Tuberous Sclerosis Complex in Children with Apical Hypertrophic Cardiomyopathy as the First Manifestation: A Case Report and Literature Review

Abstract Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant hereditary neurodermal syndrome with diverse clinical manifestations, implicating multiple organs including the nervous system, skin, kidney, lung, heart, eyes and others. Most of the children are first diagnosed with seizures or facial hemangiofibroma, 45% to 60% of patients with TSC lesions can affect the heart resulting in cardiac rhabdomyoma. Although most cardiac rhabdomyomas are asymptomatic, some children may develop severe symptoms such as hemodynamic abnormalities, arrhythmias, and even heart failure in the neonatal period and early infancy. But Tuberous sclerosis complex with apical hypertrophic cardiomyopathy as the first manifestation is rare. Hence, physicians may delay diagnosis and treatment of TSC due to the lack of comprehensive thinking on this atypical presentation.Case presentation A 5-year-old girl was admitted to our hospital due to syncope for more than 10 days. When she was 8 months old, she was diagnosed with hypertrophic cardiomyopathy and received long-term oral propranolol treatment. After her admission, a thorough examination was performed. Heart exam revealed the revelant problem. Brain MRI demonstrated mutiple nodules in bilateral frontal parietal occipital cortex, subcortical cortex and bilateral lateral ventricular margin consistent with TSC. Genetic analysis (high-precision clinical display PLUS, JiaJian Medicine Company) revealed that the patient had inherited the TSC2 mutation c.1343T> C (p.L448P) from her mother (heterozygous), who was clinically unaffected.Conclusions: This report highlights that TSC occurs in different ways. Given the possibility of insidious and atypical tuberous sclerosis, when apical hypertrophy or cardiac tumors are identified, it is recommended to broaden the systemic examination even including genetic testing to further determine the cause, in order to reduce the misdiagnosis rate of tuberous sclerosis.

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Tuberous sclerosis with cardiac rhabdomyoma: a case report

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20170730 ◽

2017 ◽

Vol 4 (2) ◽

pp. 666

Author(s):

Sunita Arora ◽

Harnoorjit Kaur Brar ◽

Prabhjot Kaur Dhillon

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Female Child ◽

The Body ◽

Cardiac Rhabdomyoma ◽

Cardiac Evaluation ◽

Benign Tumours ◽

High Index Of Suspicion

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a genetic disorder, caused by mutations on either of two genes TSC1 and TSC2. Clinical manifestations are caused by growth of benign tumours in different parts of the body. Ten months old female child with four major criteria of tuberous sclerosis complex and asymptomatic cardiac rhabdomyoma is presented. A case of TSC warrants cardiac evaluation for the presence of cardiac rhabdomyoma and if a cardiac rhabdomyoma is detected on antenatal ultrasound or postnatal echocardiography, one should have high index of suspicion for the diagnosis of TSC. Continued research on this disease has unfolded many realities regarding its etiology as well as treatment.

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Everolimus treatment of a fetal intracardiac rhabdomyoma not associated with the tuberous sclerosis complex: a case report

Case Reports in Perinatal Medicine ◽

10.1515/crpm-2016-0067 ◽

2017 ◽

Vol 6 (2) ◽

Author(s):

Monica Schmidt-Fittschen ◽

Stephan Spahn ◽

Ammar Al Naimi ◽

Dietmar Schranz ◽

Franz Bahlmann

Keyword(s):

