Presentation and Diagnosis of Tuberous Sclerosis Complex In

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Peter E. Davis, MD,a Rajna Filip-Dhima, MS,b Georgios Sideridis, PhD,c Jurriaan M. Peters, MD, PhD,a, d Kit Sing Au, PhD,e PresentationHope Northrup, MD,e E. Martina Bebin, MD, and MPA,f Joyce DiagnosisY. Wu, MD,g Darcy Krueger, MD, PhD,ofh Mustafa Sahin, MD, PhD,a, b Tuberouson behalf of the Tuberous Sclerosis Sclerosis Complex Autism Center Complex of Excellence Research Network in Infants

OBJECTIVES: abstract

Tuberous sclerosis complex (TSC) is a neurocutaneous genetic disorder with a high prevalence of epilepsy and neurodevelopmental disorders. TSC can be challenging to diagnose in infants because they often do not show many clinical signs early in life. In this study, we describe the timing and pattern of presenting and diagnostic features in a METHODS: prospective longitudinal study of infants with TSC. Two multicenter, prospective studies enrolled 130 infants with definite TSC by clinical or genetic criteria and followed them longitudinally up to 36 months of age. Periodic study visits included medical and seizure histories, physical and neurologic examinations, and developmental assessments. Ages at which major and minor features of TSC and RESULTS: seizures were first identified were analyzed. The most common initial presenting features of TSC were cardiac rhabdomyomas (59%) and hypomelanotic macules or other skin findings (39%), and 85% of infants presented with either or both. Ultimately, the most prevalent diagnostic TSC features were hypomelanotic macules (94%), tubers or other cortical dysplasias (94%), subependymal nodules (90%), and cardiac rhabdomyomas (82%). Thirty-five percent of infants presented prenatally, 41% presented at birth or within the first month of life, and 74% met criteria for TSC diagnosis at or within 30 days of presentation. Seizure onset occurred before or at initial presentation in only 15% of infants, but 73% developed epilepsy within the first year CONCLUSIONS: of life. Infants with TSC can often be identified early, before the onset of neurologic sequelae, enabling earlier diagnosis, surveillance, and possibly disease-modifying NIH treatment.

dDivision of Epilepsy and Clinical Neurophysiology, Departments of aNeurology and cPediatrics, and bF.M. What’s Known on This Subject: Tuberous Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Harvard University, Boston, sclerosis complex (TSC) can be challenging to Massachusetts; eDepartment of Pediatrics, McGovern Medical School, University of Texas Health Science diagnose in infants because they often do not show f Center at Houston, Houston, Texas; Department of Neurology, University of Alabama at Birmingham, many clinical signs early in life. Early diagnosis Birmingham, Alabama; gDivision of Pediatric Neurology, University of California at Los Angeles Mattel Children’s Hospital, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; enables more effective disease surveillance, and hDepartment of Neurology and Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, especially for epilepsy, which is highly prevalent in Cincinnati, Ohio TSC. Dr Davis conceptualized the study, performed data analysis, drafted the initial manuscript, and What This Study Adds: In this prospective revised the manuscript; Ms Filip-Dhima performed data collection and analysis, participated longitudinal study, a majority of infants with TSC in manuscript preparation, and critically reviewed and revised the manuscript; Dr Sideridis could be identified early by cardiac rhabdomyomas performed statistical analyses, participated in manuscript preparation, and critically reviewed or hypomelanotic skin macules before epilepsy and revised the manuscript; Dr Peters contributed to the study design and data interpretation onset. Different presentation patterns may be and critically reviewed and revised the manuscript; Dr Au reviewed and interpreted genetic data related to risk of developing epilepsy. and critically reviewed and revised the manuscript; Drs Bebin, Krueger, Northrup, and Wu are co-principal investigators of the multicenter prospective study that supplied the data for this study, submitted and reviewed data, and critically reviewed and revised the manuscript; Dr Sahin To cite: Davis PE, Filip-Dhima R, Sideridis G, et al. Pre sentation and Diagnosis of Tuberous Sclerosis Complex in Infants. Pediatrics. 2017;140(6):e20164040

