Multiple Cardiac Rhabdomyomas Research Articles

A Novel Variant of Tuberosclerosis: c.2458A>T p.(Lys820*) in the TSC1 Gene 19th Exon

Rhabdomyomas are the most common congenital heart tumors. Rhabdomyomas are hamartomas of myocytes and benign heart tumors. In the postnatal period, it may be asymptomatic, or there may be findings such as murmur, arrhythmia, heart failure, and even hydrops. Echocardiography (ECHO) is a very valuable method in its diagnosis. Rhabdomyomas can regress spontaneously. Rhabdomyoma of the heart is seen in 43-60% of tuberous sclerosis cases. Tuberous sclerosis is an autosomal dominant inherited neurocutaneous disease that causes the development of benign tumors called hamartoma in many systems such as brain, retina, kidneys, heart, skin and lungs. In this article, we wanted to contribute to the literature by presenting a new pathogenic c.2458A> T (p.Lys820Ter) variant that developed de novo in the TSC1 gene by genetic analysis of a patient with multiple cardiac rhabdomyomas.

Multiple cardiac rhabdomyomas not associated with tuberous sclerosis in a dizygotic twins: a case report

BackgroundRhabdomyomas comprise the majority of cardiac tumors in fetuses and are found in association with tuberous sclerosis complex. More than 90% of fetuses and neonates with multiple cardiac rhabdomyomas have signs of tuberous sclerosis complex. However, solitary cardiac rhabdomyoma cases are largely unrelated to tuberous sclerosis complex. Here, we report a case involving multiple cardiac rhabdomyomas not associated with tuberous sclerosis complex in a dizygotic twin.Case presentationA 36-year-old Japanese woman was diagnosed with a dizygotic twin pregnancy in the first trimester. Consistent with dizygosity, the fetal sex was discordant (male and female). At 27 weeks of gestation, hydrops and multiple echogenic cardiac masses were noted in the male baby, with the largest mass measuring 34 × 30 mm. The female fetus appeared normal. The cardiac masses enlarged gradually with the progression of the hydrops. At 32 weeks of gestation, intrauterine death of the male fetus was confirmed. The next day, autopsy of the male fetus was performed after cesarean section. Three well-demarcated white-tan-colored nodules were formed in the ventricular walls and interventricular septum, with the largest nodule (40 × 30 mm) in the left ventricular wall. Histologically, these lesions were diagnosed as rhabdomyomas.ConclusionsWe encountered a case involving multiple cardiac rhabdomyomas arising in one of dizygotic twin fetuses. Unlike most reported cases of multiple cardiac rhabdomyomas, this case was not accompanied by tuberous sclerosis complex. To the best of our knowledge, this is the first case report of multiple cardiac rhabdomyomas that developed in only one of dizygotic twins in the English literature.

Everolimus treatment in a 3-month-old infant with tuberous sclerosis complex cardiac rhabdomyoma, severe left ventricular outflow tract obstruction, and hearing loss.

Tuberous sclerosis complex is a rare multisystem genetic disorder characterised by the growth of numerous tumour-like malformations in many parts of the body including skin, kidneys, brain, lung, eyes, liver, and heart. Mutations in the TSC1 or TSC2 genes have been reported to cause disruption in the TSC1-TSC2 intracellular protein complex, causing over-activation of the mammalian target of rapamycin protein complex. In this study, we present a 3-month-old male infant diagnosed with tuberous sclerosis, bilateral neurosensorial hearing loss, Wolff-Parkinson-White syndrome on electrocardiography, multiple cardiac rhabdomyomas with severe stenosis in the left ventricular outflow tract, who responded well to the Everolimus therapy.

TSC1 intragenic deletion transmitted from a mosaic father to two siblings with cardiac rhabdomyomas: Identification of two aberrant transcripts

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by non-cancerous tumors in multiple organs including the brain, kidney, lung, heart, and skin. We encountered a Japanese family consisting of two siblings (a four-year-old boy and a one-year-old girl) with multiple cardiac rhabdomyomas conveying a high risk of TSC and apparently unaffected sibling (a two-year-old girl) and parents. Whole exome sequencing and application of Integrative Genomic Viewer revealed an identical intragenic TSC1 deletion with the breakpoints on intron 15 and exon 19 in the affected siblings, but not in the apparently unaffected sibling and parents. Subsequently, PCR-based analyses were performed using primers flanking the deletion, showing that the deletion was also present in the father and that the deletion occurred between chr9:135,777,038 (bp) and chr9:135,780,540 (bp) in association with a one bp overlap. Furthermore, RT-PCR analyses were carried out using lymphoblastoid cell lines, revealing a major in-frame insertion/deletion transcript produced by aberrant splicing using a cryptic ″ag″ splice acceptor motif at intron 15 (r.1998_2438delinsTTCATTAGGTGG) and a minor frameshift transcript generated by aberrant splicing between exon 15 and exon 20 (r.1998_2502del, p.Lys666Asnfs*15) in the affected siblings. These findings imply that the intragenic deletion producing two aberrant transcripts was generated as a somatic pathogenic variant involving the germline in the father and was transmitted to the affected siblings.

