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Efficacy of Everolimus Low-Dose Treatment for Cardiac Rhabdomyomas in Neonatal Tuberous Sclerosis: Case Report and Literature Review
case-report
Author(s):
Luisa Federica Nespoli
1 ,
Elena Albani
2 ,
Carla Corti
1 ,
Luigina Spaccini
3 ,
Enrico Alfei
4 ,
Irene Daniele
5 ,
Gian Vincenzo Zuccotti
2
,
6 ,
Gianluca Lista
5 ,
Valeria Calcaterra
2
,
7 ,
Savina Mannarino
1
,
*
Publication date (Electronic):
01 March 2021
Journal:
Pediatric Reports
Publisher:
MDPI
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Abstract
Background: Cardiac rhabdomyomas (CRs) are the most common cardiac tumors in newborns. Approximately 80–90% of cases are associated with tuberous sclerosis complex (TSC). In selective cases, Everolimus has resulted in a remarkable tumoral regression effect in children with TS. The optimal dosage for neonates is still unknown. Case presentation: We describe the use of Everolimus in a neonate with multiple biventricular CRs, causing subaortic obstruction, in which a low-dose treatment (0.1 mg/die), in an effort to maintain serum trough levels of 3–7 ng/mL, was successfully used off-label, without adverse effects. Conclusions: We showed that a low-dose Everolimus regimen may be an effective and safe treatment for CR regression in TS neonates, when the minimum therapeutic range was maintained.
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Most cited references23
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Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference.
Hope Northrup, Darcy Krueger, Steven Roberds … (2013)
Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of disease-associated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex. Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals. Copyright © 2013 Elsevier Inc. All rights reserved.
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Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised Diagnostic Criteria and Surveillance and Management Recommendations From the International Tuberous Sclerosis Consensus Group
Robert Hinton, Ashwin Prakash, Robb L. Romp … (2014)
Introduction Tuberous sclerosis complex (TSC) is a genetic syndrome with a highly variable phenotype that may affect several organ systems. The central nervous system findings were the first to be described, and the classic triad of cognitive impairment, facial angiofibromas, and seizures was delineated shortly thereafter. 1–2 As the variability and extent of organ involvement were appreciated, diagnostic criteria evolved to include major and minor criteria that taken together would lead to a definite, probable, or possible clinical diagnosis. 3–4 Since the most recent refinement of the diagnostic criteria, dramatic advances have been made in understanding the genetic basis and pathogenesis of TSC, and new treatment strategies have been established, significantly affecting all aspects of coordinated care for TSC patients. The Tuberous Sclerosis Alliance (www.tsalliance.org) convened a Consensus Conference composed of 8 working groups that generated Revised Diagnostic Criteria 5 and new Surveillance and Management Guidelines 6 with the intention of creating “living documents” to accommodate rapid advances and the need for coordination of care. The conference was informed in part by a recent constituency survey of key opinion leaders, which summarized interim progress, areas in need of further research, unmet medical needs, and barriers to progress. 7 The goals of this report are to highlight the new diagnostic criteria and management guidelines as they pertain to cardiology and to expand consideration of the issues relevant to optimal cardiac care of patients with TSC. TSC is characterized by widespread hamartomas, or abnormal growth of normal tissues. Cardiac rhabdomyomas are hamartomatous growths or benign tumors composed of cardiac myocytes, and they represent the classic neonatal manifestation of cardiac disease in TSC. Additional cardiac diseases such as arrhythmia occur later in life, underscoring the importance of ongoing cardiology care. Here, we review what is known about the natural history of cardiac manifestations in TSC with an emphasis on diagnostic testing, surveillance, and treatment. The Revised Diagnostic Criteria Include Clinical Genetic Testing Significant changes have been implemented in the revised diagnostic criteria. 5 For example, clinical genetic testing has been added as an independent criterion, sufficient to make the diagnosis of TSC. Since TSC1 and TSC2, the genes that encode hamartin and tuberlin, were identified as the cause of TSC, 8–9 substantial strides have been made in defining the pathogenesis of TSC. Mutations in the genes TSC1 and TSC2 cause 75% to 90% of cases (Figure A). Given the increasing appreciation for disease variability and an assortment of mild disease phenotypes that may be on the TSC spectrum, the inclusion of a molecular test represents an important change in the approach to diagnosis. While approximately one‐third of cases have a positive family history, this has not been included as diagnostic criteria but remains informative given the various challenges with performing genetic testing. Importantly, the designation of a definite, probable, or possible clinical diagnosis has been simplified to either “definite” or “possible.” Additional changes were made in several of the clinical criteria (Table 1), and changes regarding cardiovascular features are considered next in detail. Table 1. Revised Diagnostic Criteria for TSC Genetic diagnostic criteria The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, out of frame indel or nonsense mutation), prevents protein synthesis (eg, large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment (www.lovd.nl/TSC1, www.lovd.nl/TSC2, 10–11 ). Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are not sufficient to make a definite diagnosis of TSC. Note that 10% to 25% of TSC patients have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC, or have any effect on the use of Clinical Diagnostic Criteria to diagnose TSC. Clinical diagnostic criteria Major features 1. Hypomelanotic macules (≥3, at least 5‐mm diameter) 2. Angiofibromas (≥3) or fibrous cephalic plaque 3. Ungual fibromas (≥2) 4. Shagreen patch 5. Multiple retinal hamartomas 6. Cortical dysplasias* 7. Subependymal nodules 8. Subependymal giant cell astrocytoma 9. Cardiac rhabdomyoma 10. Lymphangioleiomyomatosis (LAM)* 11. Angiomyolipomas (≥2)* Minor features 1. “Confetti” skin lesions 2. Dental enamel pits (>3) 3. Intraoral fibromas (≥2) 4. Retinal achromic patch 5. Multiple renal cysts 6. Nonrenal hamartomas Definite diagnosis: 2 major features or 1 major feature with ≥2 minor features. Possible diagnosis: either 1 major feature or ≥2 minor features. TSC indicates tuberous sclerosis complex. * Includes tubers and cerebral white matter radial migration lines. * A combination of the 2 major clinical features LAM and angiomyolipomas without other features does not meet criteria for a definite diagnosis. Reproduced with permission from Northrup et al. 5 Figure 1. Genetic basis, pathology, and early and late cardiovascular manifestations of TSC. Sequencing of TSC2 demonstrates a missense mutation 1513C>T known to cause TSC (A). Gross pathology shows a discrete well‐demarcated nonencapsulated cardiac rhabdomyomas with heterogeneous tissue (B). Histopathologic examination of the rhabdomyomas demonstrates the classic finding of spider cells representing abnormal myocardial cells (C). Echocardiography shows multiple cardiac rhabdomyomas in the ventricular myocardium (D). ECG shows supraventricular tachycardia with aberrant conduction that can result from cardiac rhabdomyomas or in isolation (E). MRI shows thoracoabdominal aortic aneurysm (arrows) with tortuosity of the descending thoracic aorta (F). LA indicates left atrium; LV, left ventricle; MRI, magnetic resonance imaging; TSC, tuberous sclerosis complex. Overall Recommendations Have Shifted to Careful Surveillance and Early Intervention Guidelines for the management and surveillance of TSC patients were comprehensively addressed in a companion article to the revised diagnostic criteria. 6 Given the successful clinical trials establishing mammalian target of rapamycin (mTOR) inhibition as a new pharmacologic treatment strategy, a variety of surveillance issues have been considered (Tables 2 and 3). The addition of genetic testing to the diagnostic criteria has implications for screening that were addressed as well. These recommendations affect cardiologists directly with respect to surveillance and potentially in rare circumstances with respect to medical therapy. There is an increasing appreciation for latent cardiovascular phenotypes, indicating a need for continued surveillance of these patients. As the natural history of disease in the cardiovascular system is better understood, continued care in adulthood needs to be defined, underscoring efforts to transition care from pediatric to adult cardiology and to maintain surveillance vigilance in adulthood. Table 2. Surveillance and Management Recommendations for Newly Diagnosed or Suspected TSC Summary Table Organ System or Specialty Area Recommendation Genetics Obtain 3‐generation family history to assess for additional family members at risk of TSC Offer genetic testing for family counseling or when TSC diagnosis is in question but cannot be clinically confirmed Brain Perform MRI of the brain to assess for the presence of tubers, subependymal nodules (SEN), migrational defects, and subependymal giant cell astrocytoma (SEGA) Evaluate for TSC‐associated neuropsychiatric disorder (TAND) During infancy, educate parents to recognize infantile spasms, even if none have occurred at time of first diagnosis Obtain baseline routine electroencephalogram (EEG). If abnormal, especially if features of TAND are also present, follow up with a 24‐hour video EEG to assess for subclinical seizure activity Kidney Obtain MRI of the abdomen to assess for the presence of angiomyolipoma and renal cysts Screen for hypertension by obtaining an accurate blood pressure Evaluate renal function by determination of glomerular filtration rate Lung Perform baseline pulmonary function testing (PFT and 6‐minute walk test) and high‐resolution chest computed tomography (HRCT), even if asymptomatic, in patients at risk of developing lymphangioleiomyomatosis (LAM), typically female patients 18 years or