The Effect Of Rhabdomyomas On Underlying Cardiomyopathy: A Case Report

Case Presentation: Term male infant born to SARS-CoV-2 positive mother with infant testing negative. ECG for perinatal bradycardia revealed ventricular pre-excitation. Echocardiogram showed asymmetric LV hypertrophy with prominent trabeculations, subaortic narrowing with no pressure gradient, and normal biventricular systolic function. Rapid increase in RV pressure estimates and NT-proBNP in first week if life concerning for diastolic dysfunction. Anti-arrhythmic therapy initiated for SVT with subsequent resolution. Later, developed progressive LV dilation and systolic dysfunction. Myocardium showed regions resembling non-compaction and others concerning for infiltrative process. Cardiac MRI showed no obvious tumors, but rhabdomyomas could not be ruled out given similar appearance to myocardium. Due to worsening heart failure, everolimus therapy initiated to target potential rhabdomyomas while awaiting genetic testing for tuberous sclerosis. Subaortic narrowing and LV hypertrophy improved within days, and LV appearance became more consistent with non-compaction. Genetic testing revealed a TSC2 gene variant consistent with tuberous sclerosis. Systolic function improved, and patient discharged on afterload reduction. Echocardiogram 6 months post-discharge shows continued LV dilation and mild systolic dysfunction. Discussion(s): Although outflow obstruction and arrhythmias are common with cardiac rhabdomyomas and can cause dysfunction, our patient developed progressive dysfunction in the absence of outflow tract gradient or prolonged arrhythmia. As rhabdomyomas subsided, it became clearer that he had an underlying cardiomyopathy. We suspect that rhabdomyomas in the setting of abnormal myocardium led to abnormalities in myocardial contractility and compliance causing combined systolic and diastolic dysfunction. After complete resolution of rhabdomyomas, cardiac function has improved. However, he continues to have ventricular dilation and mild dysfunction attributable to cardiomyopathy. It is unlikely that mother's SARS-CoV-2 infection played a role as infant tested negative and clinical picture was not consistent with myocarditis.

Shared decision-making and the caregiver experience in tuberous sclerosis complex: results from a UK survey.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic condition commonly accompanied by neurological and neuropsychological disorders, resulting in a high burden of illness for individuals and a substantial impact on their caregivers. Due to the diversity and complexity of clinical manifestations, patients with TSC need aligned multidisciplinary healthcare services starting in childhood through to adulthood. However, patients and caregivers are sometimes dissatisfied with the care provided, for which one of the most common reasons is a lack of involvement in clinical decision-making. Shared decision-making, whereby clinicians make clinical management decisions together with patients and their caregivers, is advocated for in the management of epilepsy, but evidence of its benefit in managing TSC is currently lacking. In this cross-sectional, UK-based analysis we used an online survey to capture the experiences of primary caregivers for individuals with TSC, including the impact on work productivity, clinical shared decision-making, satisfaction with care, and the impact of the coronavirus disease 2019 (COVID-19) pandemic. RESULTS: In total, 73 eligible caregivers provided consent (analysis set), with 14 completing the survey partially and 59 completing the full survey. Many caregivers (72%) reported receiving recommendations about new treatments from their doctor and discussing the treatment together, with a high proportion (89%) preferring that treatment was initiated at a low dose. Most caregivers (69%) were satisfied or extremely satisfied with pediatric TSC healthcare services, but only 25% were satisfied or extremely satisfied with the transition to adult TSC healthcare services. Several (n = 30) caregivers specified the impact of caring on their work productivity and career in optional open-ended survey responses. Finally, 80% of caregivers indicated that the COVID-19 pandemic had a "large" or "very large" impact on their caring activities, negatively affecting the emotional wellbeing and behavior of individuals with TSC, and caregivers' ability to work and arrange medical appointments. CONCLUSIONS: Caregivers largely feel involved in treatment decisions, and the majority were satisfied with healthcare services for children with TSC. However, many highlighted the need for an improved transition from pediatric to adult healthcare services. The survey also showed that COVID-19 has considerably affected caregivers and individuals with TSC.