Genetic analysis of three fetusesaffected with cardiac rhabdomyomas

To report on echocardiographic finding and genetic testing of three fetuses with cardiac rhabdomyoma. Clinical data of the three fetuses was collected. High-throughput sequencing was carried out to analyze the whole exomes of the three fetuses. Suspected variants were confirmed by Sanger sequencing. Multiple hyperechoic masses were found in both ventricles of the three fetuses, suggesting the presence of fetal cardiac rhabdomyoma. Genetic testing revealed that fetus 1 carried a heterozygous c.740G>A (p.W247*) variant of the TSC1 gene, fetus 2 carried a previously known heterozygous c.3352C>T (p.Q1118*) variant of the TSC2 gene. Fetus 3 carried a previously known heterozygous c.1579C>T (p.Q527*) variant of the TSC1 gene. None of their parents carried the same variant. Literature review has identified 109 fetuses with relatively complete data. Cardiac rhabdomyomas in ventricles and ventricular septum was reported in 89, and multiple cardiac rhabdomyoma was reported in 79. Out of the 94 cases who underwent genetic testing, 74 have carried variants of the TSC1 or TSC2 genes. Fetal cardiac rhabdomyoma may present as multiple hyperechoic intraventricular masses. Most of them are associated with other manifestation of tuberous sclerosis. Such cases may warrant prenatal genetic testing.

Fetal Echocardiographic Detection of Cardiac Tumors: A Case Report of Multiple Fetal Cardiac Rhabdomyomas

Cardiac rhabdomyomas are the most common fetal cardiac tumor. They can be detected in the second and third trimesters. Rhabdomyomas are most commonly associated with the genetic disorder tuberous sclerosis complex. When associated with tuberous sclerosis complex, cardiac rhabdomyomas usually regress within the first few years of life, without complications. Symptoms depend on the size, number, and location of the rhabdomyomas. A case report of multiple cardiac rhabdomyomas that was found at 35 weeks’ gestation and is discussed.

A novel TSC2 missense variant associated with a variable phenotype of tuberous sclerosis complex: case report of a Chinese family

BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the development of hamartomas in multiple organs, including the brain, heart, skin, kidney, lung and retina. A diagnosis of TSC is established with a recently revised clinical/radiological set of criteria and/or a causative mutation in TSC1 or TSC2 gene.Case presentationWe report a Chinese TSC family with two siblings presenting with multiple hypomelanotic macules, cardiac rhabdomyomas and cortical tubers associated with a small subependymal nodule. The older child had seizures. A novel heterozygous missense variant in the TSC2 gene (c.899G > T, p.G300 V) was identified and shown to be inherited from their father as well as paternal grandfather, both of whom presented with variable TSC-associated signs and symptoms.ConclusionWe identified a novel heterozygous TSC2 variant c.899G > T as the causative mutation in a Chinese family with TSC, resulting in wide intrafamilial phenotypic variability. Our study illustrates the importance of clinical evaluation and genetic testing for family members of the patient affected with TSC.

Rapamycin therapy for neonatal tuberous sclerosis complex with cardiac rhabdomyomas: A case report and review.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that varies greatly in its expression. The current study reports a novel case of TSC caused by a TSC2 mutation (TSC2c.1642_1643insA or TSC2p.K549fsX589), in which multiple cardiac rhabdomyomas were detected by fetal echocardiography in week 31 of pregnancy. The infant was delivered successfully; however, seizures began 16 days following birth. Subsequent genetic tests confirmed a diagnosis of TSC. Rapamycin treatment resulted in regression of cardiac rhabdomyomas and controlled seizures. The current study demonstrates the value of fetal echocardiography in the diagnosis of TSC and suggests that inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway may be considered as a potential antiepileptogenic therapy for neonatal TSC. In addition, it was demonstrated that rapamycin treatment was therapeutically beneficial for preventing disorders caused by abnormal mTOR signaling, such as cancer. According to the literature, cardiac rhabdomyomas, seizures and skin lesions are well established markers for TSC in neonates. MRI scans of the brain and genetic screening of TSC1 and TSC2 genes may facilitate an early diagnosis of TSC.

