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Diagnosis of Tuberous Sclerosis Complex
Abstract
Tuberous sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of tuberous sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for tuberous sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for tuberous sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis. The addition of DNA testing complements clinical diagnosis and allows more precise genetic counseling and, in some individuals, prenatal diagnosis. Nevertheless, the 15% false-negative rate for DNA testing and the occurrence of germline mosaicism in about 2% of individuals with tuberous sclerosis complex make it difficult to exclude the diagnosis of tuberous sclerosis complex in family members.
... 2,3 Typically, ungual fibromas present as smooth, firm, nodular, or fleshly lesions that are adjacent to the nails near the proximal nail fold (Figures 4 and 5). 8,16 At times, they may appear underneath the nail plate or over the lateral nail groove (Figure 6). 4 One of the initial features of ungual fibroma is a groove in the nail plate in the absence of an obvious tumor (Figure 7). 8 Ungual fibromas are slow-growing. ...
... 8,15 They are found in approximately 20% of unselected patients with tuberous sclerosis complex and are more commonly observed in adolescents and adults than in young children. 3,16 These lesions occasionally develop subsequent to trauma. 3,16 Two or more nontraumatic ungual fibromas constitute a major feature of tuberous sclerosis complex. ...
... 3,16 These lesions occasionally develop subsequent to trauma. 3,16 Two or more nontraumatic ungual fibromas constitute a major feature of tuberous sclerosis complex. 3,16 Before correlating an ungual fibroma to tuberous sclerosis complex, one should explore the possibility whether the lesion is trauma-induced. ...
... Pathogenic mutations in either the TSC2 gene at chromosome 16p13.3, or the TSC1 gene at chromosome 9q34, cause a multisystem disorder that greatly varies in extent and severity [3]. TSC has an autosomal dominant mode of inheritance, with almost complete penetrance, but variable expressivity [1]. ...
... Percutaneous embolization is the first choice of management. Smaller angiomyolipomas do not usually cause symptoms, but lesions larger than 4 cm in diameter are associated with an increased risk of serious hemorrhage [3,12]. ...
The tuberous sclerosis complex (TSC) is highly variable as far as its clinical presentation is concerned. For the implementation of appropriate medical surveillance and treatment, an accurate diagnosis is compulsory. TSC may affect the heart, skin, kidneys, central nervous system (epileptic seizures and nodular intracranial tumors—tubers), bones, eyes, lungs, blood vessels and the gastrointestinal tract. The aim of this paper is to report renal manifestations as first clinical signs suggestive of TSC diagnosis. A 20-year-old patient was initially investigated for hematuria, dysuria and colicky pain in the left lumbar region. The ultrasound examination of the kidney showed bilateral hyperechogenic kidney structures and pyelocalyceal dilatation, both suggestive of bilateral obstructive lithiasis, complicated by uretero-hydronephrosis. The computer tomography (CT) scan of the kidney showed irregular kidney margins layout, undifferentiated images between cortical and medullar structures, with non-homogenous round components, suggestive of kidney angiomyolipomas, bilateral renal cortical retention cysts, images of a calculous component in the right middle calyceal branches and a smaller one on the left side. The clinical manifestations and imaging findings (skull and abdominal and pelvis CT scans) sustained the diagnosis.
... The manifestations and the severity of the disease are variable, even between relatives, and depend on size, number, location and distribution of the lesions (3,4). Common locations include the brain, kidneys, lungs, skin, heart, and eyes (4)(5)(6)(7)(8). However, no single symptom is observed in all patients, and none of the symptoms can be considered as absolutely pathognomonic (6). ...
... Common locations include the brain, kidneys, lungs, skin, heart, and eyes (4)(5)(6)(7)(8). However, no single symptom is observed in all patients, and none of the symptoms can be considered as absolutely pathognomonic (6). ...
Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC.
... The first official diagnostic criteria were established by the International Tuberous Sclerosis Consensus Conference in 1998, focusing on major and minor clinical features identified through imaging and physical examination without incorporating genetic testing 98 . Advancements in imaging techniques, particularly MRI, have enhanced the detection of brain lesions associated with TSC, prompting further refinement of the diagnostic criteria 98,99,102 . In 2012, the criteria were revised to include genetic testing as a major diagnostic component, acknowledging the role of pathogenic variants in TSC1 or TSC2 87 . ...
... TSC-related manifestations may not be pathognomonic or may be non-specific in the early stages [17]; therefore, if the clinician who treats the early-onset manifestations does not notify about the manifestations in other organs, then the diagnosis of TSC is presumably delayed. A multidisciplinary team approach is essential for the early diagnosis of TSC and the detection of associated lesions. ...
Background
Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organs. However, precise diagnosis is challenging owing to the lack of truly pathognomonic symptoms. This retrospective observational study aimed to explore the real-world diagnostic flow of Japanese patients with TSC by examining time to diagnosis (TTD) from the onset of each TSC-related manifestation to TSC diagnosis and the role of TSC clinic in timely diagnosis, using data from a health insurance database.
Methods
Analyses were performed using data derived from the JMDC Claims Database between January 2005 and December 2020. Patients with at least 1 confirmed diagnosis of TSC were stratified into 2 cohorts: Cohort 1 included cases diagnosed after 2 years of age, and Cohort 2 included cases diagnosed before 2 years of age. The primary endpoint was TTD in Cohorts 1 and 2. Secondary endpoints were the incidence of each manifestation in Cohort 1 and the incidence and risk ratios of TSC-unrelated symptoms in Cohort 2.
Results
Cohorts 1 and 2 included 106 and 42 patients, respectively. In Cohort 1, patients with a renal tumor diagnosis as a primary TSC-related manifestation had the longest TTD with a wide range (median: 23 months to up to 91 months); patients with non-specific TSC-related manifestations such as brain tumor/intraventricular tumor, epilepsy, or intellectual disabilities also experienced a delay in TTD. In patients with TSC who developed epilepsy, those attending facilities with a TSC clinic were diagnosed with TSC more quickly than those attending facilities without a TSC clinic (median: 11.5 and 19.0 months, respectively; p = 0.0379). Epilepsy was the manifestation with the highest incidence (29.2%) among Cohort 1 patients, while cardiac rhabdomyoma had the highest incidence (54.8%) among Cohort 2 patients. Dry skin was the most common TSC-unrelated symptom in Cohort 2, with a 1.7-fold higher incidence rate than that in controls (N = 619,936).
Conclusion
Japanese patients with renal lesions as a primary TSC-related manifestation had the longest delay for a definitive diagnosis of TSC, followed by those with epilepsy, brain tumor/intraventricular tumor, and intellectual disabilities. The TSC clinic played an important role in the early diagnosis of TSC.
... 가장 흔하며, 안면의 혈관섬유종은 환자의 약 75%에서 동반되는 것으로 알려져 있고[12], 손톱 혹은 손톱 주위 섬유종은 환자의 약 20%에서 동반된다[13]. 얼굴의 혈 관섬유종은 다발성의 살색 혹은 붉은색의 구진으로 대개 5 세 무렵까지는 출현하고, 주로 코, 뺨, 아래턱 등에 나타나는 반면, 손톱 혹은 손톱주위 섬유종(ungual fibroma)은 청소 년기와 성인기에 붉은색 결절의 형태로 손발톱에 나타난다[14]. 신경계 이상으로는 경련이 가장 흔해서 환자의 75%-90%에서 발생하고[15], 또한 뇌피질 결절(tubers), 상의하 결절(subependymal nodules), 상의하 거대세포 성상세포 종(subependymal giant cell astrocytomas) 등의 소견이 두개강내 병변으로 나타날 수 있다[16]. ...
Tuberous sclerosis is a genetic disorder that affects every organ system, has a diverse presentation and progression, and can be life threatening. The authors encountered a case of a choking death caused by a fragment of rice cake. The deceased was an inmate of a social welfare institution due to mental retardation. The deceased was a 60-year-old male, 170 cm in height, and weighed 74 kg. Autopsy revealed multiple tubercles on the face, undigested food material, including rice cake, in the stomach, cardiomegaly (460 g) with mild coronary atherosclerosis, fatty infiltration into the myocardium, severe pulmonary congestion and edema with froth in the bronchus, and a yellowishbrown mass in each kidney. The brain showed firmness of the cortex in the parietal lobe and blurring of the white-grey matter interface. Histologically, the kidney masses were consistent with angiomyolipoma, and the brain lesion revealed abnormal neurons and astrocytes with a ballooned appearance and glassy cytoplasm, suggestive of tuberous sclerosis. Fatty infiltration and focal interstitial fibrosis were observed in the heart. Toxicology results were negative. The authors determined that the autopsy findings were consistent with tuberous sclerosis and that it may have been the cause of mental retardation, which served as an indirect cause of choking.
... Tuberous sclerosis complex (TSC) is an autosomal dominant disease that involves neurological manifestations and benign tumors in multiple organs, including the brain, heart, lung, skin, and kidneys (Cook et al., 1996;Lam et al., 2018;Trnka & Kennedy, 2021). TSC occurs in about every 1 in 6000 births, and afflicts about 2 million people worldwide (Henske et al., 2016;Nair et al., 2020;Roach & Sparagana, 2004). TSC most commonly results from de novo spontaneous mutations in TSC1 or TSC2 tumor suppressor genes but can also be inherited from parents (Carbonara et al., 1994;Green et al., 1994). ...