Unilateral multiple facial angiofibromas as a solitary manifestation of tuberous sclerosis

We describe the case of a 12-year-old boy who presented via teledermatology with a 5-6-year history of multiple lesions on the right side of his face. They were unchanged since their initial appearance at 6 years of age but were slowly increasing in number across his right cheek and extending onto the chin. Although the lesions were asymptomatic, growing older had made him feel increasingly self-conscious. He was otherwise fit and well, and attended mainstream school, with no past medical history or family history of note. Perinatal and birth history were also uneventful. On examination, he had multiple, 1-2-mm, erythematous papules confined to the right cheek and right chin. Dermoscopy showed an unusual pattern of vessels with nonspecific globules in between. The rest of the skin, hair and nails were entirely normal in appearance. There were no systemic symptoms and a detailed general and systemic examination, as well as radiological imaging, did not reveal any abnormality. An excisional biopsy was taken of one of the lesions, with histological examination demonstrating focal superficial telangiectasia with associated bland round-tospindle cell proliferation, appearances most in keeping with an angiofibroma. This correlated well clinically, apart from unilateral facial angiofibromas being the solitary finding in our patient. Facial angiofibromas - also called adenoma sebaceum - are well described as part of the cutaneous manifestations of tuberous sclerosis (TSC). Classically, these appear as a facial rash in the form of small pink or red spots across the cheeks and nose in a butterfly distribution, at between 3 and 10 years of age, increasing in size and number until adolescence. TSC is an autosomal dominant disorder with defective mammalian target of rapamycin (mTOR) signalling, characterized by hamartomas in many organs, particularly the skin, central nervous system, renal and cardiovascular systems. The clinical presentation is variable, with other well known and frequently reported cutaneous findings such as shagreen patches, ash-leaf macules and periungual fibromas. Unilateral multiple facial angiofibromas in the absence of other cutaneous or systemic manifestations of TSC - as in our patient - are rare, with only 13 reported cases. These may form part of the clinical spectrum of TSC as a probable consequence of cutaneous mosaicism in which a postzygotic genetic mutation has occurred. Our patient was referred for genetic testing, but this has been delayed as a result of the COVID-19 pandemic. Topical sirolimus 1% - an mTOR inhibitor - has been used with good effect for facial angiofibromas, and our patient also responded well to this.

COVID 19 in a family with rare genetic disease of the nervous system

We present familial tuberous sclerosis (TS) case complicated by COVID-19. COVID-19 aggravates the course of TS and may lead to a fatal outcome. We review the role of mTORC1 (mechanistic/mammalian Target of Rapamycin Complex 1) in the development and functions of the nervous system and the pathogenesis of TS and COVID-19 with emphasis on the involvement of the brain and lungs. We observed that COVID-19 worsens the course of epilepsy in patients with TS. In TS patients, lymphangioleiomyomatosis may predispose to SARS-CoV-2 invasion into the respiratory system because of the increased expression of ACE2 and TMPRSS2 in type II pneumocytes and thus may worsen the prognosis. We also review the current data on the continuation/termination of everolimus administration in patients with TS associated with COVID-19.

Safety of inactivated COVID-19 vaccine in tuberous sclerosis complex patients with epilepsy treated with rapamycin.

PURPOSE: To assess the safety of inactivated coronavirus 2019 disease (COVID-19) vaccine in tuberous sclerosis complex (TSC) patients with epilepsy. METHODS: All patients with epilepsy were selected from Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSPIT) project and younger than 17 years old. The patients were treated with mTOR inhibitors (rapamycin). A total of 44 patients who completed the two-dose inactivated COVID-19 vaccine between July 7, 2021, and January 1, 2022, were enrolled. RESULTS: The median age of seizure onset was 23 months. About two-thirds of patients have focal seizures. Thirty-three patients use antiseizure medications. The mean duration of rapamycin treatment was 55.59 ± 18.42 months. Adverse reactions within 28 days after injection occurred in 11 patients (25%), all were under 12 years old. Injection site pain was the most reported event (20.45%), which was mild in severity and improved within one day. All patients had no seizure-related changes after vaccination. CONCLUSION: This study shows that the inactivated COVID-19 vaccine was well tolerated and safe in TSC patients with epilepsy, as well as for those treated with mTOR inhibitors.

