BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.
METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.
RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).
CONCLUSIONS: Sirolimus\'s long-term administration is not associated with adverse effects on children\'s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration.
BACKGROUND: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

UNASSIGNED: Tuberous sclerosis complex is a genetic neurocutaneous autosomal dominant syndrome, characterized by the development of multiple benign tumors (hamartomas) affecting various systems. Heart-benign tumors that result from the complex are called cardiac rhabdomyomas. Unlike hamartomas that occur in other organs, cardiac rhabdomyomas are most prevalent in infants and very young children with tuberous sclerosis complex. We present a case of a young adult with tuberous sclerosis who had an unusually late diagnosis of cardiac rhabdomyomas.
UNASSIGNED: A 22-year-old male patient of Afro-descendant, diagnosed with tuberous sclerosis complex in childhood, presented with refractory epilepsy and was treated only with lacosamide. The patient came to medical consultation due to a recent history of episodic, persistent chest pain in the sternal region, associated with physical effort. Echocardiography revealed a non-dilated left ventricle, with several rounded masses of high echogenicity without pedicles at the apical level, the largest measuring 14 × 11 mm, consistent with cardiac rhabdomyomas.
UNASSIGNED: Cardiac rhabdomyomas rarely develop in adulthood for individuals with tuberous sclerosis. These late-onset cases can exhibit various symptoms, from simple to complex presentations. Regular clinical checkups are essential for adults with tuberous sclerosis complex.

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus.

BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes.
METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery.
RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP.
CONCLUSIONS: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

OBJECTIVE: Historically, epilepsy has been the most frequently presenting feature of tuberous sclerosis complex (TSC). Advances in TSC health care have occurred over the past decade; thus, we studied whether TSC epilepsy outcomes have changed.
METHODS: A retrospective chart review was undertaken for all children with TSC in Queensland, Australia. Epilepsy outcome and TSC diagnosis data were extracted, and data were compared between children born before 2012 with those born in or after 2012.
RESULTS: In this retrospective cohort, TSC diagnosis in children born in or after 2012 is now predominantly antenatal (51%, p < .05). Most patients with epilepsy are now known to have TSC before they develop epilepsy. Despite earlier TSC diagnosis, the frequency of epilepsy (85%) has not changed (p = .92), but diagnosis trends toward an earlier age (median = 3 months for patients born in or after 2012 vs. 5.5 months for those born before 2012, p = .23). Most (95%) patients had focal seizures as their initial clinical seizure type; it was rare (5%) for epileptic spasms (ES) to be the initial seizure type. The frequency of ES was lower in patients born in or after 2012 (36% vs. 50%, p = .27). Infantile (<24 months) onset ES was not associated with worse epilepsy outcome. Late onset ES was seen in 14%, and these patients had a lower rate of epilepsy remission. Lennox-Gastaut syndrome was seen in 7%. Febrile/illness-related status epilepticus occurred in 12% of patients, between 1 and 4 years of age. Despite many (78%) patients having multiple daily seizures at maximal seizure frequency, and 74% meeting criteria for treatment-refractory epilepsy, most patients achieved epilepsy remission (66%), either with epilepsy surgery (47%) or with age (53%). At the time of inclusion in this study, only 21% of patients had uncontrolled frequent (daily to 3 monthly) seizures and 14% had uncontrolled infrequent (3 monthly to <2 yearly) seizures.
CONCLUSIONS: This study provides updated information that informs the counseling of parents of newly diagnosed pediatric TSC patients.

Angiofibromas are a common facial manifestation of tuberous sclerosis (TS). However, current treatments have proven ineffective due to high recurrence rates and noncompliance. To address this issue, we developed a new triple laser therapy protocol for more effective management of angiofibromas. We conducted tests to validate its efficacy. This is a prospective study of 10 patients with TS (4 women and 6 men, mean age 26.3 years [15-37 years]) with angiofibromata who received triple sequential laser therapy at our private dermatological clinic conducted from January 2000 to December 2022. We evaluated the outcome with the Facial Angiofibromata Severity Index (FASI) via clinical photography (0, 6 months, 1 year, and 2 years), and Dermatology Life Quality Index (DLQI). All patients had a successful recovery without any complications. Among these 10 patients, 4 experienced localized recurrences at their 6-month follow-up. These recurrences were treated with a second single carbon dioxide laser session. After 2 years of follow-up, we observed no recurring facial cutaneous manifestations. Furthermore, all patients experienced a decrease in their FASI score after treatment. According to the Visual Analogue Scale, patients reported 95% satisfaction, and DLQI indicated only a minor impact on their everyday lives. We believe that this protocol of three-step laser treatment is effective, safe, and compliable for patients with facial angiofibromata, providing a satisfactory outcome adaptable to the daily dermatological and plastic surgery practice.