older. Adult male patients, if symptomatic, should also undergo testing Provide counsel on smoking risks and estrogen use in adolescent and adult female patients Skin Perform a detailed clinical dermatologic inspection/examination Teeth Perform a detailed clinical dental inspection/examination Heart Consider fetal echocardiography to detect individuals with high risk of heart failure after delivery when rhabdomyomas are identified via prenatal ultrasound Obtain an echocardiogram in pediatric patients, especially if 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first‐line therapy. Selective embolization or kidney‐sparing resection is acceptable second‐line therapy for asymptomatic angiomyolipoma Lung Perform clinical screening for LAM symptoms, including exertional dyspnea and shortness of breath, at each clinic visit. Counseling regarding smoking risk and estrogen use should be reviewed at each clinic visit for individuals at risk of LAM Obtain HRCT every 5 to 10 years in asymptomatic individuals at risk of LAM if there is no evidence of lung cysts on their baseline HRCT. Individuals with lung cysts detected on HRCT should have annual pulmonary function testing (PFT and 6‐minute walk) and HRCT interval reduced to every 2 to 3 years mTOR inhibitors may be used to treat LAM patients with moderate to severe lung disease or rapid progression. TSC patients with LAM are candidates for lung transplantation, but TSC comorbidities may affect transplant suitability Skin Perform a detailed clinical dermatologic inspection/examination annually Rapidly changing, disfiguring, or symptomatic TSC‐associated skin lesions should be treated as appropriate for the lesion and clinical context, using approaches such as surgical excision, laser(s), or possibly topical mTOR inhibitor Teeth Perform a detailed clinical dental inspection/examination at minimum every 6 months and panoramic radiographs by age 7 years, if not performed previously Symptomatic or deforming dental lesions, oral fibromas, and bony jaw lesions should be treated with surgical excision or curettage when present Heart Obtain an echocardiogram every 1 to 3 years in asymptomatic pediatric patients until regression of cardiac rhabdomyomas is documented. More frequent or advanced diagnostic assessment may be required for symptomatic patients Obtain an ECG every 3 to 5 years in asymptomatic patients of all ages to monitor for conduction defects. More frequent or advanced diagnostic assessment such as ambulatory and event monitoring may be required for symptomatic patients Eye Perform annual ophthalmologic evaluation in patients with previously identified ophthalmologic lesions or vision symptoms at the baseline evaluation. More frequent assessment, including those treated with vigabatrin, is of limited benefit and not recommended unless new clinical concerns arise TSC indicates tuberous sclerosis complex; MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma; mTOR, mammalian target of rapamycin; TAND, TSC‐associated neuropsychiatric disorder; EEG, electroencephalography; ACTH, adrenocorticotropic hormone; LAM, lymphangioleiomyomatosis; HRCT, high‐resolution chest computed tomography; PFT, pulmonary function tests; GFR, glomerular filtration rate. Reproduced with permission from Krueger et al. 6 The Natural History and Diagnosis of TSC The Natural History of Cardiac Rhabdomyomas Cardiac tumors are rare, and ascertaining incidence is difficult. 12–13 Based on clinical studies and autopsy series, primary cardiac tumors occur in 0.2% of children. 14 Cardiac rhabdomyomas are by far the most common primary cardiac tumor in childhood. 15–16 After the advent of echocardiography, but before clinical genetic testing was available, studies estimated that up to 70% to 90% of children with rhabdomyomas have TSC, 17–19 and at least 50% of children with TSC have rhabdomyomas, 18 representing a significant increase in the proportion of cardiac rhabdomyomas attributed to TSC compared with historic clinical data. 20–22 In 1 study, Allan et al analyzed 52 cardiac tumor cases, among which 44 (86%) were rhabdomyomas. 23 Tumors are diagnosed more frequently in fetal series than in postnatal series, resulting in an increased sensitivity when examining fetal echocardiograms. 18–19 Cardiac rhabdomyomas tend to appear at 20 to 30 weeks' gestation, with the earliest diagnosis having been made at 15 weeks at the current technical limits of ultrasonography, 24 suggesting rhabdomyomas may be present earlier in development. The frequency of fetal detection is increasing dramatically; therefore, it is reasonable to anticipate that the rate of fetal diagnosis will increase significantly. Fetal cardiac tumors may present in utero as a mass on ultrasonography, irregular heart rhythm, hydrops fetalis, or pericardial effusion. Cardiac rhabdomyomas can increase in size during the second half of gestation, and this has been attributed to maternal hormonal changes associated with pregnancy. When larger tumors result in hemodynamic compromise in utero, intrauterine fetal demise may occur. Fetal loss has been reported to be ≈11% in 1 small series of 44 cases. 