Patients with tuberous sclerosis complex (TSC) develop an array of multi-organ disease manifestations, with angiomyolipomas (AML) and cysts in the kidneys being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital in lowering TSC patient morbidity and mortality. However, current standard of care for imaging-based methods are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified seven highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. This study highlights serum metabolites as novel biomarkers for TSC kidney tumor diagnosis and offers valuable metabolic insights into the disease.
... Mutations in the TSC1 (OMIM, #605284) and TSC2 (OMIM, #613254) genes, which encode hamartin and tuberin, respectively, and regulate cell growth and proliferation, are responsible for this disease (Randle, 2017).The phenotype of TSC is highly variable, even within the same family. Due to this phenotypic variability, diagnosing TSC can be challenging, especially in young individuals or those with subtle manifestations (Roach & Sparagana, 2016). This phenotypic variation could be attributed to the randomness of second-hit events in TSC or as-yet-unidentified genetic modifiers (Lyczkowski et al., 2007). ...
Background
Tuberous sclerosis complex (TSC), an autosomal‐dominant disorder, is characterized by hamartomas affecting multiple organ systems. The underlying etiology of TSC is the pathogenic variations of the TSC1 or TSC2 genes. The phenotype variability of TSC could lead to missed diagnosis; therefore, the latest molecular diagnostic criteria for identifying a heterozygous pathogenic variant in either the TSC1 or TSC2 gene filled this gap. Furthermore, the pathogenicity of numerous variants remains unverified, potentially leading to misinterpretations of their functional consequences.
Methods
In this study, a single patient presenting with atypical vitiligo‐like skin lesions suspected to have TSC was enrolled. Targeted next‐generation sequencing and Sanger sequencing were employed to identify a pathogenic variant. Additionally, a minigene splicing assay was conducted to assess the impact of TSC1 c.1030‐2A>T, located in intron 10, on RNA splicing.
Results
A novel TSC1 : c.1030‐2A>T heterozygosis variant was identified in intron 10. In vitro minigene assay revealed that the c.1030‐2A>T variant caused exon 11 skipping, resulting in a frameshift in the absence of 112 base pairs of mature messenger RNA and premature termination after 174 base pairs (p.Ala344Glnfs*59).
Conclusion
The detection of this novel pathogenic TSC1 variant in the patient with atypical vitiligo‐like skin lesions enrolled in our study ultimately resulted in the diagnosis of TSC. As a result, our study contributes to expanding the mutational spectrum of the TSC1 gene and refining the genotype–phenotype map of TSC.
... 4 Approximately 50% of patients with TS develop Shagreen patch which presents in the lumbosacral region as thick leathery skin with a pebbly texture. 5 These dermatological findings of TS are the only manifestations that can be observed in physical examination and considered as major criteria in the diagnosis of TS. 2 Epilepsy is the most common presenting symptom of TS. Seizure is discovered in 98% of patients with TS and 75% have a seizure in the first year of life. ...
... The disease is often named as tuberous sclerosis complex (TSC) as the disease simultaneously affects various organ systems. [2] The TSC1 and TSC2 genes are responsible for TSC pathology, and the penetrance of these genes varies widely from patient to patient. Although it is known that there are approximately 2 million people with TSC worldwide and 50,000 people are affected by this disease in the USA alone, currently the incidence of the disease is approximately 1 in every 6,000-10,000 live births; and the prevalence is estimated as 1 in 20,000. ...
... 1908 yılında Vogt nöbet, adenoma sebaseum ve mental retardasyondan oluşan klinik triadını tanımladı (20). Farklı organda (beyin, deri, kalp, böbrek vb) benign hamartomları içeren çeşitli anomaliler ile karekterizedir (21). ...
NÖROKUTANÖZ SENDROMLARDA KRANİAL GÖRÜNTÜLEME BULGULARI
... For instance, with a focus on general intelligence, varying prevalence estimates of cognitive impairment (IQ < 70) in individuals with TSC are reported in the literature. Some studies report that between 44% and 70% of individuals with TSC present with cognitive impairment (Prather & de Vries 2004;Roach & Sparagana 2004;Winterkorn et al. 2007;Jansen et al. 2008;Van Eeghen et al. 2012), whereas others suggest that over half of the TSC population's general intelligence falls within the normal general population range of intelligence (i.e. >70; Joinson et al. 2003). ...
Background:
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder associated with a wide spectrum of cognitive impairments that can often result in impaired academic, social and adaptive functioning. However, studies investigating TSC have found it difficult to determine whether TSC is associated with a distinct cognitive phenotype and more specifically which aspects of functioning are impaired. Furthermore, children with TSC living in low-income and middle-income countries, like South Africa, experience additional burdens due to low socio-economic status, high mortality rates and poor access to health care and education. Hence, the clinical population of South Africa may vary considerably from those populations from high-income countries discussed in the literature.
Methods:
A comprehensive neuropsychological battery composed of internationally recognised measures examining attention, working memory, language comprehension, learning and memory, areas of executive function and general intellectual functioning was administered to 17 children clinically diagnosed with TSC.
Results:
The exploration of descriptive data indicated generalised cognitive difficulties in most cognitive domains, aside from memory. With only two participants performing in the average to above-average ranges, the rest of the sample showed poor verbal comprehension, perceptual reasoning, working memory, processing speed, disinhibition, and problems with spatial planning, problem solving, frustration tolerance, set shifting and maintaining a set of rules. Furthermore, correlational findings indicated several associations between socio-demographic and cognitive variables.
Conclusions:
Importantly, this is the first study to comprehensively examine multiple domains of neurocognitive functioning in a low-resource setting sample of children with TSC. Current study findings showed that children with TSC have generalised impairments across several cognitive domains, rather than domain-specific impairments. Therefore, although examining individual aspects of cognition, such as those found in previous literature, is important, this approach is limiting. With a comprehensive assessment, including understanding the associations between domains, appropriate and directed support can be provided to ensure all aspects of development are addressed and considered.
... TSC is a genetic disorder with autosomal dominant inheritance that can affect the brain, heart, skin, kidneys, lungs, and retina (Roach and Sparagana, 2004). It is characterized by the growth of numerous noncancerous (benign) tumors in different parts of the body caused by mutations in the TSC-1 and/or TSC-2 genes (Huang and Manning, 2008;Knowles, et al, 2003;Sampson, 2003). ...
This is a case review of a male Chinese adult, BK, who has been previously diagnosed with tuberous sclerosis complex, syndromic low-functioning/non-verbal autistic savantism and intellectual disability. He has the gift of painting and has since produced many works that show he has an eye for detail, color, texture, and stroke application (Camulli, Goh and Chia, 2018). This paper adopts a different perspective to study the case by re-examining BK’s systemizing ability, i.e., his innate drive to analyze or construct any kind of system, and in his case, painting. Systemizing is defined as the ability to follow a certain set of implicit rules that is governing the system in order to predict how that system will behave (Baron-Cohen 2006). In BK’s case, the focus is on his gift of systemizing ability in the cognitive process of acrylic painting using the following cognitive formulation: [input]->[operation]->[output].
... Other skin lesions seen in TSC are leaf-shaped discolorations (leaf-shaped leukoderma), often located on the scalp, showing a characteristic discoloured strand of hair growing out of the lesion. "Confetti" stains are observed, too, showing as colourless marks on the extensor surfaces of limbs, shagreen patches in the sacral region of the body or squamous fibromas in the forehead region which occur in about 25% of the patients [27]. Gingival fibromas, similarly to fibromas of the nail folds called Koenen's nodules, appear later, mainly in adults [26]. ...
... [3][4][5] Brain manifestations of TSC are characterized by cortical tubers, WM abnormalities (radial migration lines [RMLs]), and periventricular subependymal nodules (SENs). [6][7][8] On MR imaging, cortical tubers and RMLs are diagnosed mainly by T2WI or FLAIR images. 9 The effectiveness of T1WI with magnetization transfer contrast (T1WI-MTC) imaging has been reported, [10][11][12][13] but the usefulness of other MR images has not been reported since then. ...
Background and purpose:
CNS lesions of tuberous sclerosis complex are diagnosed mainly by T2WI, FLAIR, and sometimes T1WI with magnetization transfer contrast. The usefulness of T1WI with chemical shift selective images was recently reported in focal cortical dysplasia type IIb, which has histopathologic and imaging features similar to those of tuberous sclerosis complex. We investigated the usefulness of the T1WI with chemical shift selective images in detecting CNS lesions of tuberous sclerosis complex.