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of tuberous sclerosis complex facial angiofibromas, and pulmonary2 (1) Potential EEG Biomarkers and (TSC) have advanced1 significantly lymphangioleiomyomatosis. Most Antiepileptogenic Strategies for in the last 2 decades. After the patients with TSC also develop Epilepsy in TSC (P20NS080199) identification and sequencing of neurologic and neuropsychiatric and (2) Early Biomarkers of Autism

the genes responsible for TSC disorders:8,9 up to 90% develop Spectrum Disorders in Infants in the 1990s, the biochemical epilepsy,10 ‍ and up to 50% develop with Tuberous Sclerosis Complex pathway at the root of the disorder autism. Studies have shown that (U01NS082320, a TSC Autism was mapped, leading to effective mTOR inhibitors may have disease- Center of Excellence grant). The

treatments aimed at2, the3 underlying modifying effects in TSC-associated enrollment goal was 150 infants; disease mechanism. ‍ However, neurologic11 and neuropsychiatric infants were eligible if they met much remains to be discovered. disorders. Treating infants with genetic or clinical diagnostic criteria Why does TSC vary widely in TSC and epilepsy earlier with for TSC on the basis of current

presentation and severity from antiepileptic medications or surgery recommendations14 for diagnostic patient to patient, particularly in its may result in better neurologic evaluation. Data collected at study

neurodevelopmental effects? How outcomes, reinforcing12,13 the importance visits included medical and seizure early can we identify patients with of early diagnosis. ‍ histories, physical and neurologic TSC? Could targeted treatment safely TSC can be diagnosed by the examinations, and developmental and effectively modify the course and presence of clinical criteria and assessments. Full inclusion and prognosis of the disease? The TSC by genetic testing. Two major exclusion criteria, protocols, and Autism Center of Excellence Research features or 1 major and 2 minor study design are detailed in Table 1. Network is conducting prospective The study protocols were approved features are needed14 for a definite longitudinal observational studies clinical diagnosis. The variability by the internal review boards at in infants with TSC to answer these each site with direction from the of presentation and later onset of ’ and other questions. In this article, certain clinical features can make leading regulatory core at Cincinnati we analyze the timing and pattern Children s Hospital Medical Center. diagnosing TSC15,16 in infants more of clinical presenting and diagnostic challenging. ‍ Early identification Informed consent was obtained features in infants with TSC to better of infants with TSC allows from the parents or legal guardians understand how TSC presents in this clinicians to provide appropriate, of all participants. The study was unique population and how it can be disease-related surveillance and conducted in accordance with Good diagnosed and treated earlier. anticipatory guidance to patients. Clinical Practice guidelines. Data from each study site were entered ∼ Early identification is also critical TSC is a neurocutaneous genetic for clinical researchers, who can into a Web-based, distributed data management system meeting disease with an incidence4 of 1 in study these infants from early in 6000 live births. It presents with life to better understand the natural Health Insurance Portability a wide range of manifestations history of TSC and develop targeted and Accountability Act privacy caused by localized cellular treatments. regulations. Subject demographics are summarized in Table 2. overgrowth, leading to benign Methods Data Collection and Analysis tumors (hamartomas) in multiple organs. In the brain, these include Study Protocols, Design, and areas of abnormal cortical and Participant Demographics subcortical cellular development Data from 130 participants were used (tubers), subependymal nodules in this interim analysis. The date of (SENs), and subependymal giant Participants were enrolled across onset for each TSC feature was used ’ cell astrocytomas (SEGAs). The skin, 5 geographically distributed to calculate the days between date ’ heart, eyes, kidneys, and lungs may5 sites: Boston Children s Hospital; of birth and onset or to determine also be affected in varying degreesTSC1 . Cincinnati Children s Hospital if reported onset was prenatal. If TSC2Dysfunction of hamartin and tuberin, Medical Center; the University a date of onset was unknown, the the protein products of the and of Alabama at Birmingham; the date of the study visit when the genes, results in upregulation University of California, Los Angeles; feature was first noted was used as of the mechanistic (formerly and the University of Texas Health a conservative replacement when mammalian) target of the rapamycin Science Center at Houston. Two needed for calculations. The date of

(mTOR) pathway and produces6,7 concurrent prospective longitudinal diagnosis was defined as the earliest dysregulated cellular growth. ‍ observational studies were date when the subject met genetic mTOR inhibitors are used to treat conducted, and eligible participants or clinical criteria for a definite TSC Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 Davis et al