23 Cardiac rhabdomyomas do not cause symptoms or hemodynamic compromise in the vast majority of patients but may become symptomatic shortly after birth or in the first year of life. Tumors may obstruct inflow or outflow, which can cause ventricular dysfunction and heart failure, as well as redirection of flow across the foramen ovale. 19,25–26 Nearly 100% of fetuses with multiple rhabdomyomas have TSC, underscoring the practical importance of identifying additional tumors at the time of fetal assessment for diagnosis and prognosis. 17,27 In light of emerging human genetic and molecular knowledge, it is a possibility that the underlying pathogenesis of all rhabdomyomas is a result of a spectrum of TSC disease. Cardiac rhabdomyomas are typically well circumscribed and nonencapsulated (FigureB). Micropathologic examination demonstrates abnormal myocyte architecture, including vacuolization and pathognomonic “spider cells” (FigureC). The individual cardiac rhabdomyomas range in size from a few millimeters to several centimeters and are multiple in number in 90% of cases. There is an equal predilection for left, right. and septal ventricular myocardium. 26,28 Tumors are typically located in the ventricles, where they can compromise ventricular function and on occasion interfere with valve function or result in outflow obstruction. Tumors may be located in the atria, where they can compress the coronary arteries, leading to myocardial ischemia. 29 Diagnosis of Cardiac Rhabdomyoma Echocardiography is the imaging modality of choice for assessing cardiac involvement in TSC. Cardiac rhabdomyomas can be detected prenatally or postnatally. In prenatal life, ultrasound detection of multiple cardiac tumors is often the first sign of TSC. 30 Typically, cardiac rhabdomyomas are visible as multiple, echogenic, nodular masses embedded in the ventricular myocardium, sometimes protruding into the involved chamber (FigureD). They are homogeneous and hyperechoic compared with normal myocardium. Diagnosis of cardiac rhabdomyomas is made easily when these typical features are present, but differentiation from other cardiac tumors may be difficult when there is a large solitary tumor or when tumors are located in an atypical location, such as the atria. Doppler echocardiography is also useful in assessing the presence of obstruction to ventricular inflow or outflow. Echocardiography is also used to assess ventricular function, which may be impaired by multiple confluent tumors. Cardiac rhabdomyomas are seen readily in fetal life after 20 weeks of gestation and are seen in a majority of infants with TSC. Rhabdomyomas can enlarge significantly in size during gestation and may be seen later in gestation when they are not visible prior to 20 weeks. Cardiac rhabdomyomas regress spontaneously in a large majority of patients during the first year of life and as a result are seen with decreasing frequency in patients with TSC after 2 years of age. 31 There is some suggestion that the incidence of identifiable cardiac rhabdomyomas in TSC increases during adolescence, 31 but this observation has not been validated in additional studies. Sensitivity and Specificity of Echocardiography to Identify Cardiac Rhabdomyomas This varies with patient age, related to the previous discussion. In fetal life, of patients diagnosed with cardiac rhabdomyomas by echocardiography, 75% to 80% are found to satisfy criteria for TSC postnatally. 32–33,24 The presence of multiple ventricular tumors seems to be the finding best associated with TSC. 24 The presence of a family history of TSC also increases the likelihood of TSC. 34 In fetuses with a single ventricular tumor, only 30% satisfy criteria for TSC postnatally. 24 Because a diagnosis of TSC during fetal life is often prompted by the presence of cardiac rhabdomyomas, the negative predictive value of fetal echocardiography is not established. In early infancy, the predictive value of echocardiography is similar to that in fetal life, with ≈80% of infants with cardiac rhabdomyomas eventually satisfying a diagnosis of TSC. Conversely, 80% to 85% of children with confirmed TSC have identifiable rhabdomyomas when younger than 2 years. 31 Beyond 2 years of age, the incidence of identifiable rhabdomyomas is significantly lower (≈20% to 25%), although if they are readily seen on echocardiography, the likelihood of TSC likely remains high. In late childhood and adolescence (9 to 14 years of age), the incidence of cardiac rhabdomyomas in patients with confirmed TSC seems to increase again (≈40%) in small series. 31 It has been speculated that this may be related to hormonal changes. Alternative Imaging Modalities for Cardiac Rhabdomyomas Cardiac magnetic resonance imaging (MRI) can also be used to detect cardiac rhabdomyomas; however, its strength lies in more specific tissue characterization. 