Materials and methods:
We retrospectively reviewed 25 consecutive patients with tuberous sclerosis complex (mean age, 11.9 [SD, 8.9] years; 14 males) who underwent MR imaging including T1WI, T1WI with magnetization transfer contrast, T1WI with chemical shift selective, T2WI, and FLAIR images. Two neuroradiologists assessed the number of CNS lesions in each sequence and compared them in 2 steps: among T1WI, T1WI with magnetization transfer contrast and T1WI with chemical shift selective images, and among T2WI, FLAIR, and T1WI with chemical shift selective images. We calculated the contrast ratio of the cortical tubers and of adjacent normal-appearing gray matter and the contrast ratio of radial migration lines and adjacent normal-appearing white matter in each sequence and compared them.
Results:
T1WI with chemical shift selective images was significantly superior to T1WI with magnetization transfer contrast for the detection of radial migration lines and contrast ratio of radial migration lines. There was no significant difference between T1WI with chemical shift selective images and T1WI with magnetization transfer contrast for the detection of cortical tubers and the contrast ratio of the cortical tubers. Both T2WI and FLAIR were statistically superior to T1WI with chemical shift selective images for the detection of cortical tubers. T1WI with chemical shift selective images was significantly superior to T2WI and FLAIR for the detection of radial migration lines.
Conclusions:
The usefulness of T1WI with chemical shift selective images in detecting radial migration lines was demonstrated. Our findings suggest that the combination of T1WI with chemical shift selective images, T2WI, and FLAIR would be useful to evaluate the CNS lesions of patients with tuberous sclerosis complex in daily clinical practice.
... 2. The patient can only have minor issues and perform similarly to peers in terms of academic, social, and physical abilities. Alternatively, The patient's health and developmental concerns may be more severe, resulting in a life that is less autonomous or different from what the patient anticipated [14]. ...
Introduction: Tuberous sclerosis is a rare hereditary disease that creates noncancerous tumours in the brain, kidneys, heart, liver, eyes, lungs, and skin. Seizures, intellectual incapacity, developmental delays, and behavioral issues are just a few of the warning symptoms. Like Skin problems, and lung and kidney problems. A hereditary mutation in one of two genes causes TSC.TSC1 and TSC2 are two distinct TSC types. The proteins hemartin and tuberin, which act as tumour suppressors and govern cell proliferation and differentiation, are produced by these genes. [1]. Background: Tuberous sclerosis complex (TSC) is a rare genetic disorder that affects 1 in every 6,000 to 1 in every 18,000 people. It's a life-threatening condition caused by the formation of benign tumors/lesions in several organs. Tumors can affect organ growth and/or function and are frequent in the brain, heart, skin, kidneys, and lungs. The number of organs affected, as well as the size of tumours inside each organ, varies greatly. As a result, the disease's symptoms are extremely variable and unexpected [2]. Case Presentation: A 35-year old female admitted to AVBRH on date 25/11/2021 with the chief complaint of fever chills, nausea, vomiting and itching and back skin over mouth and eye surrounding area since in 10 days. History of Present Illness: Tuberous sclerosis, also known as tuberous sclerosis complex, is a rare genetic disease that causes non-cancerous (benign) tumours in the brain, skin, kidneys, heart, eyes, and lungs. A 35-yearold female admitted to hospital on date 25/11/2020 with the chief complaint was fever chills, nausea, vomiting and itching and back skin over mouth and eye surrounding area since in 4month. Interventions: The patient was treated the patient was started on Injection- Ceftriaxone, 1gm - Intravenous – BD- Antibiotic, Injection- Pan, 40mg – Intravenous- BD – Antacid, Injection- Livipril, 100mg – Intravenous- BD- Anticonvulsant, Injection- Paracetamol, 150mg – Intra muscular- SOS- Antipyretic. Conclusion: During hospital stay with the chief complaint of patient are fever chills, nausea, vomiting and itching and back skin over mouth and eye surrounding area since in 10 days. Her situation was critical, therefore she was brought to AVBR Hospital and treatment was started right away.
... In addition to lesions of lymphatic vessels and neoplasms in the abdomen (angiomyolipomas and lymphangioleiomyomas), patients with LAM present with multiple cysts in the lung tissue [1,2]. In addition to occurring sporadically, LAM can also be associated with a hereditary neurocutaneous syndrome, which is the TSC; the latter often presents with hamartomas, brain tissue calcifications, mental retardation, and epilepsies [13,14]. The pathophysiological mechanism of LAM includes genetic changes in the TSC; these genetic changes cause functional loss in hamartin and tuberin proteins that have the role of inhibiting the mTOR, a protein molecule that regulates cell growth and multiplication [15]. ...
Patient: Female, 34-year-old
Final Diagnosis: COVID-19 • lymphangioleiomyomatosis
Symptoms: Dyspnea • fever • hypoxemia • myalgia
Medication: Sirolimus
Clinical Procedure: —
Specialty: Pulmonology
Objective
Unusual clinical course
Background
There is growing concern about the clinical course of certain diseases in patients who are simultaneously infected by SARS-CoV-2. This report is of a 34-year-old woman from Brazil with a recent diagnosis of pulmonary lymphangioleiomyomatosis (LAM) diagnosed by raised serum VEGF-D levels and the finding of lung cysts on computed tomography (CT) imaging, who presented with COVID-19 pneumonia.
Case Report
Five months after the diagnosis of pulmonary LAM, which was based on the presence of diffuse and bilateral cystic lesions on CT scan associated with high serum VEGF-D levels, the patient presented with worsening dyspnea, drop in peripheral oxygen oxygenation, fever, and diffuse myalgia. She was using Sirolimus because it inhibits the development of LAM cells. A worsening of lung abnormalities was demonstrated in a chest CT examination, with the appearance of areas of consolidation and ground-glass abnormalities. A nasal swab sample tested positive for SARS-CoV-2 infection using reverse-transcription polymerase chain reaction. Thus, Sirolimus was suspended because of concern about its immunosuppressive action. She received hospital support following the institutional protocol in force at the time, without the need for invasive mechanical ventilation. After 2 weeks, she was discharged from the hospital, with supplemental oxygen at home and return of Sirolimus.
Conclusions
This report has described the presentation of COVID-19 pneumonia due to SARS-CoV-2 infection in a 34-year-old woman with a recent diagnosis of LAM involving the lungs.
... Epilepsy is found in 75-90% of patients, with infantile spasms, generalized tonic-clonic seizures and motor focal seizures standing out. 50% of patients have cognitive impairment and a good part of these patients have epilepsy [12]. ...
Tuberous Sclerosis Complex or Bourneville’s disease is an autosomal dominant disease with high penetrance and variability characterized by multisystem involvement by benign lesions, originally defined by the classic triad of Vogt: sebaceous adenoma, epilepsy and mental retardation. The involvement of the brain is responsible for a significant proportion of the morbidity and mortality of this disease and skin lesions are the most common manifestations. The authors report 31-year-old patient case referred to the service by intractable epilepsy with definitive clinical criteria for tuberous sclerosis.
... Epilepsy is found in 75-90% of patients, with infantile spasms, generalized tonic-clonic seizures and motor focal seizures standing out. 50% of patients have cognitive impairment and a good part of these patients have epilepsy [12]. ...
Resumo Tuberous Sclerosis Complex or Bourneville's disease is an autosomal dominant disease with high penetrance and variability characterized by multisystem involvement by benign lesions, originally defined by the classic triad of Vogt: sebaceous adenoma, epilepsy and mental retardation. The involvement of the brain is responsible for a significant proportion of the morbidity and mortality of this disease and skin lesions are the most common manifestations. The authors report 31-year-old patient case referred to the service by intractable epilepsy with definitive clinical criteria for tuberous sclerosis.
... They appear in the central face and increase in number with age, which is a common source of concern [73]. TSC patients can also present with fibrous plaques in the forehead (20%), shagreen patches in the lumbosacral region (20%), and ungual or gingival fibromas (20%) [74]. ...
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in With the advent of genetic and molecular techniques, mutations in TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with the neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated to the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin is FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC Associated Neuropsychiatric Disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder represent significant challenges but remain underdiagnosed and undertreated. TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan based on the specific problems and needs of individuals is key in the management of this genetic condition. Ongoing research studies are providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.
Introdução: A esclerose tuberosa (ET) é uma síndrome neurocutânea hereditária autossômica dominante, caracterizada pela formação de hamartomas multissistêmicos devido a alterações gênicas de supressores tumorais. Cerca de 65% dos casos ocorrem sem histórico familiar, resultando de mutações esporádicas. A inativação dos genes ET1 e ET2 leva à proliferação descontrolada de hamartomas. Objetivo: Este trabalho visa avaliar as manifestações multissistêmicas da ET, protocolos diagnósticos e estratégias terapêuticas. Metodologia: Trata-se de uma revisão de literatura integrativa. As buscas foram realizadas nas bases de dados PubMed, LILACS, BVS e SciELO entre fevereiro e março de 2024, utilizando descritores específicos. Foram inicialmente localizados 263 artigos que após a aplicação dos critérios de elegibilidade, restando 8 estudos. Critérios de inclusão: artigos em português e inglês, publicados entre 2000 e 2023, disponíveis gratuitamente e relacionados ao tema. Resultados: A ET é uma doença genética que afeta o sistema nervoso central, pele, olhos e órgãos internos. Clinicamente, caracteriza-se por epilepsia, deficiência mental e adenoma sebáceo. O diagnóstico segue critérios estabelecidos. O acompanhamento multidisciplinar é crucial, com observações clínicas periódicas. Conclusão: A ET é uma doença progressiva com variabilidade fenotípica. A abordagem multidisciplinar é essencial, com tratamento sintomático e seguimento contínuo para melhorar a gestão da doença.