Davis et al https://doi.org/10.1542/peds.2016-4040 December 2017 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants 6 140 Pediatrics 2017 ROUGH GALLEY PROOF TABLE 1 Study Protocol and Design TABLE 2 Participant Demographics TACERN study inclusion criteria TSC-EBS study inclusion criteria Sex Meets genetic or clinical diagnostic Meets genetic or clinical diagnostic criteria for Female 62 48% criteria for TSC on the basis of current TSC on the basis of current recommendations Male 68 52% recommendations for diagnostic for diagnostic evaluation, including Mean enrollment age, 5.2 3.3 evaluation, including physical examination, physical examination, neuroimaging, and mo, SD neuroimaging, and echocardiogram14 echocardiogram14 Race Age criteria: 3–12 mo at time of enrollment. For Age criteria: <6 mo at time of enrollment. White 115 88% study purposes, 3 mo is defined as≥ 9 wk, 1 Black or African 4 3% d and 12 mo is defined as≤ 13.5 mo. American — Seizure free at the time of study enrollment Asian American 10 8% TACERN study exclusion criteria TSC-EBS study exclusion criteria American Indian or 5 4% Gestational age <36 wk at time of delivery Gestational age <30 wk at time of delivery Alaskan native Taking an mTOR inhibitor such as rapamycin, Taking vigabatrin or mTOR inhibitor before study Native Hawaiian 1 1% sirolimus, or everolimus (other than enrollment or other Pacific topical formulations) at the time of study Islander enrollment Other 8 6% Has taken an investigational drug as part of Participant’s neonatal course, time of delivery, Not reported 7 5% another research study within 30 d before or history includes CNS infection, hypoxic- Reported >1 race 17 13% study enrollment ischemic encephalopathy, or intraventricular Ethnicity hemorrhage Hispanic or Latino 23 18% SEGA requiring medical or surgical treatment History of seizures and/or infantile spasms Not Hispanic or 107 82% at the time of study enrollment Latino History of epilepsy surgery at the time of study — enrollment Contraindications to MRI scanning, such as — metal implants and/or noncompatible medical devices or medical conditions available. Some subjects who had not TACERN study visit ages TSC-EBS study visit ages had clinical genetic testing had testing 3, 6, 9, 12, 18, 24, and 36 mo Before 3 wk, at 6 wk, and at 3, 4.5, 6, 9, 12, 18, done on a research basis; research and 24 mo P χ Information collected at baseline visit in both studies results were included when2 available. Demographics and medical history including seizures, medications, family history, physical and Reported values are for tests of neurologic examinations, developmental assessment, and EEGs independenceLatent Class A nalysisexcept whenand noted. Information collected at follow-up visits in both studies Relationship to Genetic Variant Seizures types and frequency, interval medical history, medications, physical and neurologic examinations, developmental assessment, EEGs, and results of yearly clinical brain MRI TSC-EBS (P20NS080199 and NCT01767779) TACERN (U01NS082320 and NCT01780441) TSC manifestations of 103 CNS, central nervous system; TACERN, TSC Autism Center of Excellence Research Network; TSC-EBS, Potential EEG participants with available Biomarkers and Antiepileptogenic Strategies for Epilepsy in TSC; —, not applicable. neuroimaging and genetic testing were analyzed by means of latent class (LC) mixture modeling to 14 17 identify the presence of classes diagnosis. For participants who studies. If an imaging report that share similar patterns of TSC had cardiac rhabdomyomas or other referred to findings seen in previous manifestations. After identification imaging findings reported at birth imaging for comparison, the date of of distinct classes on the basis of or as an initial presenting feature, the previous imaging was used as latent factors of TSC features and study sites provided the reason for the date of onset for that feature; seizures, theTSC1 classesTSC2 were regressed the imaging study and the date it otherwise, the date of the first report on genetic testing results indicating was performed. For participants who with a finding was used as the date a variant in , , or no did not have neuroimaging findings of onset. For participants who did mutation identified (NMI). See the reported in the study database, sites not have ophthalmologic findings Supplemental Information for details provided anonymized reports from reported, sites provided dates and of the mathematical analysis used in any MRI neuroimaging performed findings from documented clinical LC modeling. at the study site. These reports ophthalmologic examinations; Results were reviewed for any findings of ophthalmologic examination results cortical tubers or dysplasia, SENs, were reported for 87 subjects. For Timing and Pattern of Presenting or SEGAs. A SEGA was defined as a participants who did not have full Features and TSC Diagnosis tumor at the caudothalamic groove genetic testing results reported, larger than 10 mm in any direction sites provided deidentified copies of or any SEN that had demonstrated reports from clinical genetic testing, The most common initial presenting growth over consecutive imaging including parental testing, when features were cardiac rhabdomyomas Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 140, number 6, December 2017 3

Davis et al https://doi.org/10.1542/peds.2016-4040 December 2017 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants 6 140 Pediatrics 2017 ROUGH GALLEY PROOF (59%) and hypomelanotic macules (39%), and 85% of patients presented with either or both. Cardiac rhabdomyomas were seen on prenatal imaging in 35% of patients, and 3% met diagnostic criteria for TSC prenatally with brain involvement also seen on imaging (Fig 1). Of 12 infants with rhabdomyomas recorded postnatally as the initial presenting feature, 4 had a heart murmur, 3 had another clinical indication for an echocardiogram (concern for aortic coarctation, abnormal heart FIGURE 1 sounds, and perinatal distress), and Prevalence of TSC features at initial presentation. Thirty-six infants (28%) had >1 initial presenting feature. 2 had a positive family history. No reason for imaging was reported for the remaining 3 infants with rhabdomyomas and for 2 others who had other imaging findings reported as the initial presenting feature. However, all 5 had hypomelanotic macules reported as present within the first few months of life, so early skin findings may have prompted imaging but were reported by parents as occurring later.

