August 2026 Research Update

Across a cohort study, a systematic review, and two case reports, fetal cardiac rhabdomyoma (a non-cancerous heart tumor) was the most common fetal heart tumor and was frequently linked with tuberous sclerosis complex (TSC). A consistent pattern was that having more than one tumor made TSC more likely, while short-term newborn risk was more closely tied to complications such as fluid build-up in the fetus, heart failure, tumor growth over time, early delivery, or abnormal heart rhythms. [1] [2] [3]

In a single-center, retrospective group of 81 fetuses with fetal heart tumors, rhabdomyoma made up most cases and about 7 in 10 rhabdomyoma cases were diagnosed with TSC. Multiple rhabdomyomas were much more likely to be tied to TSC than a single rhabdomyoma, and the largest tumor volume did not differ between TSC-related and isolated rhabdomyomas. [1]

The same cohort study found that adding a fetal brain MRI to ultrasound increased prenatal detection of TSC compared with ultrasound alone, likely because MRI can show brain changes linked to TSC. After birth, many rhabdomyomas regressed, and children with isolated rhabdomyoma had normal neurodevelopment in follow-up, while many children with TSC developed seizures and some had neurodevelopmental disorders. [1]

A systematic review of 859 reported fetal rhabdomyoma cases (drawn from previously published cases) found that newborn death was more likely when the fetus developed fluid build-up (hydrops), when tumors progressed, when fetal heart failure occurred, or when fetal growth restriction was present, with hydrops the strongest predictor. The review also found that about 73% of the 683 cases analyzed for this had TSC and that multiple tumors increased the likelihood of TSC. [2]

Two individual pregnancies illustrated how outcomes can differ depending on whether a tumor blocks blood flow. One newborn needed surgery soon after birth because a large left-sided tumor obstructed the mitral valve, and early follow-up showed no remaining mass, while the other newborn had no obstruction and the tumors shrank on their own with a favorable course; testing in that second case did not find TSC changes on targeted gene testing or brain MRI. [3]

For families facing fetal cardiac rhabdomyoma, these studies mainly help with understanding what tends to matter most when doctors discuss likely causes and near-term risks. The research suggests that multiple heart tumors raise the chance of TSC, and that serious pregnancy or heart complications (like fetal fluid build-up, heart failure, or rhythm problems) are more closely tied to the highest newborn risk than tumor size alone; at the same time, many tumors shrink after birth. Uncertainty remains because much of the larger evidence base comes from published case reports and because individual outcomes can vary widely, especially when a tumor affects blood flow or when TSC-related brain and developmental issues appear later. [1] [2] [3]

Together, these papers show that tuberous sclerosis complex (TSC) may be identified through visible skin changes plus organ imaging, but diagnosis can still be delayed into adulthood in some people. They also show that genetic testing of the TSC1 and TSC2 genes can confirm the cause in many people who already meet clear clinical features of TSC, while results are less often positive when the clinical picture is only possible TSC. Overall, the evidence here is based on small, exploratory studies and individual case reports, so patterns may not apply to everyone. [4] [5] [6]

One case report described a 26-year-old woman diagnosed with TSC after a dermatology exam noted multiple typical skin features, and imaging and eye exams showed kidney angiomyolipomas and retinal astrocytic hamartomas. This illustrates how skin signs can be a key entry point to recognizing TSC, even when the diagnosis is made later than expected. The report also noted that further brain evaluation was not completed and follow-up was lost, leaving unknowns about possible brain involvement in this person. [4]

In a Greek cohort study of 34 unrelated people evaluated for TSC, targeted next-generation sequencing identified 22 disease-causing or likely disease-causing variants across TSC1 (7 variants) and TSC2 (15 variants), including 7 variants not previously reported in that paper. The gene testing yield was higher in people with definite TSC than in those with possible TSC, suggesting that genetic confirmation is more likely when clinical features are clearer. The study also reported a trend toward more severe features in people with TSC2 variants, but the sample size limited how confidently this could be interpreted. [5]

