Genetics and cardiac anomalies : The heart of the matter

The recent exponential increase in knowledge in genetics has revolutionized all aspects of medicine. The completion of the first draft of the human genome project has provided for clinicians a range and depth of information never before imagined. Over the last 25 years understanding the anatomical and physiological basis of a number of congenital cardiac anomalies has led to better care and outcome for the patients born with congenital cardiac defects. In the last decade the role of genes, their critical timing of expression, and understanding of important downstream pathways for optimizing normal development and control of the left right asymmetry have emerged. The progress in cardiac genetics has been supplemented by advances in cardiac imaging modalities leading to improvements in diagnosis of the cardiac anomalies. About 30% of all congenital heart diseases are associated with extracardiac malformations. Chromosomal anomalies are more common in patients with cardiac anomalies than the general population. Presence of facial dysmorphic features and associated extra-cardiac anomalies should alert the pediatricians to an underlying syndrome diagnosis. Newer molecular cytogenetics techniques such asfluorescence in situ hybridization (FISH) and molecular tests are now routinely utilized for confirming clinical diagnoses. In this review we have summarized clinical features and discussed the genetic basis of several syndromes (for example, 22q11 deletion syndrome, Williams syndrome, Down Syndrome, Kabuki syndrome etc.) where specific cardiac anomalies are frequently encountered. The importance of establishing an accurate clinical diagnosis cannot be over emphasized. The families need genetic counselling with accurate information on the recurrence risks. With the advent of the Internet and rapid access to information, the clinicians and the patient families can access valuable information regarding the prognosis, natural history, and clinical interventions for the affected child, and useful support groups for the family. Detection of cardiac anomalies during antenatal period warrants a genetics assessment.     

重视导致危重症及猝死的潜在遗传代谢病及内分泌疾病

不明原因猝死综合征是高收入国家儿童死亡的主要原因。猝死可发生在新生儿期至成人,貌似健康的人在日常活动、睡眠或运动中意外死亡,潜在的遗传病是导致心脏性猝死和脑死亡的病因。1977年美国首先关注到不明原因猝死综合征,美国、英国、泰国、日本等国家通过对猝死者的病因研究,证实多种遗传病导致的心脏病、脑病是猝死的两组主要疾病。其中心脏性猝死占一半以上,猝死或猝死样发作也常常是潜在遗传病的首发表现。已知多种遗传代谢病及内分泌疾病可导致猝死,如：原发性肉碱缺乏症、长QT综合征、心律失常、低镁血症、低钾血症、高钾血症、低钙血症、低血糖、线粒体病等。遗传代谢病及内分泌疾病包括氨基酸、有机酸、糖、脂肪等近千种先天性代谢缺陷,其中许多疾患可导致急性危重症甚至猝死。运用生化、电生理、影像、病理和基因诊断等技术,一些疾病可通过新生儿筛查及高危筛查获得早期诊断,通过饮食及药物干预,有望减少意外死亡,降低残障的发生。     

Genetic syndromes predisposing to paediatric brain tumours: the chicken or the egg?

Cancer in childhood is a disorder of growth and development. Up to 10% of patients diagnosed with cancer during childhood have a known underlying genetic predisposition syndrome. Affected individuals usually have multisystem involvement from the underlying syndrome and certain syndromes are associated with development of characteristic tumours with sites of predilection within the neuraxis. For the healthcare professionals involved with paediatric patients it is important to have basic knowledge of the cancer susceptibility syndromes. A holistic multidisciplinary approach is required for the overall management of the syndrome itself with specific recommendations for imaging surveillance and genetic counselling based on the pattern of inheritance and the relative risk of developing a tumour. Appropriate knowledge of these syndromes will help paediatricians manage and refer patients at risk to specialist neuro-oncology centres. A typical brain tumour diagnosis can also indicate certain underlying genetic disorders and examples of such tumours include optic pathway glioma, choroid plexus carcinoma and subependymal giant cell astrocytoma. A detailed family history can be helpful in identifying at risk patients and families as the typical clinical signs associated with the genetic condition are often not fully apparent in young children. This article focuses on well-known genetic diagnoses associated with or predisposing to childhood brain tumours. In some instances, the brain tumour diagnosis subsequently leads to the diagnosis of an underlying genetic syndrome.     