The mean postnatal age of initial feature onset was 48 days (SD 72 days). The median age, including prenatal presentations, was at birth. Thirty-five percent of infants presented prenatally, whereas 41% initially presented at birth FIGURE 2 or within the first month of life. Age of onset or recognition of the most prevalent TSC features in infants. Hypomelanotic macules, The mean postnatal diagnosis age tubers, SENs, and cardiac rhabdomyomas are often seen before the onset of seizures, whereas other was 72 days (SD 85 days), and manifestations are more commonly first seen later in life. the median diagnosis age was 32 days. Fifty percent were diagnosed with TSC within the first month (94%), tubers or other cortical with definite TSC on the basis of of life. Twenty-four percent met dysplasias (94%), SENs (90%), and genetic testing. Thus, minor criteria TSC diagnosis criteria at initial did not contribute to the diagnosis of presentation; an additional 49% met cardiac rhabdomyomas (82%). Every TSC in any infant. No TSC diagnostic diagnosis criteria within 1 month of infant had at least 1 of these features, P criteria differed significantly by sex initial presentation. Age of onset or and 61% had all 4. Of 87 infants ( > .05). recognition of the most prevalent with documented ophthalmologic TSC Features in Infants Presenting major TSC features plus seizures and examinations or findings, 43% had Prenatally Prevalencerenal cysts is of shown Major inand Fig Minor 2. retinal hamartomas, and 6% had TSC Features and Contribution to retinal achromic patches. Renal cysts Diagnosis were the only relatively common As expected, infants presenting minor criteria, occurring in 45% of prenatally had a higher prevalenceP patients (Table 3). All patients with of cardiac rhabdomyomas (100% The most prevalent major TSC only 1 major criterion had no minor prenatal, 71% postnatal; < .001). criteria were hypomelanotic macules criteria present and were diagnosed Infants presenting prenatally Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 Davis et al

Davis et al https://doi.org/10.1542/peds.2016-4040 December 2017 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants 6 140 Pediatrics 2017 ROUGH GALLEY PROOF TABLE 3 Prevalence of TSC Criteria TABLE 4 Genetic Variants % (n) TSC1, % (n) TSC2, % (n) TSC2 (VUS), % (n) NMI, % (n) Total, % (n) Major criteria Nonsense 7 (8) 18 (20) 0 (0) — 26 (28) Hypomelanotic macules 94 (122) Any frameshift 6 (6) 20 (22) 0 (0) — 26 (28) Tuber or cortical dysplasia 94a (108) Missense 0 (0) 13 (14) 2 (2) — 15 (16) SEN 90a (104) Any splice 1 (1) 12 (13) 1 (1) — 14 (15) Cardiac rhabdomyoma 82 (106) Large deletion 0 (0) 6 (7) 0 (0) — 6 (7) Retinal hamartoma 43b (37) Small deletion 0 (0) 3 (3) 0 (0) — 3 (3) Angiofibroma or cephalic 25 (32) Total 14 (15) 72 (79) 3 (3) 11 (12) 100 (109) plaque Shagreen patch 18 (24) De novo 13a (5) 58a (23) 0a (0) — 70a (28) Renal angiomyolipoma 11 (14) Inherited 8a (3) 20a (8) 3a (1) — 30a (12) SEGA 6a (7) VUS, variant of unknown significance;— , not applicable. Ungual fibroma 1 (1) a Out of 40 subjects for whom both parents also had genetic testing. Minor criteria Renal cysts 45 (58) Retinal achromic patch 6b (5) Genetic Testing Findings and Family Confetti skin lesions 5 (7) History Nonrenal hamartoma 5 (7) ‍Table 4 summarizes the prevalence Dental pits 2 (2) of each type of genetic variant by TSC Intraoral fibroma 1 (1) gene, and the full listing of variants Of 109 infants with reported results a Out of 115 participants with neuroimaging data available. TSC1 and types for each subject are listed b Out of 87 participants with documented ophthalmologic from genetic testing, 14% had a TSC2 in Supplemental Table 5. examinations. pathogenic variant, 72% had a TSC2 Epilepsy Onset pathogenic variant, 3% had a sequence variant of uncertain significance, and 11% had NMI. A family history of TSC was reported Seizures are not a diagnostic criterion also had a lower prevalence of P in 15% of infants: 5% maternal, 7% for TSC, but epilepsy prevalence8,9 in hypomelanotic macules (87% paternal, and 5% in a sibling, with TSC is as high as 90%. ‍ New-onset prenatal, 98% postnatal; = .02), P ’ 2% having both an affected parent seizures may be the symptom that confetti skin lesions (none prenatal, and a sibling. In 40 subjects for whom first brings patients with TSC to 8% postnatal; = .05; Fisher s exact P both parents also had genetic testing, medical attention, prompting closer test), and all seizure types (65% 30% had an inherited variant, and examination and studies that then prenatal, 82% postnatal; = .03), 70% had a de novo variant. Two lead to a TSC diagnosis. In this cohort, although the difference was not infants (2%) were diagnosed with 15% of infants had a seizure onset statistically significant for individual definite TSC by genetic diagnostic date before or at the recorded onset seizure types. Other TSC features 14 criteria. dates of other TSC criteria, suggesting didP not differ in prevalence across that seizure was an initial presenting prenatal and postnatal presentations We examined the relationship of each symptom. Seizure onset was within N( euroimaging > .05). Findings TSC feature and type of variant to the 3 months after initial presentation in affected TSC gene.TSC1 Seizures of any 17% of infants, within 6 months in type occurred atTSC2 a lower frequency 39%, and within 12 months in 57% Of 115 participants with in infants with P variants (20%) (Fig 3). neuroimaging results available, 94% than those with variants (87%) To date, the overall prevalence of had tubers or cortical dysplasias, or NMI (67%) ( < .001). This was TSC1 TSC2 epilepsy in this cohort is 76%, with 90% had SENs, and 89% had also the case for infantile spasms P TSC1 57% having infantile spasms, 55% both. SEGAs occurred in 6% of ( 7%, 68%, and NMI 42%; TSC2 having focal seizures, and 12% participants. Neuroimaging findings < .001) and focal seizures ( P having another seizure type. Thirty- were seen at presentation in 16% 13%, 66%, and NMI 42%; two percent of infants had 1 seizure of participants; an additional 37% < .001) but not for other seizure type, 41% had 2 seizure types, and had neuroimaging findings at types. There were no significant 3% had 3 seizure types. Both infantile diagnosis. Neuroimaging findings relationships between the affected P spasms and focal seizures were contributed to a TSC diagnosis in gene and the presence of any other seen in 36% and were more likely 38% of infants. All neuroimaging major or minor TSC criteria ( > .05). P TSC1 TSC2 to co-occur than to occur alone in an was read as normal in 4%, whereas Nonsense variants were more P individual ( = .02). 3% had initial neuroimaging that common in (53%) than was read as normal with subsequent (24%) ( = .02), and missenseTSC2 Seizure onset prevalence by age neuroimaging showing a tuber or variants and small and large and seizure type (infantile spasms, cortical dysplasia. deletions were only seen in . focal seizures, or other) is shown Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 140, number 6, December 2017 5