A separate case report described a 2-month-old boy with a newly described frameshift change in exon 31 of TSC2, with infantile spasms and small growths along the brain ventricles seen on MRI, but no other organ involvement at the time reported. The same variant was found in an affected paternal aunt, and the father was considered an obligate carrier, highlighting how genetic results can also raise family inheritance questions. The authors noted that changes in this exon, once thought less important because of alternative splicing, may still be linked to severe disease in some individuals. [6]

For patients and caregivers, these studies mainly add background on how TSC may be detected and confirmed: visible skin signs and targeted imaging can point to TSC, while gene testing often identifies a TSC1 or TSC2 cause in people with definite clinical TSC and less often when signs are incomplete. The case reports show that both late recognition (in an adult) and early recognition (in an infant) can happen, and that some gene changes may run in families. What remains uncertain is how broadly these patterns apply, because the genetic cohort was small and the other evidence comes from single patients.

In this study of children with tuberous sclerosis complex (TSC), epilepsy surgery choices often involved weighing the benefits and limits of operating, and sometimes operating again, over time. The overall pattern was that seizure control can improve after an intervention, but seizures may return because seizure activity can come from more than one brain area or change as a child grows. [7]

In a retrospective chart review of 62 children with TSC who had 120 epilepsy surgeries, seizure freedom from the targeted seizure spot was reported in 76% after one surgery and 66% after two or more surgeries. When looking at seizure freedom from all seizure spots, it was 69% after one surgery and 55% after two or more surgeries. [7]

When seizures returned, they most often came from a previously targeted spot (57%), but nearly one-third were linked to a new spot that became clear after the first surgery (29%). The study also reported that seizure-freedom rates for the targeted spot were lower after the third through fifth surgeries, suggesting diminishing returns for some children as more procedures are needed. [7]

The same study reported that earlier surgery was linked with higher seizure-freedom rates, and that abnormal electrical activity between seizures on an electroencephalogram (EEG) before surgery had modest ability to predict an eventual seizure spot (75% sensitivity). This helps explain why deciding what to treat, and when, can be complex in TSC epilepsy. [7]

For families considering epilepsy surgery in TSC, these results mainly provide context for what has been seen in one center's past experience: surgery may bring seizure freedom for some children, but seizures can return from areas already treated or from different areas that emerge later. What remains uncertain is how well these numbers apply to any one child, and how choices about timing, evaluation, and repeat procedures should be personalized in different hospitals and care teams. [7]

Across studies focused on babies and young infants, seizure care choices centered on early detection (EEG monitoring and brain scans), selecting an initial treatment, and planning for what to do if seizures return. The evidence here is mostly observational (a survey, retrospective studies, and a single-patient report), so it can describe patterns seen in real-world care but cannot prove what causes better outcomes. [8] [9] [10] [11]

A US survey of 33 tertiary pediatric hospitals reported common agreement on inpatient evaluation for new-onset infantile epileptic spasms syndrome (IESS), frequent use of overnight video-EEG, and routine use of brain MRI and genetic testing at diagnosis. However, centers differed in which genetic tests they order, which medicines or diets they use after first treatments fail, and how quickly they consider epilepsy surgery. [8]

In a retrospective cohort of 164 infants who responded to vigabatrin for IESS, 38% later relapsed, with relapse occurring at a median of 7.5 months after response. In this dataset, a moderate vigabatrin dose range (100-149 mg/kg/day) was linked to lower relapse risk than lower dosing, while earlier relapse history, other seizure types at the start, and abnormal development at diagnosis were linked to higher relapse risk. [9]

A small single-center case series of six infants diagnosed with TSC before or soon after birth reported neonatal seizures in four of six (67%). All four infants with neonatal seizures had TSC2 and higher-risk brain MRI patterns, and they developed drug-resistant epilepsy, with some later developing infantile spasms despite early treatment. [10]

One case report described a single newborn with genetically confirmed TSC and hard-to-control seizures who received early everolimus, with seizure control reported within one week and continued seizure freedom for more than one year, alongside mild intermittent diarrhea and no serious safety concerns reported. Because this is one patient, it cannot show how often this outcome happens or how it compares with other approaches. [11]

In lab research using a mouse model of TSC-related epilepsy, a brain protein involved in controlling nerve signaling (KCC2) was reduced even before seizures started. In these mice, rapamycin and selective KCC2-modulating compounds restored KCC2 levels and reduced seizures, suggesting a possible future research direction rather than a proven treatment for people today. [12]

