple scans showing an abnormal PA to aorta relationship, with an apparent 'kink' in the PA. The three-vessel view clarified that this was the DAA. In the fourth case, a woman was scanned because of a 3-kg weight gain in 1 week. The fetal ultrasound scan showed moderate polyhydramnios with normal fetal growth and normal intracardiac anatomy and flow, and the three-vessel view demonstrated a large DA. In each of these cases, the DAA appeared to have occurred in isolation with non-specific clinical findings. We advocate the use of the three-vessel view, in conjunction with the standard echocardiography views currently employed, to assist in the diagnosis of DAA.

Late-onset dysphagia lusoria assessed by 3-dimensional computed tomography of an aortic arch abnormality

Symptomatic vascular rings causing late-onset dysphagia (dysphagia lusoria) are quite unusual in adults. We present a 42-year-old woman with a 1-year history of dysphagia from a right-sided aortic arch with an aberrant left subclavian artery and left-sided ligamentum arteriosum. Using a helical CT scan of the chest and a three-dimensional reconstruction software, her anatomic abnormality was completely delineated. Arch aortogram confirmed the anomaly. The patient underwent a left posteriolateral thoracotomy. Intraoperative findings correlated precisely with the preoperative reconstruction data. Division of the ligamentum resulted in a complete decompression of the esophagus and resolution of the patient's symptoms.

Right Arm Ischemia Following Intentional Stent-Graft Coverage of an Anomalous Right Subclavian Artery

To report thoracic aortic stent-graft repair in a patient with abnormal aortic arch anatomy. An anomalous right subclavian artery was covered with a stent-graft in a 38-year-old woman being treated for a false aneurysm after coarctation repair. The right arm became relatively ischemic, but was viable and managed conservatively. Aneurysms close to left or aberrant right subclavian arteries can be safely and effectively treated by endoluminal repair without the need for revascularization procedures; ischemic symptoms that develop are often mild and transient.

Life-threatening cryoglobulinemia in HCV-negative Southern Chinese and a novel association with structural aortic abnormalities

Cryoglobulinemia is uncommon in Southern Chinese in Hong Kong, with tropical climates and low incidence of hepatitis C virus (HCV) infection. Eight positive cases were detected among 481 patients screened for cryoglobulins over a 10-year period. Three HCV carriers (38%) ran benign courses. The others included two carriers of hepatitis B virus (HBV), two patients with adenocarcinoma, and one with chronic lymphocytic lymphoma. Four of them (except one HBV carrier) ran fulminant courses and died of cryoglobulin-related complications. Interestingly, all four cases also had structural aortic abnormalities, including multiple dissections, aneurysms, and congenital aortic arch abnormalities, which were often life threatening. The association of aortic abnormality and cryoglobulinemia is hitherto unreported and may be peculiar to our ethnic group. Aggressive control of the cryoglobulin may help to reduce aortic intima damage.

OC176: The aberrant right subclavian artery is a common aortic arch abnormality in fetuses with Down's syndrome

Objective: Conversely to the normal right subclavian artery arising from the brachiocephalic artery, an aberrant right subclavian artery (ARSA) arises as a separate vessel from the aortic isthmus and crosses to the right, behind the trachea. This variant is present in less than 1% of the normal population but pediatric cardiology observations report on a frequent occurrence in subjects with Down’s syndrome (DS). The purpose of this study was to assess the possibility of detecting an ARSA in fetuses with DS. Patients and Methods: 14 fetuses with prenatally detected DS were examined between 18 and 33 weeks of gestation. The right subclavian artery was visualized in the transverse three-vesseltrachea view of the upper thorax using color Doppler to detect a normal arising vessel or an ARSA. Results: An ARSA was identified in 35.7% (5/14) of trisomy 21 fetuses. In only one fetus it was associated with a cardiac defect (AVSD) and the four others it was either isolated (n = 1) or associated with an intracardiac echogenic focus. Conclusions: This preliminary study suggests that the in utero identification of an ARSA may be a new ultrasound marker found in fetuses with Down’s syndrome.

Abnormal aortic arch.