Актуальность Туберозный склероз – генетическое заболевание с аутосомно-доминантным типом наследования, с характерной клинической картиной в виде поражения нервной системы, кожи и наличием доброкачественных опухолей (гамартом) внутренних органов. Наиболее частым проявлением заболевания является эпилепсия, которая встречается у 96% пациентов с дебютом в первые месяцы жизни. Распространенность, тяжесть эпилепсии, связанной с туберозным склерозом, а также резистентность к проводимой терапии и небольшое количество статей, посвященных данной проблеме, предполагает более углубленное изучение лечения заболевания и определяет актуальность нашего литературного обзора. Целью данного литературного обзора является изучение возможностей оптимального лечения эпилепсии при туберозном склерозе у детей. Стратегия поиска: научный поиск был проведен в базах данных PubMed, Elibrary, Google Scholar. Глубина поиска составляла 12 лет. Ключевые запросы: туберозный склероз (tuberous sclerosis), эпилепсия (epilepsy), лечение (treatment). Критерии включения: источники с 2007-2018 гг., полнотекстовые публикации, возраст участника исследования - до 18 лет, имеющие судорожный синдром в дебюте туберозного склероза, соответствие постановки диагноза «Туберозный склероз» международным критериям и Клиническим Протоколам Республики Казахстан. Критериями исключения являлись: тезисы, абстракты, которые не имеют полнотекстовую статью, дублирующиеся публикации, статьи по туберозному склерозу, но не раскрывающие вопросов лечения эпилепсии при данном заболевании и, следовательно, не подходящие по тематике, а также экспериментальные работы на животных. В связи с тем, что туберозный склероз является редкой нозологией, в использованных нами базах данных было найдено 523 статьи. Однако, только 10 источников по данной теме соответствовали критериям включения Результаты: в ходе литературного поиска найдены проспективные и ретроспективные исследования эффективного применения Вигабатрина (4-Амино-5-гексеновая кислота, Франция, Санофи) для лечения инфантильных спазмов и фокальной эпилепсии, ассоциированной c туберозном склерозом у детей. При эпилепсии, ассоциированной с субэпендимальными гигантоклеточными астроцитомами при туберозном склерозе найдены рандомизированное, плацебо-контролируемое исследования эффективной таргетной терапии препаратом Эверолимусом (Новартис фарма, Швейцария). Хирургическое лечение фармакорезистентной эпилепсии при туберозном склерозе у детей представлено в 4 исследованиях. Вывод: согласно результатам проведенного литературного обзора препарат Вигабатрин более эффективен для лечения инфантильных спазмов и фокальной эпилепсии при туберозном склерозом у детей, а препарат Эверолимус предпочтительнее для лечения эпилепсии, ассоциированной с субэпендимальными гигантоклеточными астроцитомами, при туберозном склерозе. Хирургическое лечение же применяется при фармакорезистентной эпилепсии при данном заболевании.
Relevance: Tuberous sclerosis – a genetic disease with autosomal dominant inheritance pattern with the characteristic of damage of the nervous system, skin and existence of benign tumors (hamartomas) clinical picture. The most frequent manifestation of the disease is epilepsy debuting in the first month of life, which find in 96% of patients. Prevalence, severity of epilepsy associated with tuberous sclerosis, as well as resistance in ongoing therapy and a small number of articles on this issue implies studying of treatment in greater depth and defines the relevance of our literature review. Aim: to carry out the literary review on treatment of epilepsy associated with tuberous sclerosis in children. Search strategy:: scientific search was conducted in PubMed, Elibrary, Google Scholar databases. Search depth accounts for 12 years. Key words: tuberous sclerosis, epilepsy, treatment. Inclusion criteria: sources from 2007-2018, full-text publications, the age of a research participant is under 18 years old, having convulsive syndrome in the debut of tuberous sclerosis, the diagnosis of Tuberous sclerosis is consistent with international criteria and Clinical Protocols of the Republic of Kazakhstan. Exclusion criteria were: abstracts that do not have a full-text article, duplicate publications, articles on tuberous sclerosis, but do not reveal the treatment of epilepsy in this disease and, therefore, are not appropriate in subject, as well as experimental work on animals. Due to the fact that tuberous sclerosis is a rare disease, 523 articles were found in the databases we used. However, only 10 sources on this topic met the inclusion criteria. Results: the prospective and retrospective studies of the effective application of Vigabatrin (4-amino-5-hexenoic acid, France, Sanofi) for infantile spasms and focal epilepsy treatment were found during the literature search. The randomized, placebo-controlled researches of effective targeted therapy with Everolimus (Novartis Pharma, Switzerland) for epilepsy associated with subependymal giant cell astrocytomas in tuberous sclerosis were found. Surgical treatment of pharmacoresistant epilepsy in children with tuberous sclerosis presented in 4 studies. Conclusion: according to the results of the conducted literature review, vigabatrin is more effective for treatment of infantile spasms and focal epilepsy in children with tuberous sclerosis and everolimus is more preferable for treatment of epilepsy associated with subependymal giant cell astrocytomas in tuberous sclerosis. For pharmacoresistant epilepsy surgical treatment is applied at this disease.
Кіріспе Туберозды склероз – орталық жүйке-жүйесінің, терінің және ішкі ағзаларда қатерсіз ісіктердің дамуымен жүретін, аутосомды-доминантты тұқым қуалайтын генетикалық ауру. 96 % жағдайда науқастардың өмірінің алғашқы айларында эпилепсиямен көрінеді. Туберозды склероздың жиілігі, эпилепсия ағымының ауырлығы, сонымен қатар емдеге резистенттілігі, аталған мәселеге арналған мақалалардың санының аздығы аурудың емін терең зерделеуді қажет етеді және біздің жұмысымыздың өзектілігін арттырады. Мақсаты: балалардағы туберозды склерозбен қосарланған эпилепсия ем әдістеріне арналған әдебиеттерге шолу жүргізу. Стратегиялық ізденіс: ғылыми ізденіс PubMed, Elibrary, Google Scholar ақпарат құралдарында жүргізілді. Ізденіс көлемі 12 жылды құрады. Түйінді сөздер: туберозды склероз (tuberous sclerosis), эпилепсия (epilepsy), емі (treatment). Қосу өлшемдері: 2007-2018 жж толық мәтінді басылымдар, зерттеуге қатысушылар жасы 18 жасқа дейінгі туберозды склероз бастауында тырысу ұстамалары болған науқастар, «Туберозды склероз» диагнозы ҚР клиникалық хаттамаларына және халықаралық өлшемдерге сәйкес болуы. Ығыстыру өлшемдері: толық мәтіні жоқ тезистер, абстракттер, қайталанған басылымдар, туберозды склероздыңемінің сұрақтарын толық қамтымайтын, тақырыпқа сәйкес емес мақалалар мен жануарларға жасалған тәжірибелік жұмыс нәтижелері. Туберозды склероз сирек кездесетін ауру болғандықтан, ақпараттық қорлардан барлығы 523 мақала табылды. Әйткенмен де, тек 10 дерек көзі қосу өлшемдеріне сәйкес келді. Нәтижелер: әдеби ізденіс барысында балалардағы туберозды склерозбен қосарланған фокальды эпилепсия мен инфантильді спазмның еміне арналған Вигабатрин препаратының (4-Амино-5-гексен қышқылы, Франция, Санофи) нәтижелілігін көрсететін проспективті және ретроспективті зерттеулер табылды. Субэпендимальді үлкенжасушалы астроцитомамен қосарланған эпилепсияда Эверолимус препаратының (Новартис фармасы, Швейцария) нәтижелілігі рандомизирленген орталықтандырылған, плацебо-бақылау зерттеулерінде айқын көрсетілген. Фармакорезистентті эпилепсияның хирургиялық емі 4 зерттеу жұмысында сипатталған. Қорытынды: әдебиеттік шолу қорытындыларына сәйкес, Вигабатрин препараты инфантильді спазм және фокальды эпилепсияда нәтижелі болып табылса, ал Эверолимус препараты субэпендимальді үлкенжасушалы астроцитомамен қосарланған эпилепсия емінде артықшылықтарға ие. Фармакорезистентті эпилепсияның бірден бір емі аталған мәселеде хирургиялық емдеу әдісі болып табылады.
Sleep is a brain-derived homeostatic process. Neurodevelopmental milestones typically parallel the natural ontogeny of sleep observed in humans. In fact, an early indicator of neurodivergence is commonly abnormal sleep, which may manifest as reduced duration, impaired quality, or inappropriate timing of sleep. Typically, sleep evolves with predictable changes in duration of sleep required in 24 h, progression toward consolidation of nocturnal sleep, entrainment of circadian rhythms, and maturation of ultradian patterns, as a function of age and brain development. Genetically based neurodevelopmental disorders (NDDs) are providing initial insights to further understanding the relationship between sleep and neurodevelopmental trajectories and how genetics guide these neurodivergent pathways. Recognition and intervention of sleep-wake disorders may benefit developmental trajectories, especially in these high-risk populations.