Tuberous Sclerosis Complex Secondary to the Presence of Fetal Cardiac Rhabdomyoma: A Case Report and Literature Review

Fetal cardiac rhabdomyoma is associated with tuberous sclerosis complex (TSC) which is an autosomal dominant hereditary neurocutaneous disease with an incidence of approximately 1 in 5 000 to 10 000 live birth. It is caused by mutations in the TSC1 or TSC2 gene, de novo mutations accounting for approximately 80% of TSC cases, which can involve multiple organs and systems such as the heart, brain, kidney, lung, skin, and so on. Cardiac rhabdomyoma is the most common fetal heart tumor, accounting for about 60% of cases. It is closely related to TSC and may be the only manifestation of TSC which occurs during pregnancy. This study retrospectively analyzed the clinical data of a neonate with TSC diagnosed with fetal cardiac rhabdomyomas and confirmed by amniocentesis prenatal diagnosis as gene testing TSC1 gene positively. The parents had no such mutation. However, due to the influence of the sudden coronavirus disease 2019 (COVID-19) epidemic, the TSC genetic test report was not obtained until 38 weeks of pregnancy. Multiple hypo-pigmented spots (diameter >5 mm) were found immediately after birth. The characteristic cardiac feature of TSC is a rhabdomyoma and the diagnosis of TSC is based upon genetic testing and multiple ultrasound examinations or magnetic resonance imaging. Most patients with TSC have epilepsy, and one-half or more have cognitive deficits and learning disabilities. So rigorous follow-up will continue for the case we reported.

Aortic Thrombus Embolization in A Patient with Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting many organ systems. Patients commonly develop a variety of benign tumors as well as neurological disease, including seizures, autism, and cognitive delay. We report here the case of an adolescent patient with TSC and a history of mild COVID-19 who presented with a 1-day history of altered mental status. The patient was found to have ischemic cerebral infarction of the right MCA and ACA territories. Initial angiography showed an occlusion of the right internal carotid artery without a demonstrable etiology, with follow-up echocardiography and angiography revealing a large aortic thrombus. The patient was not a candidate for thrombus removal due to her cerebral infarct and received medical anticoagulation. Thrombosis progressed to involve the left ICA, with left cerebral infarction and subsequent death. Aortic thrombus embolization as a cause of cerebrovascular accident (CVA) is a novel finding in the setting of TSC and should be considered for pediatric patients with CVA of unknown etiology. It is unclear whether this was related to the prior COVID-19 infection.

Current Approaches and Future Directions for the Treatment of mTORopathies.

The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.

First psychotic episode, related to COVID-19 pandemic, in a patient with tuberous sclerosis complex.

Clinical symptoms of tuberous sclerosis may occur because of exposure to a stressful event like COVID-19. During pandemics, specific considerations should be deserved to the mental state of people suffering from genetic diseases to prevent mental illness caused by a coronavirus.

Extremely Preterm Infant Born to a Mother With Severe COVID-19 Pneumonia.

Little is known about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women, fetuses, and neonates, especially when the virus is contracted early in pregnancy. The literature is especially lacking on the effects of SARS-CoV-2 on extremely preterm (<28 weeks gestation) infants who have underdeveloped immune systems. We report the case of an extremely preterm, 25-week 5-days old infant, born to a mother with severe COVID-19 (coronavirus disease-2019) pneumonia. In this case, there is no evidence of vertical transmission of SARS-CoV-2 based on reverse transcription-polymerase chain reaction testing, despite extreme prematurity. However, it appears that severe maternal COVID-19 may have been associated with extremely preterm delivery, based on observed histologic chorioamnionitis. This is the first reported case of an extremely preterm infant born to a mother with severe COVID-19 pneumonia who required intubation, and was treated with hydroxychloroquine, azithromycin, remdesivir, tocilizumab, convalescent plasma, inhaled nitric oxide, and prone positioning for severe hypoxemic respiratory failure prior to and after delivery of this infant. The infant remains critically ill with severe respiratory failure on high-frequency ventilation, inotropic support, hydrocortisone for pressor-resistant hypotension, and inhaled nitric oxide for severe persistent pulmonary hypertension with a right to left shunt across the patent ductus arteriosus and foramen ovale. Pregnant women or women planning to get pregnant should take all precautions to minimize exposure to SARS-CoV-2 to decrease adverse perinatal outcomes.