An LC model using 3 classes best fit the data by using both information criteria and a test of log-likelihood functions (Supplemental Table 6). All included TSC major features and seizures were significant indicators of LC membership. Renal cysts were the only minor feature prevalent enough to be included in analysis, but they were FIGURE 3 not a significant class indicator.TSC1 Time from initial presentation to first seizure. With the affected gene treated as a grouping covariate, only was significantly different among groups (Supplemental Table 7).

To compare patterns of organ system manifestations and co-occurrence across classes, we divided TSC manifestations into 5 organ systems (skin, brain, cardiac, renal, and eye), with seizures considered separately from structural brain manifestations of tubers and SENs, similar to the Medical Inventory of TSC Organ System18n Codes used by Kingswood et al. The subjects in the largest class ( = 54) had a high proportion FIGURE 4 of multisystem involvement, with a Seizure onset prevalence in TSC by age and seizure type. Infantile spasms had the highest rate of mean of 4.9 organ systems involved onset between 3 and 9 months, whereas focal seizures had a more constant rate of onset up to 21 months, and other seizure types had a rate of up to 26 months. (median 5, SD 0.8) and the highest co-occurrence rates being among TSC1the brain,TSC2 skin, and cardiac systems. The multisystem classn included in Fig 4. The rate of onset for a first significant for each individual , , and NMI variants. The seizure of any type was greatest seizure type. second-largest class ( = 36) had a ∼ in the first year of life but began neuropredominant presentation, to level off at 9 months. Infantile Of the 108 individuals with tubers with all subjects having structural spasms had the highest rate of onset or cortical dysplasias seen on brain manifestations and seizures; between 3 and 9 months, focal neuroimaging, 80% developed the highest co-occurrence rates seizures had a relatively constant seizures. Only 1 of the 7 individuals were between the brain, skin, and rate of onset up to 21 months, and without tubers or cortical dysplasias seizures. The neuropredominant other seizure types had an onset seen on neuroimaging developedP class had a mean ofTSC2 4.1 organ seizures, a significant difference systems involved (median 4, SD 0.7) up to 26 months. OverallP seizure ’ ’ prevalence was higher in girls (84%) from subjects with tubers ( < .001; and includedn only variants and than boys (69%) ( = .05), although Fisher s exact test). This individual s a single NMI subject. The smallest the difference was not statistically MRI was done at 6 months of age, class ( = 13) had an overall milder Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 Davis et al