Introduction. The majority of studies on disturbed neurodevelopment in children focus on psychiatric or psychological-pedagogical issues, but the genetic component of pathology also occupies an important place, in which is important to conduct genetic investigation to verify hereditary pathology, and to identify target organs inherent in particular hereditary disease. The aim of the study. To conduct a review of current literature dedicated to the problem of impaired neurodevelopment in children with hereditary diseases, to describe a clinical case of A. Rett genetic syndrome, accompanied by impaired neurodevelopment in a child. Materials and methods. The method of systematic and comparative analysis, as well as the biblio-semantic method of studying modern views on the influence of hereditary diseases in the disruption of neurodevelopment in children were used. A clinical case of A. Rett syndrome in a child is described, where the analysis of clinical symp- toms and laboratory-instrumental examinations were used, the main of which is the molecular genetic method of next generation sequencing (NGS). Results. Based on the literature analysis it was estimated that clinical cases of rare A. Rett syndrome in children occur with a frequency of 1:10.000-1:15.000. This syndrome is caused by a mutation in the MECP2 gene associated with X-linked A. Rett syndrome/atypical A. Rett syndrome (UID MedGen: 48441) or X-linked MECP2 duplication syndrome (MedGen: 337496). Conclusions. For a long time, the connection of impaired neurodevelopment with other clinical symptoms was not payed much attention, but the enhanced frequency of cases when a child with impaired neurodevelopment was diagnosed with other symptoms or a multisystem lesion stimulated research in this area. This is the story how the term "syndromal autism" was born. This term means developmental delay or autism spectrum disorder in children with symptoms of another hereditary disease.
Patients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.
This chapter will discuss neurocutaneous syndromes which is group of inherited and genetic disorders resulting in malproduction of several oncogenes that responsible for inhibition of tumor growth, these syndromes mainly involve the central nervous system and the skin but they may cause multiple symptoms in various organs of the body including the, the heart and the lungs, the eyes and many others. In this chapter we will discuss briefly the genetics and pathophysiology of the most famous and important of these syndromes including the Neurofibromatosis type 1, Neurofibromatosis type 2, tuberous sclerosis, Ataxia Telangiectasia, Sturge-Weber syndrome and some others. We will go through the clinical features regarding each system of the body and also the diagnostic criteria for each of these syndromes and also the etiology, we will go briefly through the management and the prognosis of these disorder as much of these has poor prognosis and the management is mostly palliative.
By its very nature autism poses significant challenges for provision of health care. These arise from the individual with autism, from a complex and often fragmented health care system, and from a lack of information on the part of health care providers. For persons with autism, the long‐term goal is to help the individual participate as much as possible in the process of getting good health care and leading a healthy lifestyle. To this end there is an emphasis on preventive care, use of the medical home model, and attention to medical problems more frequently associated with autism.
Tuberous sclerosis complex is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.
CNS tumors are a diverse group of neoplasms that emerge from a variety of different CNS cell types. These tumors may be benign, malignant, or borderline in nature. The majority of high grade glial tumors are fatal, with the exception of pilocytic astrocytoma. Primary malignant CNS tumors occur at a global annual rate of 2.1 to 5.8 per 100,000 persons. Males are more likely to develop malignant brain tumors than females, whereas benign meningiomas are more common in adult females. Additionally, gender inequalities in non-malignant tumors peak between the ages of 25 and 29 years. Only a small number of genetic variants have been associated with survival and prognosis. Notably, central nervous system (CNS) tumors exhibit significant age, gender, and race variation. Race is another factor that affects the incidence of brain and spinal cord tumors. Different races exhibit variation in terms of the prevalence of brain and CNS malignancies. This chapter discusses ongoing research on brain and spinal cord tumor epidemiology, as well as the associated risks and accompanied disorders.KeywordsEpidemiologyBrain tumorsGliomaGlioblastomaNeurological Surgery
Background Tuberous sclerosis complex (TSC) is a multisystemic disorder. Its clinical features manifest differently in several organs, prompting the need for better knowledge.
Objective The goal of the present study is to evaluate the neurological findings of TSC, such as cerebral lesions and epilepsy, and to raise awareness of non-neurological findings that could contribute to an earlier diagnosis and treatment.
Methods This was a natural history study of patients with a definitive diagnosis of TSC who were referred to a specialized outpatient clinic and followed-up for 2 years with clinical and radiological exams.
Results A total of 130 TSC patients (59 males [45.4%], mean age 20.4 years old [1 to 56 years old]); 107 patients (82.3%) were diagnosed with epilepsy. Seizures predominantly began at < 1 year old (72.8%); focal seizures predominated (86.9%); epileptic spasms occurred in 34.5% of patients, and refractory epilepsy was present in 55.1%. Neuropsychiatric disorders, cortical tubers and cerebellar tubers were significantly more frequent in the epilepsy group. Moreover, rhabdomyomas were significantly more frequent in the epilepsy group ( p = 0.044), while lymphangioleiomyomatosis was significantly less frequent in the epilepsy group ( p = 0.009). Other non-neurological findings did not differ significantly between the groups with and without epilepsy.
Conclusions The present study of TSC patients demonstrated the predominantly neurological involvement and significantly higher proportion of TSC-associated neuropsychiatric disorders in the epilepsy group. Higher proportions of cortical and cerebellar tubers may be a risk factor for epilepsy and neurodevelopmental disorders.
Background: This retrospective analysis was aimed at evaluating the clinical data of patients with renal angiomyolipoma who were treated by laparoscopic aspiration in our institution and summarizing our experience of preliminary surgery at a single center.
Methods: We retrospectively analyzed clinical data of 13 female patients with renal angiomyolipoma who were admitted to and treated in Shengjing hospital from January 2016 to December 2019. We analyzed the patients’ preoperative, intraoperative, and postoperative data and performed renal function tests and CT during the follow-up.
Results: Postoperative pathologic tests revealed renal angiomyolipoma in all patients. Twelve patients were successfully treated with laparoscopic aspiration, while one underwent laparoscopic partial nephrectomy half-way due to the small amount of fat in the tumor. The average maximum tumor diameter was 4.4 cm (range: 1.6–9.8). The average operation duration, blood loss, and postoperative hospitalization duration were 112.2 minutes (range: 60–180), 104.6 ml (range: 10–200), and 6.2 days (range: 5–10), respectively. Preoperative and postoperative creatinine levels were below the upper limit of normal values, with the mean preoperative and postoperative creatinine levels were 0.56 mg/dl (range: 0.44–0.98) and 0.57 mg/dl (range: 0.46–0.95), respectively. No postoperative complications or recurrence occurred during the average follow-up of 27.1 months.
Conclusion: Our preliminary results indicate laparoscopic aspiration is safe, effective, and minimally invasive for treating renal angiomyolipoma, particularly for the rich-fat type.
Tuberous sclerosis, or tuberous sclerosis complex (TSC), is an autosomal dominant inherited tumour suppressor disorder, which is associated with benign hamartomas and neoplastic lesions in the skin, the central nervous system and other organs. The first description and nomenclature of TSC are credited to Bourneville 1880, but von Recklinghausen was probably the first person to recognize the condition. A decade later and unaware of Bourneville’s documentation, Pringle (Brit J Derm 2:114, 1890) reported adenoma sebaceum as an inherited disorder of the skin (face) that also accompanied several other degenerative anomalies of the integument, such as naevi. The most common clinical symptoms are skin lesions, central nervous system manifestations, seizures (infantile spasms) and cellular overgrowth or hamartomas in the heart, brain, kidneys, eyes and lungs. The aetiology, genetics, signalling pathways, clinical characteristics and management options are described in this chapter.
Background and purpose:
Growth of subependymal giant cell tumor and subependymal nodules has not been well-characterized. The purpose of this study was to determine whether growth curves can differentiate subependymal giant cell tumors from subependymal nodules.
Materials and methods:
Brain MR imaging of patients with tuberous sclerosis complex were retrospectively reviewed from 2002 to 2018. All lesions in the region of the foramen of Monro were measured. Lesions were categorized on the basis of maximal diameter at the most recent scan: small lesions (<1 cm), indeterminate lesions (>1 cm), and resected lesions (>1 cm and surgically resected). Growth velocity and acceleration on serial imaging were analyzed, and growth rates were calculated between 0 and 20 years of age and compared among the 3 categories.
Results:
Forty-one patients were analyzed. The average age at the earliest scan was 5.9 (SD = 5.7) years. One hundred twenty-six small, 27 indeterminate, and 10 resected lesions were measured. Subependymal giant cell tumors grew faster than indeterminate lesions between 6 and 15 years of age. Indeterminate lesions grew faster than small lesions at 0-10 years of age. Resected lesions showed increased velocity and acceleration of growth compared with indeterminate lesions and small lesions on serial imaging.