There are a variety of aortic arch anomalies, including coarctation of the aorta, interrupted aortic arch, and vascular rings, which present with clinical signs and symptoms. We report a unique case of an abnormal aortic arch as a spurious finding in the workup of an infant with a heart murmur. A 20-day-old previously healthy, term infant was admitted with respiratory synctial virus and progressive respiratory distress. Physical examination revealed a nonspecific grade 2/6 systolic ejection murmur audible along the left sternal border. Blood pressures in the arms and legs were normal and pulses were easily palpable in all extremities. An echocardiogram showed no intracardiac abnormalities, but suprasternal and subcostal imaging suggested an abnormal aortic arch [2] (Fig. 1) but failed to adequately define its course in the thorax. Magnetic resonance imaging (MRI) was performed to further clarify the arch anatomy [1]. Double-inversion recovery sagittal images show a tortuous and elongated but unobstructed proximal descending aorta (Fig. 2) coursing lateral and posterior to the usual course of the aorta, extending into the paraspinal region posterior to the level of the vertebral bodies. Despite the unusual course, the aorta remained widely patent throughout. This unusual aortic arch variant, which was poorly defined using two-dimensional echocardiography due to its traverse through several planes of sound, was clearly defined by MRI, thus preventing more invasive evaluation and verifying that intervention was unnecessary.

Chromosome 22q11 deletion in patients with ventricular septal defect: frequency and associated cardiovascular anomalies.

A ventricular septal defect (VSD) is the most common form of congenital heart disease and is one of the most common cardiovascular anomalies in individuals with chromosome 22q11 deletion syndrome. However, the frequency of a chromosome 22q11 deletion in patients with a VSD is not known. In addition, among patients with a VSD, it is not clear whether particular types of VSD or associated cardiovascular phenotypic features are associated with a chromosome 22q11 deletion. We prospectively enrolled 125 patients with a conoventricular (n = 100), posterior malalignment (n = 14), or conoseptal hypoplasia (n = 11) VSD who were admitted to Children's Hospital of Philadelphia between November 1991 and December 2001. Patients were studied for a chromosome 22q11 deletion by using fluorescence in situ hybridization. A chromosome 22q11 deletion was detected in 12 (10%) of the 125 patients. Anatomic features that were significantly associated with a chromosome 22q11 deletion included abnormal aortic arch sidedness, an abnormal aortic arch branching pattern, a cervical aortic arch, and discontinuous pulmonary arteries. There was no correlation between the type of VSD and chromosome 22q11 deletion. Of 20 patients with an abnormal aortic arch and/or discontinuous pulmonary arteries, 45% had a chromosome 22q11 deletion compared with only 3% of those with a left aortic arch, normal aortic arch branching pattern, and continuous branch pulmonary arteries A chromosome 22q11 deletion is common in individuals with a conoventricular, posterior malalignment, or conoseptal hypoplasia VSD and anomalies of the aortic arch or branch pulmonary arteries. On the basis of these findings, at a minimum, we recommend testing for a chromosome 22q11 deletion in patients with these types of VSD who have abnormalities of aortic arch sidedness or branching, a cervical aortic arch, and/or discontinuous pulmonary arteries. Testing of patients with these types of VSD but a normal aortic arch and pulmonary arteries may be performed routinely or guided by the presence of associated noncardiovascular features of chromosome 22q11 deletion syndrome.

Chromosome 22q11 deletion in patients with truncus arteriosus.