Nonsurgical device closure of isolated ostium secundum atrial septal defect in a case of genetically proven tuberous sclerosis

Tuberous sclerosis (TSC) is an autosomal dominant multisystem disease associated with multiple cardiac Rhabdomyomas; however, congenital cardiac malformations are very rare in TSC. A 5-year-old girl with classical features of TSC had an associated large secundum atrial septal defect (ASD). The left to right shunt through the ASD was augmented by the multiple left ventricular masses. Nonsurgical closure of the ASD avoided the neurological and cardiac complications that may occur due to cardiopulmonary bypass during open-heart surgery. This first novel interventional report in TSC stresses on the value of such catheter interventions tomitigate risks in complex cardiac associations.

P24.09: Neurosonographic findings in fetal tuberous sclerosis complex

To evaluate the neurosonographic abnormalities in a group of fetuses that meets diagnostic criteria for tuberous sclerosis complex (TSC). A review of the literature and potential advantages of prenatal diagnosis of these anomalies are also discussed. Eight fetuses with multiple cardiac rhabdomyoma and cortical hamartomas (CH), subependymal nodules (SEN), subependymal giant cell tumours (SGCT) and/or abnormalities of the white matter including linear white matter lesions (LWML), from two referral centres, were included. Fetal neurosonographic images, videoclips and 3D volumes were compared with neonatal/pediatric evolution or post-mortem examination. Magnetic resonance imaging (MRI) was performed in 7/8 cases. MRI confirmed the following fetal neurosonography findings: 7/8 cases with CH, 4/8 with SEN and 3/8 with SGCT. LWML were suspected in 3/8 vaginal neurosonography, and irregular white matter and periventricular echogenicity in other 2. Three cases opted for termination of pregnancy and lesions were confirmed histologically. The remaining reached term and were followed postnatally. An accurate diagnosis of the spectrum of fetal brain lesions included in TSC is feasible by neurosonography and the findings were similar to those obtained by MRI. Considering the correlation between the number of lesions and prognosis in TSC, correct diagnosis through neurosonography allowed an appropriate prenatal counselling to parents. Moreover, there is a growing consensus that the diagnosis of TSC cerebral lesions is important in reducing the morbidity of the disease, through the selection of patients for early postnatal treatment.

Teaching Neuro Images : Huge carotid artery aneurysm in TSC2/PKD1 contiguous gene syndrome

A 1-day-old infant developed heart murmur with tachypnea. Echocardiography showed multiple biventricular cardiac rhabdomyomas (figure, A). Brain sonography showed multiple cerebral cortical tubers (figure, B) and subependymal nodules (figure, D and E), confirming tuberous sclerosis. Bilateral renal cysts were present (figure, C).

Single giant mediastinal rhabdomyoma as a sole manifestation of TSC in foetus

Presence of multiple cardiac rhabdomyomas is one of the major features of Tuberous sclerosis (TSC), but isolated progressing single giant rhabdomyoma is very rare and not typical of TSC. This report presents family without obvious history of TSC with occurrence of giant mediastinal rhabdomyoma affecting the haemodynamics in male foetus, without other TSC symptoms. Girl from the next gravidity had prenatally detected multiple rhabdomyomas and small subcortical tuber of brain detected after birth. DNA analysis found novel c.4861A>T TSC2 variant and large deletion in TSC2 in tumour tissue from male foetus. The novel TSC2 variant was also present in the girl and her healthy father, in silico analysis suggested its functional effect on TSC2. Brain MRI of the father detected mild TSC specific abnormality. We suggest the novel TSC2 mutation is a cause of mild TSC in this family and has reduced expression. The clinical and molecular findings in this family also emphasize that TSC diagnosis should be also evaluated in case of single giant foetal cardiac rhabdomyoma.

Regression of Cardiac Rhabdomyomas in a Neonate after Everolimus Treatment.

Cardiac rhabdomyoma often shows spontaneous regression and usually requires only close follow-up. However, patients with symptomatic inoperable rhabdomyomas may be candidates for everolimus treatment. Our patient had multiple inoperable cardiac rhabdomyomas causing serious left ventricle outflow-tract obstruction that showed a dramatic reduction in the size after everolimus therapy, a mammalian target of rapamycin (mTOR) inhibitor. After discontinuation of therapy, an increase in the diameter of masses occurred and everolimus was restarted. After 6 months of treatment, rhabdomyomas decreased in size and therapy was stopped. In conclusion, everolimus could be a possible novel therapy for neonates with clinically significant rhabdomyomas.

Cardiac Rhabdomyomas and Congenital Hypothyroidism: A Coincidence or Hamartia

Cardiac rhabdomyomas are the most common primary cardiac tumors in children. These tumors are generally asymptomatic, although they may be associated with neonatal tuberous sclerosis complex. Despite the fact that thyroid dysfunction rarely occurs in tuberous sclerosis, papillary adenomas (hamartomas) of the thyroid gland have been reported in a number of autopsies. Herein, we present the case of an infant with tuberous sclerosis, congenital hypothyroidism and multiple cardiac rhabdomyomas, leading to atrioventricular node dysfunction. Considering the rarity of this co-occurrence, we decided to report the present case. The co-occurrence of these two disorders in one patient may be a mere coincidence or related to hamartoma of the thyroid gland as a consequence of tuberous sclerosis gene products.