35 It can be a useful adjunct to echocardiography in situations where it is unclear whether a cardiac tumor represents a rhabdomyoma (eg, in patients with a large solitary tumor). In addition, MRI is more accurate than echocardiography in delineating the proximity of cardiac tumors to normal myocardium and the great vessels 36–37 and therefore may be a useful adjunct to surgical planning once a decision to operate has been made. It can also provide a more reliable and reproducible estimate of ventricular systolic function. Cardiac MRI in infants and young children ( 1 rhabdomyoma. Importantly, because cardiac rhabdomyomas are often the presenting manifestation of TSC, it is important to emphasize the need for pediatric cardiologists to initiate and facilitate the TSC evaluation. Specifically, the pediatric cardiologist making a new diagnosis of rhabdomyomas should obtain clinical genetic testing and make the appropriate subspecialty referrals; typically human genetics and neurology, depending on available local resources. Genetic testing practices may vary by center, prompting a need to be familiar with local processes and the closest tertiary center with specialized care for patients with TSC. Clinical genetic testing should be obtained in all multiple cardiac rhabdomyomas and most isolated or possible rhabdomyomas. Because there is benefit to early diagnosis and potential added morbidity to late diagnosis, a proactive approach is warranted. Table 4. New Cardiology‐Specific Recommendations for Tuberous Sclerosis Complex Cardiac rhabdomyomas remain a major diagnostic criterion Echocardiogram at the time of diagnosisIf fetal diagnosis, then serial observation and at least 1 postnatal echocardiogramSurveillance studies until regression demonstrated Electrocardiogram at the time of diagnosisSurveillance studies every 3 to 5 yearsHolter monitor as indicated for appropriate signs and symptoms Cardiology consultation at time of diagnosisOngoing cardiology surveillance as indicatedMedical and surgical intervention as indicatedReferral to genetics and neurology when cardiology makes initial diagnosisPediatric to adult transition plan with ongoing cardiology surveillance The Management of Cardiac Manifestations of TSC Medical Treatment for Heart Failure Cardiac rhabdomyomas can lead to hemodynamic compromise and congestive heart failure, and while this occurrence is rare, it remains one of the most frequent causes of death among TSC children 1000 TSC patients from 17 centers (Table 6). The TSC Alliance is organized to function as a network for this purpose but requires subspecialty commitments from investigators at large centers where TSC patients are cared for (not necessarily participating already within the Alliance), highlighting the importance of coordinated multidisciplinary care and standardized approaches to care. Transitioning the patient from pediatric to adult cardiology care remains a challenging and important goal, with a need for careful monitoring and a low index of suspicion for latent manifestations of cardiovascular disease, including arrhythmias. Table 5. Cardiology‐Specific Future Research Directions Why do cardiac rhabdomyomas regress and other hamartomas do not? Do cardiac rhabdomyomas completely resolve? What is the incidence of sudden death? Malignant arrhythmia? Do TSC1 and TSC2 genotypes predict cardiac phenotype or outcome? Does treatment with mTOR inhibitors decrease the long‐term risk of arrhythmia? What is the incidence of latent left ventricular hypertrophy and/or dysfunction? What is the incidence and natural history of lipidemia in TSC? mTOR indicates mammalian target of rapamycin; TSC, tuberous sclerosis complex. Table 6. Cardiology Variables Maintained in the TSC Alliance Clinical Registry Medical history, physical examination, family history Current medications ECG, CXR, echocardiogram, MRI, CT Pathology if available Other cardiac conditions (malformation, hypertension, lipidemia, aneurysm) Number, size, and location of cardiac rhabdomyomas TSC, tuberous sclerosis complex; CXR, chest radiography; MRI, magnetic resonance imaging; CT, computed tomography. TSC is a multisystem genetic disorder characterized by variable abnormalities, such that patients carrying mutations may not fulfill clinical criteria for diagnosis, raising questions regarding familial screening. For example, does the presence of fetal cardiac rhabdomyomas warrant a recommendation for family screening, which is not presently indicated? In mutation‐positive children, parents and siblings can undergo specific mutation testing as screening, but in parents and siblings of phenotypically diagnosed children, it may be prudent to perform ECG in parents and both ECG and echocardiography in children <3 years old. Some studies have demonstrated that cardiac rhabdomyomas are more frequent in those with TSC2 (54%) versus TSC1 (20%) mutations. 49 Currently, there is insufficient evidence of absolute risks to recommend surveillance by TSC1‐ and TSC2‐associated cardiac disease. Variability in pathology or natural history based on presentation with TSC1 and TSC2 mutations is unclear but potentially clinically significant. Genetic testing will facilitate early identification and provide opportunities for disease stratification and early intervention. Author Contributions The authors participated in the Cardiology Working Group for the TSC Alliance Consensus Conference (Drs Hinton, Prakash, Romp, and Knilans), from which the concept and design for this report were conceived (Drs Hinton, Prakash, Romp, and Knilans). The manuscript was drafted by Drs Hinton, Prakash, and Knilans and revised by Drs Hinton, Prakash, Romp, Knilans, and Krueger. All authors approved the final manuscript.