The association between truncus arteriosus and chromosome 22q11 deletion is well recognized, but the frequency of a chromosome 22q11 deletion has not been characterized in a large series of patients with truncus arteriosus, and little is known about cardiovascular morphologic features associated with a chromosome 22q11 deletion in this group of patients. We prospectively enrolled 50 consecutive patients with truncus arteriosus who were admitted to The Children's Hospital of Philadelphia between November 1991 and December 2001. Patients were studied for chromosome 22q11 deletion using fluorescence in situ hybridization. Correlations between anatomic features and chromosome 22q11 deletion were assessed. A chromosome 22q11 deletion was detected in 20 of the 50 patients (40%). Anatomic features that were significantly associated with a chromosome 22q11 deletion included a right-sided aortic arch, an abnormal aortic arch branching pattern, both abnormal sidedness and branching of the aortic arch, and the combined category of either abnormal sidedness or branching of the aortic arch. There was a trend toward the association of discontinuous pulmonary arteries with a chromosome 22q11 deletion. Interruption of the aortic arch and truncal valve morphology and function did not correlate significantly with the presence of a chromosome 22q11 deletion. In conclusion, a chromosome 22q11 deletion is common in patients with truncus arteriosus, and those with abnormal sidedness and/or branching of the aortic arch are significantly more likely to have a deletion. Clinically important anatomic variables, such as abnormalities of the truncal valve and interrupted aortic arch, were not associated with a chromosome 22q11 deletion in this series.

High incidence of cardiac malformations in connexin40-deficient mice.

Gap junctions are intercellular channels formed by oligomerization of a protein called connexin (Cx). The heart expresses at least three connexin isotypes: Cx40, Cx43, and Cx45. A possible role for Cx40 in cardiac morphogenesis remains to be determined. We have characterized the anatomy and histology of fetal and newborn hearts obtained from crossing Cx40-deficient mice of mixed genetic background (C57BL/6x129Sv). Hearts were serial-sectioned (5 microm) along the coronal plane, stained with hematoxylin-eosin, and visualized by conventional light microscopy. Cardiac malformations in mice lacking Cx40 in one allele (Cx40+/-) included bifid atrial appendage, ventricular septal defect, tetralogy of Fallot (TOF), and an aortic arch abnormality. In Cx40-/- mice resulting from crossing of Cx40+/- mice, the most common cardiac malformations were double-outlet right ventricle (DORV), TOF, and endocardial cushion defects. Overall incidence of cardiac malformations was 6/33 (18%) in Cx40+/- mice and 4/12 (33%) in Cx40-/- mice. No cardiac malformations were observed in 15 wild-type mice studied. In addition, we examined 39 hearts from offspring of Cx40-/- matings. Frequency of cardiac malformations was even higher in this group (44%). Over one third of the hearts (14 of 39) showed conotruncal malformations corresponding to either DORV or TOF. Endocardial cushion defects were found in 3 out of 39 hearts. Our results suggest that Cx40 participates in cardiac morphogenesis, likely in association with other (unknown) products whose expression may vary with the genetic background of the mice.

A genetic link between Tbx1 and fibroblast growth factor signaling.

Tbx1 haploinsufficiency causes aortic arch abnormalities in mice because of early growth and remodeling defects of the fourth pharyngeal arch arteries. The function of Tbx1 in the development of these arteries is probably cell non-autonomous, as the gene is not expressed in structural components of the artery but in the surrounding pharyngeal endoderm. We hypothesized that Tbx1 may trigger signals from the pharyngeal endoderm directed to the underlying mesenchyme. We show that the expression patterns of Fgf8 and Fgf10, which partially overlap with Tbx1 expression pattern, are altered in Tbx1(-/-) mutants. In particular, Fgf8 expression is abolished in the pharyngeal endoderm. To understand the significance of this finding for the pathogenesis of the mutant Tbx1 phenotype, we crossed Tbx1 and Fgf8 mutants. Double heterozygous Tbx1(+/-);Fgf8(+/-) mutants present with a significantly higher penetrance of aortic arch artery defects than do Tbx1(+/-);Fgf8(+/+) mutants, while Tbx1(+/+);Fgf8(+/-) animals are normal. We found that Fgf8 mutation increases the severity of the primary defect caused by Tbx1 haploinsufficiency, i.e. early hypoplasia of the fourth pharyngeal arch arteries, consistent with the time and location of the shared expression domain of the two genes. Hence, Tbx1 and Fgf8 interact genetically in the development of the aortic arch. Our data provide the first evidence of a genetic link between Tbx1 and FGF signaling, and the first example of a modifier of the Tbx1 haploinsufficiency phenotype. We speculate that the FGF8 locus might affect the penetrance of cardiovascular defects in individuals with chromosome 22q11 deletions involving TBX1.