Davis et al https://doi.org/10.1542/peds.2016-4040 December 2017 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants 6 140 Pediatrics 2017 ROUGH GALLEY PROOF presentation, with a mean of 2.7 organ systems involved (median 2, SD 0.8), a high prevalence of cardiac rhabdomyomas, and only 1 subject with seizures. The proportion of infants who had involvement of each organ system and the proportion who had involvement of each pair of organ systems are depicted graphically for all subjects and for each class separately in Fig 5. Discussion FIGURE 5 Frequency of organ system involvement in all subjects and in LCs. Vertex size is proportional to the prevalence of organ system involvement in a class. Edge width is proportional to relative co-occurrence of adjoining organ systems. Note the different patterns and prevalences of organ system involvement and co-occurrence in each class. A key finding of this prospective longitudinal multicenter study is that a few specific, nonneurologic TSC findings appear early in infancy. only becoming apparent later with Clinical and Molecular Biomarkers Every infant in this cohort had progressive myelination, as occurred of Epileptogenesis in a Genetic either hypomelanotic macules, in 3 individuals. Model of Epilepsy - Tuberous cardiac rhabdomyomas, or both. An Sclerosis Complex in the European analysis of developmental outcomes Different seizure types demonstrated Union [NCT02098759]). To be most in this cohort found that earlier different onset timing: most effective, treatment should be started seizure onset and higher seizure infantile spasms started between at the earliest possible opportunity frequencies were associated with 19 3 and 9 months, whereas focal in patients at the highest risk of worse developmental outcomes. 12,13, 26, 27 seizures had consistent onset of developing epilepsy. ‍ ‍ Early diagnosis of infants with TSC up to 21 months (Fig 4). This may opens a window of opportunity to reflect a relationship between mTOR inhibitors have been prevent or mitigate the often severe – infantile spasm onset and specific successfully used to treat multiple and disabling later neurologic 20 22 neurodevelopmental processes. ‍ ‍ TSC manifestations and –have shown manifestations of the disease, 23 Wu et al reported on 28 infants some efficacy as adjunctive28 31 treatment including epilepsy, developmental from this cohort enrolled in the of refractory epilepsy. ‍ ‍ Current delays, or other TSC-associated management guidelines determined Potential EEG Biomarkers and neuropsychiatric disorders. However, at an international consensus Antiepileptogenic Strategies for this window may be as small as a meeting do not recommend using Epilepsy in TSC study before epilepsy few months (Fig 3). Early findings of mTOR-inhibitor therapy in infants onset, finding that of the 19 infants 2 TSC in infants are often subtle and who are newly diagnosed with TSC. who developed epilepsy, 14 (74%) asymptomatic and may be missed if Small subgroup analyses have shown had EEG abnormalities seen before a child is not completely evaluated, that mTOR inhibitors are generally 16 the onset of clinical seizures. Early, 32,33 leading to delayed diagnosis. well tolerated in young children, ‍ prospective use of EEGs may enable but concerns remain that the use of risk stratification in studies of Epilepsy incidence in this cohort these drugs in young children may epilepsy prevention in infants with was 49% by 6 months, 73% by 12 adversely affect early development TSC. The antiepileptic medication months, and 80% by 24 months. TSC1 or cause other sequelae, especially if vigabatrin is particularly effective in 34,35 Boys, infants who presented 2,24 long-term treatment is needed. ‍ treating infantile spasms in TSC ‍ prenatally, and individuals with 25 Future studies are needed to gene variants had a lower epilepsy and has mTOR-inhibiting effects. determine the safety and efficacy of prevalence. Neuroimaging without Vigabatrin is currently in clinical mTOR inhibitors in this age group. tubers or cortical dysplasias had a trials to determine its efficacy at high negative predictive value for preventing epilepsy in patients with Neuroimaging findings of tubers, the development of epilepsy by age TSC (Preventing Epilepsy Using cortical dysplasias, or SENs were 36 months. However, neuroimaging Vigabatrin In Infants in the United highly prevalent in this cohort but in TSC may initially appear normal, States [NCT02849457] and Long- were often identified after initial with tubers or cortical dysplasias term, Prospective Study Evaluating presentation. The high prevalence of Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 140, number 6, December 2017 7

when compared with other9,18 large infants and parents and were able to demonstrates that we are capable population-based studies ‍ perform research genetic testing on of making an early diagnosis of TSC is likely due to the regression of a number of infants who did not have in many infants. Although many these tumors in older individuals clinical testing. The 30% inherited features of TSC do not appear until and is comparable to the youngest and 70% de novo rate in infants with– later in life, most infants with TSC can

patients in previous studies in both parents tested is consistent 38with42 be identified with an echocardiogram which researchers examined previously reported rates in TSC. ‍ for cardiac rhabdomyomas and a