Case Report ◽

Tuberous Sclerosis ◽

Tricuspid Valve ◽

Tuberous Sclerosis Complex ◽

Tumor Size ◽

Attractive Alternative ◽

Cardiac Tumors ◽

Cardiac Rhabdomyoma ◽

Tricuspid Valve Insufficiency ◽

Valve Insufficiency

Abstract Introduction Benign cardiac rhabdomyomas are the most common cardiac tumors in fetuses and children. They are most often located in the ventricles and may disturb myocardial function, the severity correlating with location and size of the tumor. Rhabdomyomas are commonly associated with the tuberous sclerosis complex (TSC) and are the first clinical manifestation in 50–80% of the cases [Isaacs H Jr. Fetal and neonatal cardiac tumors. Pediatr Cardiol. 2004;25:252–73, Colosi E, Russo C, Macaluso G, Musone R, Catalano C. Sonographic diagnosis of fetal cardiac rhabdomyomas and cerebral tubers: a case report of prenatal tuberous sclerosis. J Prenat Med. 2013;7:51–5]. Several authors have documented the sensitivity of TSC-associated rhabdomyomas to everolimus treatment [Hoshal SG, Samuel BP, Schneider JR, Mammen L, Vettukattil JJ. Regression of massive cardiac rhabdomyoma on everolimus therapy. Pediatr Int. 2016;58:397–9, Mlczoch E, Hanslik A, Luckner D, Kitzmüller E, Prayer D, Michel-Behnke I. Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus. Ultrasound Obstet Gynecol. 2015;45:618–21, Tiberio D, Franz DN, Phillips JR. Regression of a cardiac rhabdomyoma in a patient receiving everolimus. Pediatrics. 2011;127:e1335–7]. The present study provides convincing evidence of successful everolimus therapy in a newborn without the TSC complex. Case presentation A cardiac rhabdomyoma measuring 35 × 28 × 24 mm was seen in a fetus in pre- and postnatal echocardiography. There was no family history for TSC and amniocentesis showed no mutations in the TSC1/TSC2 genes. Off-label treatment with everolimus began when the neonate was 11 days old and was discontinued when the infant was 11 months old after echocardiography showed marked regression of tumor size and improvement of the tricuspid valve insufficiency. Echocardiography 3 months later showed an increase in size to 13.2 × 9 mm, so that everolimus therapy was re-instated. The next echocardiography, 10 weeks later, showed renewed regression of tumor size and a residual moderate tricuspid valve insufficiency under everolimus therapy. Discussion The present report of a rhabdomyoma in a newborn without an association with TSC is of interest because it identifies a treatment effect of everolimus. A medical approach in patients with cardiac decompensation due to intracardiac rhabdomyomas offers an attractive alternative to surgery.

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Clinical, cellular, and molecular characterisation of cardiac rhabdomyoma in tuberous sclerosis

Cardiology in the Young ◽

10.1017/s1047951121000172 ◽

2021 ◽

pp. 1-9

Author(s):

Hamood N. Al Kindi ◽

Ayman M. Ibrahim ◽

Mohamed Roshdy ◽

Besra S. Abdelghany ◽

Dina Yehia ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Clinical Features ◽

Tuberous Sclerosis Complex ◽

Potential Role ◽

Severe Disease ◽

Cardiac Rhabdomyoma ◽

Urgent Surgery ◽

Pathogenic Mutations ◽

Personalised Treatment

Abstract Background: Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour. Methods: All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling. Results: Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue. Conclusion: All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.

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Brain MRI in Fetuses with Cardiac Tumours

The Neuroradiology Journal ◽

10.1177/197140090702000503 ◽

2007 ◽

Vol 20 (5) ◽

pp. 494-499 ◽

Cited By ~ 3

Author(s):

E. Jurkiewicz ◽

M. Bekiesińska-Figatowska ◽

A. Romaniuk-Doroszewska ◽

J. Dangel

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Imaging Modality ◽

Brain Mri ◽

Multisystem Disorder ◽

Complete Evaluation ◽

Sonographic Examination ◽

Diagnosis And Prognosis ◽

Prenatal Mri ◽

Cardiac Tumours

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder which affects the skin, brain, heart and other organs. It is caused by mutations of two genes: TSC1 (on chromosome 9q34) or TSC2 (on 16p13.3). 70% of cases are sporadic with new mutations. This study aimed to highlight the utility of prenatal MRI as an adjunct imaging modality in the diagnosis and prognosis of tuberous sclerosis complex. Prenatal ultrasound and magnetic resonance imaging were performed in seven fetuses at a gestational age of 30, 32, 34 and 35 weeks using a 1.5 T MRI scanner. SSFSE,T2- and FGRE/T1-weighted images were obtained in axial, coronal and sagittal planes. Postnatal MRI was performed in two cases. Intracardiac tumors (rhabdomyomas) were revealed on ultrasound in all fetuses. On sonographic examination the brain tissue appeared normal in all cases. Brain MRI revealed focal low-signal-intensity lesions, localized along the walls of the lateral ventricles of five fetuses. Another hypointense lesion was seen at the grey/white matter junction in one case. Brain MRI of two fetuses was normal. The diagnosis of TSC was established in five cases. Postnatal MRI in two cases confirmed prenatal findings. MRI allows more complete evaluation of the fetus and helps to determine the diagnosis and prognosis in cases of TSC. The use of prenatal MR imaging in addition to prenatal sonography has the potential to improve genetic counseling and prenatal diagnosis of patients with tuberous sclerosis.