Electrocardiographic ST elevation (mosque sign) without myocardial ischemia in an infant with tuberous sclerosis

Rhabdomyomas, the most common primary cardiac tumors seen in infants and children, are often associated with tuberous sclerosis. However, these cardiac rhabdomyomas may cause hemodynamic disturbances and arrhythmias. In the present case, we demonstrated an infant with electrocardiographic ST elevation suggesting myocardial ischemia associated with multiple cardiac rhabdomyomas.

Regression of symptomatic multiple cardiac rhabdomyomas associated with tuberous sclerosis complex in a newborn receiving everolimus.

Cardiac rhabdomyoma is the most common primary cardiac tumor, is considered to be a hamartoma of developing cardiac myocytes. Cardiac rhabdomyoma is associated with tuberous sclerosis complex (TSC) in 50-86% of cases. Mutations in TSC-1/TSC-2 genes result in increased mammalian target of rapamycin (mTOR) pathway activation responsible for the hamartomatous lesions of tuberous sclerosis complex. Therapy with mTOR inhibitors is currently under investigation as a treatment option for tumors associated with TSC. In this report we present a case with multiple symptomatic rhabdomyomas associated with tuberous sclerosis complex, deemed to be ineligible for surgical removal, treated with everolimus (mTOR inhibitor). As we observed in our patient, in cases with inoperable symptomatic rhabdomyomas associated with TSC, everolimus, an mTOR inhibitor, may be the treatment of choice, which should be confirmed with additional studies.

Multiple cardiac rhabdomyomas in a newborn infant- a case report

Cardiac tumours in the paediatric age group are extremely rare, occurring approximately 1 in 100,000 live births. Rhabdomyomas are the most common type of cardiac tumours. Approximately 70-95% of rhabdomyomas are associated with tuberous sclerosis. We are reporting a rare case of term neonate, with antenatally diagnosed cardiac tumour. Finally diagnosed as tuberous sclerosis with secondary epilepsy with large multiple cardiac rhabdomyomas. Child is now 2 years old, under follow-up without any cardiac manifestations and rhabdomyomas are regressing on repeat echocardiograms. Only few such cases are reported in literature so far and none from Rajasthan.

頭部超音波検査で2つの結節パターンを認めた結節性硬化症の新生児例

We report a neonatal case of tuberous sclerosis (TS) presenting two types of tubers on cranial ultrasound (US) images. Multiple cardiac rhabdomyomas (CRs) were detected at 36 weeks’ gestation by intrauterine US. Postnatally, the patient had no heart problems. On her second day after birth, she experienced generalized tonic clonic seizures. On the same day, tubers, white matter lesions, and subependymal nodules were recognized on her brain magnetic resonance imaging (MRI) scan. In addition, cranial US showed multiple brain lesions. The patient fulfilled the diagnostic criteria for TS. Two types of tubers were detected on US: an incomplete ring resembling a half-eaten doughnut and a solid mass. These could be observed more clearly with a 12-MHz linear probe than with a 7-MHz sector probe. If the fetal US examination had been performed with suitable probes, her brain lesions could have been prenatally detected. When CRs can be detected on fetal US, neuroimaging enables a rapid diagnosis of TS. In addition to genetic testing and the morphology of tubers as seen on MRI, it is likely that the types of tubers seen on US facilitate forecasting of the postnatal severity of the neuronal manifestations of TS.

Multiple Intracardiac Rhabdomyomas, an Antenatal Clue to the Diagnosis of Tuberous Sclerosis.

Antenatal detection of multiple cardiac rhabdomyomas is an important clue to the diagnosis of tuberous sclerosis in the foetus. These antenatally detected cardiac rhabdomyomas undergo spontaneous resolution in majority of the case but our case lead to severe left ventricular outflow flow tract obstruction and consequent cardiac failure and death. Examination of first degree relatives for features of tuberous sclerosis TSC is mandatory for diagnosis of TSC.

Incessant ventricular tachycardia due to multiple cardiac rhabdomyomas in an infant with Tuberous Sclerosis

We report a case of incessant ventricular tachycardia managed successfully with medications. The transthoracic echocardiogram showed multiple cardiac rhabdomyomas involving ventricular free wall and outflow tracts. Computerized tomography of brain showed multiple subependymal tubers confirming Tuberous Sclerosis. The follow up assessment showed sinus rhythm and regressing cardiac rhabdomyomas.