TSC manifestations36,37 in pediatric Future studies of more detailed skin examination for hypomelanotic populations. ‍ Minor TSC genotype-phenotype relationships macules; both are noninvasive tests features other than renal cysts in infants with TSC are needed, and that do not require sedation. Early were infrequently found, and minor data from this study will contribute TSC diagnosis in infants opens a features did not contribute to the to those studies. window of opportunity to treat diagnosis of any infant. before the onset of epilepsy or other To date, this is the largest prospective neurodevelopmental disorders LC analysis identified 3 classes: the study of infants with TSC. Data were and allows for close surveillance largest, with multisystem organ collected in a standardized, rigorous for sequelae of TSC. Studies are involvement; the next largest, with manner, and study sites were queried TSC1 underway to treat infants with TSC a neuropredominant presentation for clarifications and to provide with the intention of preventing and no variants; and the missing data. Other limitations epilepsy, and future studies of smallest, with a milder presentation generally reflected the study design. disease-modifying therapies in TSC and fewer organ systems affected The onset dates of some features will also require early diagnosis. (Fig 5). This suggests that there were based on parental report Because of the many neuro may be identifiable subtypes of TSC and thus were susceptible to recall developmental comorbidities associated with specific patterns bias, inaccurate reporting, or were seen in TSC, findings gleaned from of organ system involvement and unknown. However, in most cases, early diagnosis, surveillance, and co-occurrence. Clinicians should onset dates were based on physical treatment of children with TSC be aware that early involvement examination findings or testing may also be applicable to other of multiple organ systems may reports. When dates of onset were 43 neurodevelopmental disorders. indicate a patient is at higher risk unknown, conservative replacements of seizures. Previous genotype- were used, making it more likely Acknowledgments phenotypeTSC2 studies found an overall that the true age was earlier than the more severe phenotype in patients estimated age of feature onset or TSC with variants but with a diagnosis. Because study enrollment We are indebted to the families and

high degree38 of variability across was restricted to infants, individuals patients in TSC clinics across the United individuals. Additional studies with milder or mosaic forms of States who contributed their time and are needed to investigate whether TSC (who typically present and are effort to this study. We also thank the groupings of TSC manifestations can diagnosed later in life) may not have Tuberous Sclerosis Alliance for its be mechanistically related to specific been included. Infants from urban continued support of TSC research. genetic variants and their effects areas closer to the 5 TSC center study The members of the TSC Autism on TSC protein function and if they sites were probably overrepresented Center of Excellence Research predict clinical or developmental in this cohort and more likely to come Network include the following: outcomes. to medical attention early. Thus, principal investigators were Sahin, TSC1 these infants probably represent 1 2 3 4 One limitation of this study is that M ; Krueger, D ; Bebin, M ; Wu, J ; TSC2 a best-case scenario in early TSC 5 genetic testing was limited to and Northrup, H . Co-investigators diagnosis, demonstrating the 1 1 and sequence and deletion were Warfield, S ; Peters, J ; Scherrer, opportunity for prompt recognition 1 3 or duplication testing. Twenty- B ; and Goyal, M . Project managers of signs of TSC with rapid follow-up 1 1 one patients did not have genetic were Filip-Dhima, R ; Dies, K ; and testing, leading to early diagnosis, 2 testing results available, and in Bruns, S . The neuropsychological surveillance, and treatment. many cases, 1 or both parents had assessment team included Hanson, Conclusions 1 1’ 2 2 not had testing for variants found E ; Walsh,3 A ; Bing, N 3; Kent, B ; in their child, possibly because of a Bucher,4 L ; O Kelley,5 S ; William,5 lack of parental availability or family M ; Pearson,6 D ; Mansour, R ; and inability to obtain or pay for testing. This prospective study of infants with Murray,1 D . Study coordinators1 were1 We attempted to obtain all available TSC recruited from 5 major medical Valle, M ; Gerhardt, R ; Carmody, E ; Downloaded from www.aappublications.org/news by guest on September 25, 2021 8 Davis et al

Davis et al https://doi.org/10.1542/peds.2016-4040 December 2017 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants 6 140 Pediatrics 2017 ROUGH GALLEY PROOF 2 3 3 Griffith, M ;4 Krefting, J ; 5 Ohio; University of Alabama at Institute of Child Health and Human Martinez, A ; and Salazar, E . From 4Birmingham, Birmingham, Alabama; Development, Rockville, Maryland. the Data 7Coordinating Center was University of California,5 Los Angeles, Abbreviations Cutter, G . From the Tuberous Los Angeles, California; University