Cardiac tumors and the nevoid basal cell carcinoma syndrome

Nevoid basal cell carcinoma syndrome is a multisystem disease with a wide range of initial symptoms that can be seen at any age. The most characteristic features are vertebral or rib anomalies, intracranial falx calcification, multiple basal cell carcinomas, odontogenic keratocysts of the jaw, and palmar and/or plantar pits. Pediatricians need to be aware that if any one of these major anomalies is seen, this diagnosis should be considered. There now appears to be an established association between cardiac tumors and nevoid basal cell carcinoma syndrome. Primary cardiac tumors have been associated with cerebral tuberous sclerosis and neurofibromatosis, and evaluation of cardiac status is recommended when these genetically determined syndromes are diagnosed. This communication should serve to alert pediatricians to the need for complete cardiac evaluation and genetic counseling when a diagnosis of nevoid basal cell carcinoma is made.     

Imaging of cancer predisposition syndromes

Pediatric cancer predisposition syndromes comprise a group of diseases characterized by specific tumors or a concomitance of tumors in infants, children and adolescents, suggesting a genetic cancer susceptibility condition. Most but not all have germline pathogenic variants on genetic testing. For some children with cancer predisposition syndromes, this diagnosis is based on their own or a family history of related neoplasms, or associated clinical manifestations. These tumors have variable incidence and age of onset. Imaging encompasses investigation in symptomatic children for diagnosis, staging and monitoring for treatment response and metastatic disease, as well as surveillance for primary tumors in asymptomatic children. In this review the author focuses on the role of surveillance imaging in childhood cancer predisposition syndromes, whole-body magnetic resonance imaging (whole-body MRI) in particular. Diagnosis and staging of specific tumors are addressed elsewhere in this series. The benefits of surveillance imaging include early detection and improved outcomes and are still being established for a number of cancer predisposition syndromes. The benefits must be weighed against risks including potential technique-related issues relating to sedation or contrast agents, false-positive imaging findings, and cost — both financial and psychosocial. The author discusses general principles for whole-body MRI interpretation along with findings in specific syndromes where whole-body MRI screening is recommended, such as Li–Fraumeni syndrome.     

Genetics of cardiological disorders

Information generated by work on the human genome means that we now understand the genetic basis of many of the cardiac anomalies that present in the fetal and neonatal periods. This allows for an earlier and more definitive diagnosis of an underlying syndrome, although it does not replace the need for an accurate recognition of clinical signs. The implications of this new information are considered in the context of some of the more frequently encountered conditions with cardiac associations.     

Neonatal Atrial Fibrillation After Surgical Repair of Tracheoesophageal Fistula With Esophageal Atresia

Atrial fibrillation is rare in childhood that had not been reported in neonates with normal cardiac morphology and function. The authors present a newborn who underwent surgical repair of a tracheoesophageal fistula with esophageal atresia at the age of 2 days and experienced atrial fibrillation 16 days after the procedure. A report of 35 pediatric patients in a single center over a period of 22 years identified atrial fibrillation in children with a variety of ailments including congenital cardiac anomalies before and after corrective surgery, rheumatic valve disease, Marfan's syndrome with mitral regurgitation, infective endocarditis, cardiomyopathy, endocardial fibroelastosis, paroxysmal atrial tachycardia of infants, and cardiac tumors [2]. All these patients had underlying cardiac disease.     

Cardiac rhabdomyoma in familial tuberous sclerosis

Case report of a previously healthy girl who presented at the age of 9 months a paroxysmal supraventricular tachycardia. Echocardiography revealed multiple cardiac tumors. The detection of a few hardly visible unpigmented patches of skin allowed the diagnosis of tuberous sclerosis with cardiac rhabdomyomas. Computerised tomography of the brain showed typical calcifications and multiple hypodense parenchymal lesions. In the further course of the disease, progressive multifocal epilepsy and severe retardation of psychomotor development occurred, angiofibromas appeared on the face, and a suspected angiomyolipoma on renal sonography. A very mild form of this autosomal dominant phacomatosis could be detected in the patient's mother. As cardiac rhabdomyomas and tuberous sclerosis are frequently associated, investigations for both these findings with modern methods of body imaging are recommended in order to allow early diagnosis and genetic counselling.     

Fetal and Neonatal Cardiac Tumors

Primary tumors of the heart are uncommon in the fetus and neonate. Nevertheless, the widespread use of new imaging techniques has contributed significantly to earlier diagnosis, treatment, and thus improved survival. The clinical findings, imaging studies, pathology, and outcome of 224 fetuses and neonates with cardiac tumors collected from the literature are evaluated and discussed. Most tumors are benign, and of these rhabdomyoma is the most common, followed by teratoma, fibroma, oncocytic cardiomyopathy, vascular tumors, and myxoma. Malignant and metastatic tumors are described but are rare. Murmurs, arrhythmias, cyanosis, respiratory distress, and cardiac failure are the main presenting signs of cardiac tumors in the perinatal period. Disturbances in hemodynamic function are correlated with the size and location of the tumor. Cardiac vascular tumors have the best outcome, whereas malignant tumors have the worst. The purpose of this review is to concentrate on the fetus and neonate in an attempt to determine the various ways cardiac tumors differ clinically and morphologically in this age group from those occurring in older children and adults and to show that certain types of tumors have a better prognosis than others.     