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BACKGROUND: Subependymal giant cell astrocytoma is a benign brain tumor that occurs in patients with tuberous sclerosis complex. Surgical removal is the traditional treatment, and expert opinion is strongly against the use of radiotherapy. Recently, success has been reported with the mTor inhibitor everolimus in reducing tumor volume, but regrowth has been observed after dose reduction or cessation.
METHODS: We present the case of a 40-year-old Asian female patient treated successfully for growing bilateral subependymal giant cell astrocytoma with fractionated stereotactic radiotherapy before everolimus became available. After a follow-up of 8 years, everolimus was administered for renal angiomyolipoma and the patient was followed up until 13 years after radiotherapy. Successive magnetic resonance imaging demonstrated an 80% volume reduction after radiotherapy that increased to 90% with everolimus. A review of the literature was done leveraging Medline via PubMed, and we assembled a database of 1298 article references and 780 full-text articles in search of evidence for contraindicating radiotherapy in subependymal giant cell astrocytoma. Varying results of single-fraction radiosurgery were described in a total of 13 cases. Only in two published cases was the radiation dose of fractionated radiotherapy mentioned. One single publication mentions an induced secondary brain tumor 8 years after whole-brain radiotherapy.
CONCLUSIONS: There is no evidence of contraindication and exclusion of fractionated radiotherapy in treating subependymal giant cell astrocytoma. Our experience demonstrates that subependymal giant cell astrocytoma, as other benign intracranial tumors, responds slowly but progressively to radiotherapy and suggests that fractionated stereotactic radiotherapy holds promise to consolidate responses obtained with mTor inhibitors avoiding regrowth after cessation.

UNASSIGNED: Perivascular epithelioid cell tumors (PEComa) are rare tumors of mesenchymal origin that exhibit perivascular epithelioid cell phenotype. One of its most common localizations is uterus, whereas only a few studies reported PEComa localization as liver. There is a correlation between the presence of PEComa and tuberous sclerosis complex (TSC). TSC is a rare disease which leads to the development of mostly non-cancerous tumors in various organs. We would like to present a case of a kidney transplant recipient with a PEComa detected post-transplant in the liver.
UNASSIGNED: A 27-year-old patient, 3 years after kidney transplantation (KTx) due to chronic renal failure in the course of autosomal dominant polycystic kidney disease and concomitant TSC, was admitted to the Clinic and Department of General and Transplant Surgery for abnormal findings in computed tomography (CT). A CT scan was conducted for oncological follow-up after a kidney transplant (KTx) because before the transplantation, a small cystic lesion measuring 7 mm in diameter was removed from the donor kidney and diagnosed as papillary renal cell carcinoma (PRCC). Two tumors in the liver were detected - one 27mm in diameter in segment VII/VIII and the other 8mm in diameter in segment II/III. Because of typical radiological signs hepatocellular carcinoma was suspected, but the serum level of alpha fetoprotein was within normal limits and liver function was preserved. The intraoperative biopsy and the radiofrequency ablation (RFA) of the larger tumor were performed three months later. In the histopathological examination benign PEComa (HMB45 +, Melan A +) was detected.
UNASSIGNED: The oncological surveillance made it possible to detect liver lesion in early stage and in 3,5-year follow-up no sign of recurrence of PEComa was found. This case is the second to show RFA as treatment method of liver PEComa and first in kidney transplant recipient.

Cytomegalic neurons, characterized by increased size and a hyperactive mechanistic target of rapamycin complex 1 (mTORC1), are pathognomonic for tuberous sclerosis complex (TSC). To model these neurons, we recently generated a murine Tsc1 conditional knockout model in which Tsc1 deletion in late embryonic radial glia results in neuronal hypertrophy of a subset of isocortical pyramidal neurons. In the current study, we compared the cellular pathology of these cytomegalic neurons to those of the enlarged neurons in human cortical tubers. Neurons from the mice showed unique features, such as cytoplasmic vacuoles associated with Golgi complexes and the ectopic formation of perineuronal nets (PNNs), a feature of inhibitory neurons, rarely present in excitatory cortical neurons. The membranes of these vacuoles were enriched for the plasma membrane proteins CD44, KCC2, and Na+/K+ ATPase, suggesting deficits in Golgi membrane trafficking. These aberrant features in the mouse appeared only after the onset of seizures, probably due to the prolonged seizure activity in the context of constitutive mTORC1 activation. Similar PNNs and cytoplasmic vacuoles were present in the cytomegalic neurons of human cortical tubers. Our findings reveal novel pathological features of Golgi complexes and PNNs in the cytomegalic neurons in TSC.