For patients and caregivers, these studies mainly help set expectations about early-life epilepsy care: many centers use intensive early testing, relapse can happen after an initial response, and some infants with TSC (especially in small reports with TSC2 and higher-risk MRI patterns) had more severe seizure courses. What remains uncertain includes which monitoring and treatment choices are best for specific children, because several results come from retrospective data, a survey of practice patterns, animal research, or a single case report rather than head-to-head trials. [8] [9] [10] [11] [12]

Across these papers, autism-related differences in tuberous sclerosis complex (TSC) were most consistently connected to epilepsy (especially infantile spasms) and to how brain lesions are distributed and connected in the brain, rather than to a single simple marker. In adults with TSC and mild intellectual disability or better, a randomized trial testing everolimus for thinking and memory skills found many people improved on at least one test in both the everolimus and placebo groups, and side effects were reported more often with everolimus. [13] [14] [15]

In a longitudinal cohort followed from diagnosis to about 10 years later, around 40% of children with TSC met criteria for autism and another 42% had elevated autistic traits. The study modeled indirect pathways suggesting that TSC gene changes related to autism through cortical tuber burden together with infantile spasms, and also through infantile spasms alone; higher autism scores were also linked to more severe seizures and lower IQ. [13]

An imaging-based lesion network mapping study suggested that where tubers sit and how they are connected to typical brain networks may matter for specific autism symptom areas. Tubers functionally connected to a region in the right cerebellum (Crus V) were linked to greater social communication difficulties, while no similar link was seen for overall autism severity scores or for restricted and repetitive behaviors. This was an observational, exploratory analysis and cannot prove cause and effect. [14]

In a multicentre randomized controlled trial in people ages 16 to 60 with TSC (IQ over 60) who had low scores on at least one memory or executive-function test, 87% of those who completed assessments on everolimus met the study's definition of a responder (at least a 1 standard deviation improvement in one measure), compared with 75% on placebo. Side effects were more frequent in the everolimus group (22/25) than placebo (8/13), and the authors noted that high responder rates in both groups could reflect practice effects or how response was defined. [15]

One mouse study developed a learning task to separate learning, memory storage, and later recall, and found that the balance between threat cues and safety cues can shift behavior toward either clear discrimination or overgeneralization. In a Tsc2 haploinsufficient mouse model focused on oxytocin-responsive cells, male mice learned the task but showed persistent generalization that did not improve with more training, and the study connected these effects to oxytocin receptor-expressing cells in the medial prefrontal cortex and mTORC1-related protein production signaling. Because this is animal research, it mainly informs possible mechanisms rather than directly predicting day-to-day outcomes in people. [16]

For patients and caregivers, this set of studies mainly adds context about why autism and learning differences are common in TSC and why experiences can vary between individuals. The child studies point toward epilepsy history (including infantile spasms) and brain lesion burden or connectivity as factors linked to autism traits, while the adult trial shows that short-term changes on thinking and memory tests can occur even with placebo and that side effects were reported more often with everolimus. Important uncertainties remain, including how well imaging-network results translate into practical supports, and whether test-score changes over 24 weeks reflect lasting, everyday functional improvements. [13] [14] [15] [16]

Across these papers, most clinical evidence focused on mTOR-targeting medicines for tuberous sclerosis complex (TSC) problems affecting the kidneys and lungs. In an adult cohort, everolimus reduced the size of kidney angiomyolipomas, while a long-term single-patient report described lung improvement on sirolimus and worsening after stopping it. Separate case and lab-style studies added detail on uncommon skin and eye changes that may also relate to mTOR pathway biology, and on an acute muscle problem in one person with TSC. [17] [18] [19] [20] [21]

For TSC-related kidney angiomyolipomas, a multicenter prospective Chinese cohort of adults reported that everolimus was linked to meaningful tumor shrinkage over months, and tumors described as "fat-poor" on CT scans shrank more than "fat-rich" tumors. The study also observed that tumor size tended to rebound toward baseline after everolimus was discontinued, suggesting the effect may not persist once the medicine is stopped. Because the dose comparison was not randomized and follow-up was short, it remains uncertain how well lower dosing performs over longer periods. [17]