Metachronous multifocal desmoid-type fibromatoses along the neuraxis with adenomatous polyposis syndrome

Desmoid-type fibromatosis, aggressive fibromatosis, or desmoid tumor is an uncommon benign but locally aggressive fibroblastic lesion. Although intraabdominal desmoid-type fibromatoses are well described in association with adenomatous polyposis syndrome, their occurrence along the neuraxis is extremely rare. The authors report the case of a 14-year-old boy with metachronous intracranial and spinal desmoid-type fibromatoses with preceding medulloblastoma. He was ultimately diagnosed with adenomatous polyposis syndrome. This is the first reported case of spinal desmoid-type fibromatosis in association with adenomatous polyposis syndrome. The identification of an underlying genetic instability allows for screening to detect lesions and institute measures to avoid preventable mortality from nonneurological tumors.     

Imaging of pediatric cardiac tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

Cardiac tumors in children are rare and the majority are benign. The most common cardiac tumor in children is rhabdomyoma, usually associated with tuberous sclerosis complex. Other benign cardiac masses include fibromas, myxomas, hemangiomas, and teratomas. Primary malignant cardiac tumors are exceedingly rare, with the most common pathology being soft tissue sarcomas. This paper provides consensus-based imaging recommendations for the evaluation of patients with cardiac tumors at diagnosis and follow-up, including during and after therapy.     

Primitive neuroectodermal tumor arising in long-standing cerebellar atrophy

Primitive neuroectodermal tumors (PNETs) account for one fifth of childhood brain tumors. Although little is known of the pathobiology of this tumor type, there are associations with both genetic syndromes and exposures to specific environmental agents. Progressive cerebellar atrophy predating the presentation of a primary brain tumor, in the absence of a genetic syndrome, has not been reported with PNETs. We report a case of a posterior fossa PNET occurring in association with long-standing cerebellar atrophy without evidence of a genetic syndrome. This case may represent an unrecognized paraneoplastic syndrome or a unique subtype of PNET.     

Selected Aspects of Cardiac Tumors in Infancy and Childhood

Considerable literature concerning cardiac tumors in infancy and childhood has accumulated summarizing the prevalence, histologic types, clinical presentation and outcome, and changing imaging algorithms [1, 7, 10, 14, 20, 24, 33, 37, 43, 48, 57, 58, 60–62, 67, 69, 70, 90, 105, 106, 110, 124, 139, 140, 142, 143, 149]. In this review, we focus on selected aspects of cardiac tumors in the neonate, infant, and child, with an emphasis on imaging modalities [6, 13, 15, 18, 21–23, 60, 71, 77, 80, 92, 98, 99, 103, 107, 112, 114, 119, 146]. Various types of primary cardiac tumors in childhood are discussed in this article.     

KCNQ1OT1 hypomethylation: A Novel disguised genetic predisposition in sporadic pediatric adrenocortical tumors?

Pediatric adrenal tumors, other than neuroblastoma, are rare and can be associated with a genetic predisposition. In this report we describe two patients with an isolated and apparently sporadic adrenocortical tumor; one girl with a carcinoma, the other girl with an adenoma. In both patients genetic screening revealed hypomethylation of the KCNQ1OT1 gene, well-known for its association with the Beckwith-Wiedemann syndrome. This represents a likely novel genetic predisposition in patients with adrenocortical tumors without clear phenotypic features of the Beckwith-Wiedemann syndrome.     

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) with multiple vascular complications misdiagnosed as Dubowitz syndrome

To date, the genetic basis of Dubowitz syndrome (short stature, microcephaly, facial abnormalities, eczema) is unknown and vascular complications are not known to be associated with this syndrome. In microcephalic osteodysplastic primordial dwarfism type II (MOPD II; disproportionate short statue, microcephaly, facial abnormalities), however, cerebral aneurysms and other vascular abnormalities are frequent complications. MOPD II is a genetic disorder caused by mutations in the pericentrin (PCNT) gene (21q22). We report on a patient who came to our attention as a 22-year-old with subarachnoid bleeding due to a ruptured cranial aneurysm. Until then, the patient was thought and published to have Dubowitz syndrome; previously, he was treated with coronary bypass surgery for extensive coronary angiopathy. Consecutive genetic testing revealed MOPD II. After clinical stabilization, the patient was discharged to a specialized rehabilitation center where he died due to re-rupture of a cranial aneurysm. Conclusion: In patients with short stature—especially when clinical features are accompanied by vascular complications—MOPD II should be considered as a differential diagnosis leading to consecutive genetic testing. After detection of mutations in the PCNT gene, a full vascular status including cerebral imaging and cardiac evaluation needs to be determined in order to analyze vascular abnormalities and initiate prophylactic treatment.     