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A novel TSC2 c.4511 T > C missense variant associated with tuberous sclerosis complex

BMC Medical Genetics ◽

10.1186/s12881-020-01120-z ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Shunzhi He ◽

Na Lv ◽

Hongchu Bao ◽

Xiong Wang ◽

Jing Li

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Genetic Diagnosis ◽

Missense Variant ◽

Sporadic Case ◽

Hereditary Disease ◽

Multiple Organ ◽

Cardiac Rhabdomyoma ◽

Pathogenic Variants ◽

Organ Systems

Abstract Background Tuberous sclerosis complex (TSC) is an autosomal-dominant hereditary disease characterized by hamartomas of multiple organ systems, including the brain, skin, heart, kidney and lung. Genetically, TSC is caused by pathogenic variants in the TSC1 or TSC2 gene. Case presentation We reported a sporadic case of a 32-year-old Han Chinese male diagnosed with TSC, whose spouse had a history of two spontaneous miscarriages and an induced abortion of a 30-week fetus identified with cardiac rhabdomyoma by ultrasound. A novel heterozygous missense variant in the TSC2 gene (Exon35:c.4511 T > C:p.L1504P) was identified in the male patient and the aborted fetus by next-generation sequencing, but not in his wife or both his parents. According to the ACMG/AMP criteria, this variant was classified as a “likely pathogenic” variant. Conclusion The novel TSC2:c.4511 T > C variant identified was highly likely associated with TSC and could potentially lead to adverse reproductive outcomes. IVF-ET and pre-implantation genetic diagnosis for TSC are recommended for this patient in the future to prevent fetal TSC.

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

Journal of Diagnostic Medical Sonography ◽

10.1177/8756479319847641 ◽

2019 ◽

Vol 35 (5) ◽

pp. 426-430

Author(s):

Bailey Sarff ◽

Randall Floyd ◽

Amy Bildner ◽

Janell Stormo ◽

Kelsy Fisher

Keyword(s):

Case Report ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cardiac Tumor ◽

Genetic Disorder ◽

Cardiac Tumors ◽

Size Number

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.

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LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION (LVOTO) FROM CARDIAC RHABDOMYOMA AND TUBEROUS SCLEROSIS COMPLEX (TSC) IN A NEONATE

Critical Care Medicine ◽

10.1097/00003246-200412001-00657 ◽

2004 ◽

Vol 32 (Supplement) ◽

pp. A185

Author(s):

Cindy S Barrett ◽

Ira Cheifetz ◽

James Jaggers

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Left Ventricular Outflow Tract ◽

Ventricular Outflow Tract ◽

Left Ventricular ◽

Outflow Tract ◽

Cardiac Rhabdomyoma ◽

Ventricular Outflow Tract Obstruction ◽

Left Ventricular Outflow

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Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex

Frontiers in Neurology ◽

10.3389/fneur.2021.673583 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rony Cohen ◽

Jacob Genizi ◽

Liora Korenrich

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Genetic Disorder ◽

Neuropsychiatric Symptoms ◽

Brain Mri ◽

Spatial Location ◽

Neuropsychiatric Disorders ◽

Temporal Area ◽

Radial Migration ◽

Parietal Area

Objective: Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous genetic disorder. The clinical manifestations are extensive and include neurological, dermatological, cardiac, ophthalmic, nephrological, and neuropsychiatric manifestations. The prediction and pathophysiology of neuropsychiatric disorders such as emotional symptoms, conduct problems, hyperactivity, and poor social behavior are poorly understood. The aim of the study was to diagnose neuropsychiatric symptoms in individuals with TSC, and to examine their possible correlations with quantity, magnitude, and spatial location of tubers and radial migration (RM) lines.Methods: The cohort comprised 16 individuals with TSC, aged 5–29 years, with normal or low normal intelligence. The participants or their parents were requested to fill Strengths and Difficulties Questionnaire (SDQ) and the TAND (TSC-associated neuropsychiatric disorders) Checklist for assessment of their neuropsychiatric symptoms. Correlations were examined between these symptoms and the magnitude, quantities, and locations of tubers and white matter RM lines, as identified in T2/FLAIR brain MRI scans.Results: The SDQ score for peer relationship problems showed correlation with the tuber load (r = 0.52, p < 0.05). Tuber load and learning difficulties correlated significantly in the temporal and parietal area. Mood swings correlated with tubers in the parietal area (r = 0.529, p < 0.05). RM lines in the temporal area correlated with abnormal total SDQ (r = 0.51, p < 0.05). Anxiety and extreme shyness were correlated with RM lines in the parietal area, r = 0.513, p < 0.05 and r = 0.593, p < 0.05, respectively. Hyperactive/inattention correlated negatively with RM lines in the parietal area (r = −707, p < 0.01).Conclusions: These observations may lead to future studies for precise localization of neuropsychiatric symptoms, thereby facilitating directed therapy.

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