Sclerosis8 Alliance were8 Roberds, of Texas Health Science Center6 at S and Nakagawa, JA . National Houston, Houston, Texas; Autism LC: latent class Institutes of Health project scientists Speaks, Boston, Massachusetts; 9 10 7 mTOR: mechanistic target of were Mamounas, L and Kau, A . University of Alabama at 1 rapamycin Others included Scherrer, B and Birmingham, Birmingham, Alabama; 4 8 NMI: no mutation identified Leuchter, A . Tuberous Sclerosis Alliance, Silver ’ 9 SEGA: subependymal giant cell Spring, Maryland; National Institute 1 ’ astrocytoma Boston Children s Hospital, Boston, 10of Neurological Disorders and 2 Eunice Kennedy Shriver SEN: subependymal nodule Massachusetts; Cincinnati Children s Stroke, Bethesda, Maryland; and TSC: tuberous sclerosis complex Hospital Medical Center, Cincinnati, National

conceptualized the study, is co-principal investigator of the multicenter prospective study that supplied the data for this study, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted. This trial has been registered at www.clinicaltrials.gov (identifiers NCT01780441 and NCT01767779). DOI: https://doi.org/10.1542/peds.2016-4040 Accepted for publication Aug 25, 2017 Address correspondence to Mustafa Sahin, MD, PhD, Department of Neurology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: mustafa. [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Bebin receives National Institutes of Health funding (U01NS082320, P20NS080199, and U01NS092595); Dr Wu receives research funding from the US Department of Defense and the Congressionally Directed Medical Research Program and the National Institutes of Health (P20NS080199, U01NS082320, R01NS082649, and U01NS092595); Dr Krueger has received research funding from the National Institutes of Health (U01NS082320 and U01NS092595); and Dr Sahin has received research funding from the National Institutes of Health (U01NS082320, U01NS092595, and U54HD090255) and the US Department of Defense (W81XWH-15-1-0189). Other than the items listed under Potential Conflicts of Interest, the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers U01NS082320 and P20NS080199, and by the Tuberous Sclerosis Alliance. Dr Davis is supported by the Neurology Resident Research Education Program of the National Institute of Neurological Disorders and Stroke (R25NS070682), the Boston Children’s Hospital Office of Faculty Development, and the Tuberous Sclerosis Alliance. Dr Wu is supported by the University of California, Los Angeles Clinical and Translational Research Center National Institutes of Health grant UL1TR0000124. Drs Au, Bebin, Wu, Krueger, and Sahin are supported by the Developmental Synaptopathies Consortium (U54NS092090), which is a part of the National Center for Advancing Translational Sciences Rare Diseases Clinical Research Network. The Rare Diseases Clinical Research Network is an initiative of the Office of Rare Diseases Research of the National Center for Advancing ranslationalT Sciences and is funded through collaboration between the National Center for Advancing Translational Sciences, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: Dr Bebin serves on the scientific advisory board for Novartis Pharmaceuticals Corporation and GW Pharmaceuticals and receives clinical research support from both. Dr Wu serves on the professional advisory board for the Tuberous Sclerosis Alliance, has received honoraria from and serves on the scientific advisory board and the speakers’ bureau for Novartis and H. Lundbeck A/S, and has received research support from the Tuberous Sclerosis Alliance, Novartis, and Today’s and Tomorrow’s Children Fund. Dr Sahin has received research funding from F. Hoffman-La Roche AG, Novartis, Pfizer, and LAM Therapeutics; has served on the scientific advisory board of Sage Therapeutics Inc. and PTEN Research Foundation; and serves on the professional advisory board of the Tuberous Sclerosis Alliance. Dr Krueger has received research funding from Novartis, the Clack Foundation Inc., and the Tuberous Sclerosis Alliance; has received consultant fees from Novartis; and serves on the professional advisory board of the Tuberous Sclerosis Alliance. The other authors have indicated they have no potential conflicts of interest to disclose.

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Davis et al https://doi.org/10.1542/peds.2016-4040 December 2017 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants 6 140 Pediatrics 2017 ROUGH GALLEY PROOF Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants Peter E. Davis, Rajna Filip-Dhima, Georgios Sideridis, Jurriaan M. Peters, Kit Sing Au, Hope Northrup, E. Martina Bebin, Joyce Y. Wu, Darcy Krueger, Mustafa Sahin and on behalf of the Tuberous Sclerosis Complex Autism Center of Excellence Research Network Pediatrics 2017;140; DOI: 10.1542/peds.2016-4040 originally published online November 3, 2017;

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants Peter E. Davis, Rajna Filip-Dhima, Georgios Sideridis, Jurriaan M. Peters, Kit Sing Au, Hope Northrup, E. Martina Bebin, Joyce Y. Wu, Darcy Krueger, Mustafa Sahin and on behalf of the Tuberous Sclerosis Complex Autism Center of Excellence Research Network Pediatrics 2017;140; DOI: 10.1542/peds.2016-4040 originally published online November 3, 2017;

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