A Teenager with Marfan Syndrome and Left Ventricular Noncompaction

We report a teenager with Marfan syndrome who presented to Cincinnati Children’s Hospital Medical Center as part of a preoperative evaluation for an orthopedic procedure after asymptomatic arrhythmia was recognized. Continuous cardiac monitoring showed frequent premature ventricular contractions and nonsustained runs of ventricular tachycardia. Cardiac magnetic resonance imaging showed left ventricular noncompaction (LVNC), prompting insertion of an implantable cardiac defibrillator. Although Marfan syndrome is associated with cardiac lesions, it has not previously been described with LVNC. Likewise LVNC has been seen in association with other cardiac lesions; however, this report represents the first reference of LVNC in the context of Marfan syndrome.     

Primary intraventricular cardiac tumors in children: Contemporary diagnostic and management options

Summary We reviewed the intraventricular cardiac tumors presenting at our institution between 1985–1991, studying the presentation, modes of investigation, and evidence of hemodynamic compromise. Thirteen patients presented with intraventricular tumors during the study period. Two of the tumors were rhabdomyosarcomas, one was a myxoma, and 10 were rhabdomyomas. All patients were evaluated with two-dimensional and pulsed Doppler echocardiography and B-color imaging was undertaken in three patients. Four patients presented for elective scans to complement investigations for tuberous sclerosis, seven patients had cardiac symptoms, and two patients presented prenatally. Obstruction to intracardiac flow was present in five patients. Two patients had the tumor excised and one had an open biopsy of the tumor. One patient had an transvascular biopsy at cardiac catheter. Early detection of cardiac tumors is increasing, particularly rhabdomyomas. With fetal echocardiography, more patients should come to attention prenatally. B-color may be a useful addition in assessing cardiac tumors, aiding detection and definition of intramural lesions.     

The pathogenesis and imaging of the tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by the formation of hamartomatous lesions in multiple organ systems. It is the second most common neurocutaneous syndrome after neurofibromatosis type 1 and has been recognized since the late 1800s. Although the disease has complete penetrance, there is also high phenotypic variability: some patients have obvious signs at birth, while others remain undiagnosed for many years. In addition to skin lesions, TSC patients develop numerous brain lesions, angiomyolipoma (AMLs), lymphangiomyomatosis (LAM) in the lungs, cardiac rhabdomyomas, skeletal lesions, and vascular anomalies, all of which are well seen with medical imaging. Our knowledge of TSC genetics and pathophysiology has expanded dramatically in recent years: two genetic loci were discovered in the 1990s and recent elucidation of TSC's interaction with the mTOR pathway has changed how we manage the disease. Meanwhile, medical imaging is playing an increasingly important role in the diagnosis, management, and treatment of TSC. We provide an update on the genetics and pathophysiology of TSC, review its clinical manifestations, and explore the breadth of imaging features in each organ system, from prenatal detection of cardiac rhabdomyomas to monitoring rapamycin therapy to treatment of AMLs by interventional radiology.     

Antenatal imaging of cutis verticis gyrata

Cutis verticis gyrata (CVG) is a skin condition characterized by thick folds and deep furrows, resembling a cortical gyral pattern. There is a recognized but rare association with Noonan syndrome. We report the antenatal imaging, including three-dimensional surface-rendered sonography and MRI, of a fetus with CVG who was subsequently diagnosed with Noonan syndrome. The case illustrates the antenatal appearances of congenital CVG and the potential yield of antenatal imaging in excluding a major central nervous system anomaly. This is important because without prior knowledge of this condition and its imaging characteristics, it is possible to get a false impression of an underlying skull defect on mid-trimester imaging.     

Cardiac tumour in a neonate with tuberous sclerosis: echocardiographic demonstration and magnetic resonance imaging

In a neonate with tuberous sclerosis, cardiac tumours were diagnosed by two-dimensional echocardiography and evaluated by electrocardiogram-gated magnetic resonance imaging (MRI). The tumour size, shape and mobility in the ventricular cavities were more precisely determined by two-dimensional echocardiography than electrocardiogramgated MRI, while the extent of tumour mass at the apex was more clearly delineated by MRI. As two-dimensional echocardiography provides real-time imaging of cardiac anatomy without sedation, it is useful for initial evaluation of cardiac masses in neonates with genetic predisposition to tuberous sclerosis.Abbreviation MRI magnetic resonance imaging