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Tuberous sclerosis complex: review based on new diagnostic criteria *
Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as skin, central nervous system, kidney and lung. Due to the wide phenotypic variability, the disease is often not recognized. Tuberous sclerosis complex affects one in 10,000 newborns and most patients are diagnosed during the first 15 months of life. The diagnostic criteria for tuberous sclerosis were reviewed in 2012, at the second International Tuberous Sclerosis Complex Consensus Conference. The diagnosis is based on genetic criteria, by the identification of inactivating pathogenic mutation of tumor suppressor genes TSC1 and TSC2, and clinical criteria, including cutaneous, renal, pulmonary, cardiac and neurological manifestations. The treatment of tuberous sclerosis complex consists, mainly, in management of the symptoms caused by hamartomas and in prevention of organ failure. Multidisciplinary approach is recommended, in order to obtain better clinical outcomes.
Author and article information
Journal
Journal ID (nlm-ta): Pediatr Rep
Journal ID (iso-abbrev): Pediatr Rep
Journal ID (publisher-id): pediatrrep
Title:
Pediatric Reports
Publisher:
MDPI
ISSN
(Print):
2036-749X
ISSN
(Electronic):
2036-7503
Publication date
(Electronic):
01
March
2021
Publication date Collection:
March
2021
Volume: 13
Issue: 1
Pages: 104-112
Affiliations
[1
]Pediatric Cardiology Unit, “Vittore Buzzi” Children’s Hospital, 20154 Milano, Italy;
luisa.nespoli@
123456asst-fbf-sacco.it
(L.F.N.);
carla.corti@
123456asst-fbf-sacco.it
(C.C.)
[2
]Department of Pediatrics, “Vittore Buzzi” Children’s Hospital, 20154 Milano, Italy;
elena.albani1@
123456gmail.com
(E.A.);
gianvincenzo.zuccotti@
123456unimi.it
(G.V.Z.);
valeria.calcaterra@
123456unipv.it
(V.C.)
[3
]Clinical Genetics Unit, Department of Obstetrics and Gynecology, “V. Buzzi” Children’s
Hospital, University of Milano, 20154 Milano, Italy;
luigina.spaccini@
123456asst-fbf-sacco.it
[4
]Pediatric Neurology Unit, “V. Buzzi” Children’s Hospital, Milano, 20154 Milano, Italy;
enrico.alfei@
123456asst-fbf-sacco.it
[5
]Neonatal Pathology and Neonatal Intensive Care Unit, “V. Buzzi” Children’s Hospital,
University of Milano, 20154 Milano, Italy;
irene.daniele@
123456asst-fbf-sacco.it
(I.D.);
gianluca.lista@
123456asst-fbf-sacco.it
(G.L.)
Author notes
Author information
Gian Vincenzo Zuccotti
https://orcid.org/0000-0002-2795-9874
Valeria Calcaterra
https://orcid.org/0000-0002-2137-5974
Article
Publisher ID: pediatrrep-13-00015DOI: 10.3390/pediatric13010015
PMC ID: 7931111
PubMed ID: 33804320
SO-VID: beaac84a-ecaf-419a-8533-09f539f92798
Copyright © © 2021 by the authors.
License:
Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).
History
Date
received
: 14
January
2021
Date
accepted
: 25
February
2021
Categories
Subject:
Case Report
ScienceOpen disciplines: Pediatrics