Conclusions:
Growth differentiates subependymal nodules and subependymal giant cell tumors within the first 20 years of life, and the use of velocity and acceleration of growth may refine the diagnostic criteria of subependymal giant cell tumors. Additionally, 6-15 years of age may be an important period to monitor subependymal giant cell tumors at the foramen of Monro because increased growth may help to identify subependymal giant cell tumors that will continue to grow and result in obstructive hydrocephalus.
Objective
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families.
Method
We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided.
Results
There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups.
Conclusions
Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification.
Источник: Johnson S.R., Cordier J.F., Lazor R. et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur. Respir. J. 2010; 35: 14-26. В 2010 г. в Европейском респираторном журнале было опубликовано Руководство по диагностике и лечению лимфангиолейомиоматоза (ЛАМ). Это Руководство было подготовлено группой экспертов по инициативе Европейского респираторного общества (ЕРО).
Tuberous sclerosis complex (TSC) is an autosomal-dominant, multi-system, neurocutaneous disorder characterized by hamartomas in multiple organs. This study aimed to evaluate the clinical and paraclinical manifestations of children with TSC. The clinical and paraclinical characteristics of 79 children with TSC were evaluated and the possible correlations between the factors were calculated. Among the studied children which composed of 41 females (51.9%) and 38 males (48.1%), skin manifestations as hypopigmented macules as well as the brain involvement as cortical tubers in all (100%) cases, seizure in 74 (93.7%), and sub-ependymal nodules in 73 (92.4%) patients were the most common findings. The renal angiomyolipoma was diagnosed in 36 (70.6%) out of 51 patients. Subependymal giant cell astrocytoma in 25 (3/54%) out of 46 patients, retinal hamartoma in 15 (42.9%) out of 35 patients, and cardiac rhabdomyoma in 17 (41.3%) out of 46 patients were diagnosed. Furthermore, 50 (63.3%) out of 79 patients had psychological disorders that had a significant correlation with the prevalence of seizures (p = 0.002). Given the multi-systemic involvement of TSC, it is necessary that all organs of the patients even without any related clinical symptom or sign be examined regularly for proper therapeutic intervention and prevent disease progression. The growth of hamartomas in the brain and kidneys can be life-threatening; therefore, these organs have more importance to be regularly followed up and examined.
The hereditary burden of human cancer is composed of rare syndromes resulting in high risk for malignancies, often involving multiple organ systems, as well as more common genomic variants associated with a moderate risk for disease. The diagnosis of cancer predisposition syndromes can usually be confirmed with molecular genetic testing of patients based on clinical, pathologic, or family history indicators. Genetic testing can be extended to relatives as a predictive guide to their preventive management. This chapter will review the major syndromes of cancer predisposition, diagnosis, and management. Because tumor genomic analysis often includes a comparison with the inherited DNA sequence, targeted approaches to oncologic therapy also create opportunities for precision prevention in cancer-affected families.
Tuberous sclerosis complex (TSC) is a multisystem hereditary disorder characterized by the growth of benign tumors (hamartomas) in multiple organs, including the kidneys. Renal angiomyolipomas (AML) are a major diagnostic feature of TSC and are present in the majority of patients by adulthood. However, AML are usually asymptomatic during childhood when neurological and developmental manifestations are the main source of morbidity. Kidney manifestations of TSC have historically been the main cause of morbidity and mortality of adults with TSC. The recognition that the complications of TSC are caused by dysregulation of the mammalian target of rapamycin (mTOR) pathway has led to an enormous progress in the management of patients with TSC in the last two decades, the establishment of diagnostic guidelines, and trials which have shown the therapeutic benefit of mTOR inhibitors. Kidney surveillance of children with TSC now provides the opportunity for timely interventions to reduce the impact of TSC in adulthood. In this review, we discuss the current management of kidney tumors associated with TSC, including the diagnosis, surveillance, and treatment options for these lesions. We also present outcome data from international registries demonstrating the effectiveness of the current management strategies. With clear management guidelines and efficient treatment of kidney tumors, we envisage that the long-term outcomes of patients with TSC will further improve in the future.
Tuberous Sclerosis Complex (TSC) is easily discernible by a myriad of manifestations, most notably dermatological. It is associated with well known and recognised intra-abdominal tumours like angiomyolipoma of the kidney. However, rarer tumours like pancreatic neuroendocrine tumours can occur in the setting of TSC. A high index of suspicion is necessary to identify and treat these lesions early in their natural course. Early identification augurs well with complete surgical excision and excellent survival.
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Inactivating mutations to either of the TSC1 and TSC2 tumour suppressor genes are responsible for the disease. TSC1 and TSC2 encode two large novel proteins called hamartin and tuberin, respectively. Hamartin and tuberin interact directly with each other and it has been reported that tuberin may act as a chaperone, preventing hamartin self-aggregation and maintaining the tuberin–hamartin complex in a soluble form. In this study, the ability of tuberin to act as a chaperone for hamartin was used to investigate the tuberin–hamartin interaction in more detail. A domain within tuberin necessary for the chaperone function was identified, and the effects of TSC2 missense mutations on the tuberin–hamartin interaction were investigated to allow specific residues within the central domain of tuberin that are important for the interaction with hamartin to be pin-pointed. In addition, the results confirm that phosphorylation may play an important role in the formation of the tuberin–hamartin complex. Although mutations that prevent tuberin tyrosine phosphorylation also inhibit tuberin–hamartin binding and the chaperone function, our results indicate that only hamartin is phosphorylated in the tuberin–hamartin complex.
The objective of the study was to define the longitudinal evolution of cardiac rhabdomyomas (CR) in patients with tuberous sclerosis complex (TSC). A cohort of patients with TSC who had undergone videotaped echocardiographic (ECHO) examination during the 10-year interval (1984-1994) were retrospectively studied by reviewing and quantifying the CR appearance and associated cardiac abnormalities in sequentially obtained ECHO examinations. Sixteen patients with TSC (8 males) underwent a total of 35 recorded studies. Ten of the 16 (62.5%) had CR identified at initial study; none were found in the atria. Localization was the ventricular walls as compared with the ventricular septum by a ratio of 2:1. The number of CRs sequentially studied declined as follows; initial study: 23 lesions in 10 patients; second study: 16 lesions in 8 patients; third study: 12 lesions in 5 patients; and fourth study: 4 lesions in 2 patients. Total CR size index declined at each study as follows: initial index of 2,684; second index of 1,746 (-35% from initial); third index 1,141 (-57% from initial); and fourth index 705 (-74% from initial). Complete spontaneous regression of CR was seen by age 6 years with prolonged gradual resolution thereafter. Two patients had bicuspid aortic valves and two had conduction defects. Patients with TSC who have CR can be expected to experience a decline in both the number and size of CR over time; early complete regression on ECHO occurs before age 6 years.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive
tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). TheTSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein
of unknown function. Thirty-two distinct mutations were identified inTSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of
these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin
acts as a tumor suppressor.
In July 1998, the National Institutes of Health sponsored a consensus conference of international experts to review the literature on tuberous sclerosis complex (TSC), First described in the 1800s, this multiorgan disease has wide-ranging effects on the body, including the brain, kidneys, eyes, and heart. Tuberous sclerosis affects an estimated 40000 Americans and approximately 2 million people worldwide.(1) The panel provided recommendations on revised diagnostic criteria and surveillance protocols for affected individuals.(2) Areas for future research were highlighted.
Tuberous sclerosis (TSC) is an autosomal dominant multisystem disorder with loci assigned to chromosomes 9 and 16. Using pulsed-field gel electrophoresis (PFGE), we identified five TSC-associated deletions at 16p 13.3. These were mapped to a 120 kb region that was cloned in cosmids and from which four genes were isolated. One gene, designated TSC2, was interrupted by all five PFGE deletions, and closer examination revealed several intragenic mutations, including one de novo deletion. In this case, Northern blot analysis identified a shortened transcript, while reduced expression was observed in another TSC family, confirming TSC2 as the chromosome 16 TSC gene. The 5.5 kb TSC2 transcript is widely expressed, and its protein product, tuberin, has a region of homology to the GTPaseactivating protein GAP3.