For TSC-associated lymphangioleiomyomatosis (a lung condition), one case report with 17 years of follow-up described rapid breathing improvement soon after starting sirolimus and only slight lung function decline during years of maintenance therapy. The same report described a period of abrupt stopping that was followed by rapid worsening and a collapsed lung, with only partial recovery after restarting sirolimus. As a single-patient report, it cannot show how often this pattern occurs in others. [18]

Two other single-patient reports highlighted less common issues that may come up in TSC care. One person with TSC and lung lymphangioleiomyomatosis developed an acute toxic or inflammatory muscle problem while taking atorvastatin (a cholesterol medicine, later stopped) and shortly after stopping everolimus, that caused severe voice box weakness and swallowing difficulty, then fully recovered within about a month as muscle enzyme levels fell. Another described a retinal astrocytic hamartoma with unusual whitening of retinal arteries (but not veins), proposed to reflect artery-specific vascular remodeling tied to an mTOR-pathway gene change (TSC2). [19] [21]

In skin-related tissue research, an analysis of fibrous papules (including TSC-associated lesions) found overexpression of MITF and related signals across different subtypes, suggesting a shared cellular feature and a possible connection to mTOR pathway activity. This type of work is mainly biological background and does not by itself show changes in symptoms or outcomes. [20]

For patients and caregivers, this group of studies mainly adds context about how mTOR-targeting medicines relate to kidney angiomyolipoma size and severe lung lymphangioleiomyomatosis over time, including the possibility of tumor or symptom rebound after stopping in the reports presented. It also documents uncommon but important-looking events in people with TSC (sudden swallowing/voice problems from an acute muscle condition, and an unusual eye blood-vessel change) without showing how common they are; the muscle condition was described as toxic or inflammatory and was not shown to be caused by TSC. Many details here come from observational data or single-patient reports, so questions remain about how well the results apply to different ages, disease severities, and long-term treatment strategies.

Across these papers, researchers mapped several ways that turning down TSC1 or TSC2 can switch on the cell-growth pathway controlled by mTOR, even in conditions that are not tuberous sclerosis complex. The overall picture is that different tissues may reach a similar mTOR overactivity state through different upstream problems, and most evidence so far comes from lab, animal, and translational studies rather than clinical trials. [22] [23] [24]

In chronic kidney disease tissue samples and multiple mouse models of kidney scarring, higher levels of a protein called USP7 tracked with worse fibrosis, and lowering USP7 activity reduced signs of scarring. The study linked this to USP7 stabilizing another protein (KDM5B) that turns down TSC1 gene activity, which then increased mTOR signaling in kidney fibroblast cells. [22]

In a mouse model where Tsc1 was removed only in the liver, loss of Tsc1 increased mTOR signaling and also increased movement of TFEB into the cell nucleus, alongside liver cell changes that resembled higher-grade liver cancer. Removing TFEB in these mice reduced tumor progression, and human liver cancer datasets showed higher TFEB activity alongside gene programs linked to more aggressive disease. [23]

In small human disc tissue samples and a rat disc degeneration model, impaired cellular cleanup through chaperone-mediated autophagy led to buildup of MIDN, which helped break down TSC2 and increased mTORC1 signaling. Activating this cleanup process, lowering MIDN, or using rapamycin in the model reduced cell aging signals and tissue breakdown measures linked to disc degeneration. [24]

Two additional studies focused on tools that can help study TSC biology rather than testing a treatment idea. One created a set of matched human stem cell lines (including tuberous sclerosis complex) so that future work can compare how specific gene changes affect brain development in a controlled way. [25]

Another developed a 3D lab platform that can measure very small pulling forces made by developing nerve cells, and demonstrated it in cells with and without a TSC2 mutation. This type of measurement could be used in future experiments to explore how TSC2 changes might affect cell behavior in 3D environments. [26]

For people living with tuberous sclerosis complex, these papers mainly add background about how the TSC1/TSC2-mTOR pathway can be altered in different organs (kidney, liver, and spinal discs) and by different upstream triggers. Because the key results come from lab and animal models, it is still uncertain how directly these mechanisms apply to individual patients, and whether any of the specific targets discussed will matter in day-to-day care.