Index Foreword by H. Sarnat Preface Historical background, Paolo Curatolo Diagnostic criteria, Paolo Curatolo Neurological manifestations, Paolo Curatolo and Magda Verdecchia Seizures, Paolo Curatolo and Stefano Seri Intellectual and cognitive impairments, Patrick F. Bolton Autism, Michael Dowling and Paolo Curatolo Neuroimaging, Alessandro Bozzao, Guglielmo Manenti and Paolo Curatolo Positron emission tomography, Eishi Asano, Diane C. Chugani and Harry T. Chugani Dermatologic and stomatologic manifestations, Sergiusz Jozwiak and Robert Schwartz Ophthalmologic manifestations, Sergiusz Jozwiak Renal involvement, Sergiusz Jozwiak Cardiac and vascular involvement, Sergiusz Jozwiak Hepatic, lung, splenic and pancreatic involvement, Sergiusz Jozwiak and Paolo Curatolo Molecular genetics, David J. Kwiatkowski, Mary Pat Reeve, Jeremy P. Cheadle and Julian R. Sampson Neuropathology, Masashi Mizuguchi and Okio Hino Molecular neurobiology, Peter B. Crino Future directions, Paolo Curatolo
The ESHRE PGD Consortium was formed in 1997 to undertake a long-term study of the efficacy and clinical outcome of preimplantation genetic diagnosis (PGD). Here, the third report of the ESHRE PGD Consortium is presented, collating data received from 25 centres on referrals, cycles, pregnancies and babies born after PGD. The second report, published in December 2000, reported on 886 referrals, a total of 1318 started cycles (of which 465 for aneuploidy screening, 386 for fluorescence in-situ hybridization (FISH) and 385 for PCR going beyond oocyte retrieval), 163 pregnancies and 162 children born. This year, 675 referrals from 12 centres were added giving a total of 1561 referrals, 370 regular PGD cycles, 334 PGD-aneuploidy screening (PGD-AS) cycles and 78 cycles for social sexing from 24 centres and 215 pregnancies and 117 babies from 12 centres. Because more in-depth information was asked for the cycles, this year's data will be shown separately as well as cumulatively. One striking feature of this year's data collection is the appearance of the first data for gender screening on preimplantation embryos for social reasons. The ethical concerns regarding social sexing will be discussed, as well as the forthcoming changes in timing of data collection. When the data collection was discussed at the last meeting of the members of the ESHRE PGD Consortium in Lausanne, Switzerland (June, 2001), it appeared that the current system of data collection, although yielding results very quickly, showed fundamental flaws. The ESHRE PGD Consortium Steering Committee intends to remedy to these problems, on the one hand by introducing a new type and timing of data collection, and on the other hand by re-analysing and correcting the data which have already been sent in during the past 4 years.
To establish the frequency of fits and mental retardation in an unbiased group of tuberous sclerosis patients.
Known tuberous sclerosis families with more than one affected person were ascertained for a genetic linkage study. A number of members were born after genetic counselling had been given after identification of the proband. These subjects were then carefully examined clinically and in many cases with cranial computerised tomography, renal ultrasound, and skeletal survey but not echocardiography. They provide an unbiased group of tuberous sclerosis patients and allow affected patients with normal intellect to be diagnosed.
Thirty-seven tuberous sclerosis families were ascertained and 26 patients born after the family proband were identified.
Sixteen of these 26 patients suffered fits (62%) and 10 patients were mentally retarded (38%).
A lower incidence of fits and mental retardation has been found in an unbiased sample of tuberous sclerosis patients. The lifetime risk for fits might be higher had we been able to follow the patients for longer. However, we believe these are more appropriate figures to use in genetic counselling for this disease.
A detailed ophthalmological study was performed on a consecutive series of 100 cases with tuberous sclerosis (TS). A fundus score was given to each patient according to the size and number of fundus hamartomas to correlate them with other clinical symptoms. TS-Specific fundus hamartomas were detected in 87% of the subjects. There were no significant differences in the distribution of the scores with age, and considerably high scores were given even for younger infants and children. The fundus scores were higher in sporadic cases or the complete type than in heredofamilial cases or the incomplete type. On fluorescein fundus angiography in 25 patients with 72 hamartomas, various degrees of hyperfluorescence were found in 87% of the lesions, while no leakage was found in the rest. Other ocular findings included depigmented iris sectors in 12 cases, punched-out chorioretinal defects in 9, and unilateral visual impairment due to either primary or secondary effects of the hamartomas in 3.
Twenty-five patients with tuberous sclerosis were studied with magnetic resonance imaging (MRI), and these findings were compared with those of computed cranial tomography (CCT) and with the clinical severity of the disease. Multiple high-signal MRI lesions involving the cerebral cortex are characteristic of tuberous sclerosis and probably correspond to the hamartomas and gliotic areas seen pathologically. These cortical lesions were only occasionally seen with CCT. The periventricular calcific lesions characteristic of tuberous sclerosis are better visualized with CCT than with MRI, but the larger periventricular calcifications produce low-signal MRI abnormalities. Seven patients had high-signal MRI lesions of the cerebellum; small calcific cerebellar lesions were also noted with CCT in three patients. As in earlier studies, no clear correlation was seen between the number of abnormalities visible with CCT and the clinical severity of the disease. By contrast, the more severely affected patients tend to have a higher number of cerebral cortical lesions detected with MRI. Thus, MRI may be useful in predicting the eventual clinical severity of younger children with newly diagnosed tuberous sclerosis.
An estimate of the prevalence of autism in tuberous sclerosis (TSC) was made by interviewing the parents of 21 children between ages 3 and 11 ascertained during a previous population study of the condition in the West of Scotland. Five of the children (24%) were rated autistic and a further four (19%), all of whom were girls, had socially impaired behavior categorized as pervasive developmental disorder, without fulfilling all the DSM-III-R criteria for autism. One further boy had disruptive attention-seeking behavior that had excluded him from his normal school. The estimated prevalence from this study of autism in TSC is 1 in 4 children in general, and 1 in 2 of those with mental retardation. Tuberous sclerosis could be a significant cause of autism and pervasive developmental disorders, particularly in girls.
To evaluate the utility and possible increased sensitivity of fluid-attenuated inversion recovery (FLAIR) images for the detection of tubers in patients with tuberous sclerosis, compared with standard T2-weighted images, and to evaluate whether the tubers are correlated with neurologic symptoms.
We examined the number, size, and location of tubers in five tuberous sclerosis patients using T2-weighted and FLAIR images. Their intelligence quotients, ages at the onset of the first seizure, seizure types, and epileptic severity also were studied retrospectively.
The number of tubers observed ranged from 4 to 17 on T2-weighted images, and from 10 to 33 on FLAIR images. All the tubers, other than the myelination line on T2-weighted images, were remarkably demonstrated as high-intensity lesions on FLAIR images. No correlation was found between the neurologic outcome and the number, size, or location of tubers on FLAIR images.
FLAIR images were very sensitive for the detection of tubers, especially small subcortical ones, the number, size, and location of which are not related to the neurologic symptoms.
Although hypopigmented macules are an important manifestation of tuberous sclerosis (TS), the probability of TS in healthy individuals who have hypopigmented macules is unknown. The purpose of this study was to establish the prevalence of hypopigmented macules among a cross section of the general white population.
The skin of 423 white individuals younger than 45 years of age was screened for hypopigmented macules with ambient incandescent and fluorescent light and a Wood lamp. Indirect ophthalmoscopy was performed in patients with unexplained hypopigmentation to screen for retinal manifestations of TS.
Twenty individuals (4.7%) had at least one hypopigmented macule. Of these, four had more than one macule. None had more than three. Two (8%) of the 25 hypopigmented macules were identified only with a Wood lamp. Indirect ophthalmoscopy was performed in 13 (65%) of these 20 individuals. None showed the retinal findings of TS.
The prevalence of hypopigmented macules in the general population has been underestimated. The presence of a few hypopigmented macules on the skin of an otherwise healthy individual without a family history of TS need not prompt an evaluation to rule out this disorder.
The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.
We present 19 patients with tuberous sclerosis complex and subependymal giant cell astrocytoma. The mean age at the time of tumor diagnosis was 9.4 years (range, 1.5 to 21 years). Computed cranial tomography (CT) or cranial magnetic resonance imaging (MRI) identified the lesion which was resected in all cases. Seven patients had hydrocephalus and there was an interval increase in the tumor size or a large tumor without hydrocephalus in 12 patients. Surgical criteria included: (1) presence of hydrocephalus; (2) interval increase in tumor size; (3) new focal neurologic deficit attributable to the tumor; and/or (4) symptoms of increased intracranial pressure. Eight patients were identified through a surveillance program involving annual computed cranial tomography. All of these eight patients had their tumor removed prior to the development of symptoms, none had neurologic deficits which persisted after surgery, and none has so far developed recurrent subependymal giant cell astrocytoma. In contrast, of the 11 patients from the non-surveillance group 7 were symptomatic at tumor diagnosis, 1 had a complicated postoperative course, 2 developed recurrent giant cell astrocytoma, and 1 had an extensive lesion that could not be completely excised. Periodic cranial imaging may help to identify subependymal giant cell astrocytomas in tuberous sclerosis patients before they become symptomatic. Earlier diagnosis and treatment could reduce surgical morbidity and the risk of tumor recurrence.
Purpose:
Renal lesions, including angiomyolipoma, renal cysts (simple and polycystic kidney disease) and renal cell carcinoma, develop in patients with tuberous sclerosis complex. While there is limited information that these lesions may grow in adults with tuberous sclerosis complex, the incidence, characterization and growth rate in children have not been reported. Also, the age at which these lesions first appear, thus providing insight into their natural history, is unknown. We present our data from a longitudinal renal surveillance study of children with tuberous sclerosis complex.
Materials and methods:
Since 1985 children with tuberous sclerosis complex at our hospital have undergone periodic renal imaging by ultrasonography or computerized tomography to monitor renal lesions. A total of 35 girls and 25 boys 1 to 18 years old have undergone at least 2 or more annual renal ultrasounds.
Results:
On initial evaluation 33 of 60 children (55%) (mean age 6.9 years) had an identifiable renal lesion, which increased to 48 of 60 (80%) at followup (mean age 10.5 years). Angiomyolipoma was the most frequent lesion (75%) followed by simple renal cysts (17%). Angiomyolipomas increased in size and/or number in 10 of 18 boys (56%) and 18 of 27 girls (66%). The largest growth rate in 1 year was from 0 to 4 cm. and from 5 to 9 cm. in diameter. The youngest patient demonstrated lesions at age 2 years. The average age at which a normal ultrasound became abnormal was 7.2 years. While a total of 27 patients had a normal ultrasound on entering the study, lesions had developed in 15 at followup (11 with angiomyolipomas, 4 with cysts). Five patients had cysts that had disappeared at followup. A 7-year-old boy had a 9 cm. renal cell carcinoma removed. One patient has renal lesions characteristic of autosomal dominant polycystic kidney disease.
Conclusions:
Renal involvement in patients with tuberous sclerosis complex begins in infancy, and angiomyolipoma is the most common lesion (75%). Angiomyolipomas are more likely to grow than remain stable, although the rate of growth varies. Simple renal cysts may appear or disappear with time but angiomyolipomas do not disappear. An initially normal renal ultrasound does not rule out future development of lesions. Periodic surveillance is indicated in children with tuberous sclerosis complex.
At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation.
Two genes, mutations in which result in the phenotype of tuberous sclerosis (TSC), have recently been cloned. TSC2 on chromosome 16p13.3 encodes the protein tuberin, which appears to have growth regulating properties. TSC1 on chromosome 9q34 encodes hamartin which, as yet, has no specified cellular functions. Polyclonal antibodies were raised to synthetic peptides representing portions of tuberin and hamartin and used in immunoblots and immunohistochemical studies to localize the proteins in surgically resected neocortical tubers from four TSC patients. On Western blots of autopsy brain specimens, K-562 cell, and NT2 lysates, each antibody labelled a single band at the expected molecular weight. In immunohistochemical protocols on paraffin embedded tissue, antibodies to both tuberin and hamartin prominently labelled atypical and dysmorphic neuroglial cells that are a defining feature of TSC tubers. Some abnormal cells within cortical tuber sections were labelled with both tuberin and hamartin antisera. Our results suggest that tuberin and hamartin are both robustly expressed in similar populations of neuroglial cells of TSC tubers, even in the presence of TSC1 or TSC2 germline mutations. The roles of these gene products in normal and abnormal cortical development, tuber pathogenesis and the generation of seizures remain to be defined.
Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ-line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of-heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC.
Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.
Six families with mosaicism are identified in a series of 62 unrelated families with a mutation in one of the two tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. In five families, somatic mosaicism was present in a mildly affected parent of an index patient. In one family with clinically unaffected parents, gonadal mosaicism was detected after TSC was found in three children. The detection of mosaicism has consequences for genetic counseling of the families involved, as changed risks apply to individuals with mosaicism, both siblings and parents. Clinical investigation of parents of patients with seemingly sporadic mutations is essential to determine their residual chance of gonadal and/or somatic mosaicism, unless a mosaic pattern is detected in the index patient, proving a de novo event. In our data set, the exclusion of signs of TSC in the parents of a patient with TSC reduced the chance of one of the parents to be a (mosaic) mutation carrier from 10% to 2%. In the five families with somatic mosaicism, the parent was given the diagnosis after the diagnosis was made in the child.
To outline recent developments in the neurobiology of the tuberous sclerosis complex (TSC).
TSC may be associated with neuropsychiatric disorders including epilepsy, mental retardation, and autism. The uncontrolled growth of subependymal giant cell astrocytomas may lead to hydrocephalus and death. The recent identification of mutations in two genes (TSC1 and TSC2) that cause TSC has led to rapid progress in understanding the molecular and cellular pathogenesis of this disorder. How distinct mutations lead to the varied clinical phenotype of TSC is under intense investigation.
We report the recent diagnostic criteria for TSC and provide an overview of the molecular genetics, molecular pathophysiology, and neuropathology of TSC. Important diagnostic criteria for TSC include facial angiofibromas, ungual fibromas, retinal hamartomas, and cortical tubers. Both familial and sporadic TSC cases occur. Approximately 50% of TSC families show genetic linkage to TSC1 and 50% to TSC2. Among sporadic TSC cases, mutations in TSC2 are more frequent and often accompanied by more severe neurologic deficits. Multiple mutational subtypes have been identified in the TSC1 and TSC2 genes. The TSC1 (chromosome 9) and TSC2 (chromosome 16) genes encode distinct proteins, hamartin and tuberin, respectively, which are widely expressed in the brain and may interact as part of a cascade pathway that modulates cellular differentiation, tumor suppression, and intracellular signaling. Tuberin has a GTPase activating protein-related domain that may contribute to a role in cell cycle passage and intracellular vesicular trafficking.
Identification of tuberous sclerosis complex (TSC) gene mutations has fostered understanding of how brain lesions in TSC are formed. Further characterization of the roles of hamartin and tuberin will provide potential therapeutic avenues to treat seizures, mental retardation, and tumor growth in TSC.
Tuberous sclerosis complex is an autosomal dominant disorder that causes significant complications in multiple organ systems. Both basic science and clinical research on tuberous sclerosis complex have flourished in recent years, improving our understanding of its molecular genetics and pathophysiology. Two tuberous sclerosis complex genes cause nearly identical phenotypes, and great progress has been made towards understanding how each of these genes functions. The recognition of tuberous sclerosis complex improved with revised diagnostic criteria, and the management of many of the complications of tuberous sclerosis complex has improved.
The Tuberous Sclerosis Complex 1998 Consensus Conference clinical criteria represent an important advance in the diagnosis of tuberous sclerosis complex. Since many findings regarded as highly specific for tuberous sclerosis complex are not apparent until late childhood or adulthood, refinements by age may prove of value. We have stratified 106 children into five age groups (0 to 2 years of age, above 2 to 5 years, above 5 to 9 years, above 9 to 14 years, and above 14 to 18 years). Physicians should be alerted as to the frequency of the criteria in different stages of children.
We report our experience of 14 preimplantation genetic diagnosis (PGD) cycles in eight couples carrying five different single gene disorders, during the last 18 months. Diagnoses were performed for myotonic dystrophy (DM), cystic fibrosis (CF) [Delta F508 and exon 4 (621+1 G>T)], fragile X and CF simultaneously, and two disorders for which PGD had not been previously attempted, namely neurofibromatosis type 2 (NF2) and Crouzon syndrome. Diagnoses for single gene disorders were carried out on ideally two blastomeres biopsied from Day 3 embryos. A highly polymorphic marker was included in each diagnosis to control against contamination. For the dominant disorders, where possible, linked polymorphisms provided an additional means of determining the genotype of the embryo hence reducing the risk of misdiagnosis due to allele dropout (ADO). Multiplex fluorescent polymerase chain reaction (F-PCR) was used in all cases, followed by fragment analysis and/or single-stranded conformation polymorphism (SSCP) for genotyping. Embryo transfer was performed in 13 cycles resulting in one biochemical pregnancy for CF, three normal deliveries (a twin and a singleton) and one early miscarriage for DM and a singleton for Crouzon syndrome. In each case the untransferred embryos were used to confirm the diagnoses performed on the biopsied cells. The results were concordant in all cases. The inclusion of a polymorphic marker allowed the detection of extraneous DNA contamination in two cells from one case. Knowing the genotype of the contaminating DNA allowed its origin to be traced. All five pregnancies were obtained from embryos in which two blastomeres were biopsied for the diagnosis. Our data demonstrate the successful strategy of using multiplex PCR to simultaneously amplify the mutation site and a polymorphic locus, fluorescent PCR technology to achieve greater sensitivity, and two-cell biopsy to increase the efficiency and success of diagnoses.
TiiberoiiH sclerosis complex consensus conference; Revised clinical diiignoslic criteria../ CliHil Nniml 19i Hyniann MH, Whittemnre VH: National Institules of Hoaith con-sensns conference: Tuberous sclerosis complex
- Es Roach
- Gomez
- Northmp
Roach ES, Gomez MR, Northmp II: TiiberoiiH sclerosis complex consensus conference; Revised clinical diiignoslic criteria../ CliHil Nniml 19i Hyniann MH, Whittemnre VH: National Institules of Hoaith con-sensns conference: Tuberous sclerosis complex. Aiiii N/'iirol 2000; 57:662-665
Gcrni-line nios;u{-ism in tuber-ous sclerosis: How common?
- Vm Rose
- K- Au
- S G Poliom
Rose VM, Au K-S. Poliom G, el al: Gcrni-line nios;u{-ism in tuber-ous sclerosis: How common? Am J Hum Geiicl 1999;64:986-S)y2. r
Evaluation of RT-PCT as a clinical tool for diagnosis in PGD. A model study on the expres-sion of the tuberous sclerosis genes throughout human preim-plantation embryo development
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