Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience

Krueger, Darcy A.; Capal, Jamie K.; Curatolo, Paolo; Devinsky, Orrin; Ess, Kevin C.; Tzadok, Michal; Koenig, Mary Kay; Narayanan, Vinodh; Ramos, Federico; Jóźwiak, Sergiusz; Vries, Petrus de; Jansen, Anna; Wong, Michael; Mowat, David; Lawson, John A.; Bruns, Stephanie; Franz, David Neal

doi:10.1016/j.ejpn.2018.06.007

Cited by 60 publications

(45 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“… Its role in human fetal growth is not well established, but intrauterine growth restriction has been described in mouse models . mTOR inhibitors are generally well tolerated in young children especially if long‐term treatment is not needed . One study of 18 children specifically evaluated the growth of children on everolimus until age 3, and except for in one child, there was no negative impact of everolimus on growth rate .…”

Section: Discussionmentioning

confidence: 99%

“…34 mTOR inhibitors are generally well tolerated in young children especially if long-term treatment is not needed. 35 One study of 18 children specifically evaluated the growth of children on everolimus until age 3, and except for in one child, there was no negative impact of everolimus on growth rate. 36 Our proband was treated for 8 weeks of gestation and postnatally has shown appropriate height and head circumference velocities; though weight gain has been slower.…”

Section: Growth Restrictionmentioning

confidence: 99%

See 1 more Smart Citation

Fetal cardiac rhabdomyomas treated with maternal sirolimus

Pluym

Sklansky

et al. 2020

Prenatal Diagnosis

View full text Add to dashboard Cite

Objective To review the pathophysiology of rhabdomyomas and the emerging option of prenatal treatment of fetal cardiac rhabdomyomas. Methods We present a case of fetal rhabdomyomas causing significant hemodynamic compromise that received in utero treatment of maternal sirolimus. Genetic amniocentesis confirmed a TSC2 mutation. A treatment program was initiated with a 10‐mg loading dose titrated to a goal maternal trough of 10 to 15 ng/dL. In order to follow fetal cardiac function, a sophisticated method of speckle tracking echocardiography was used before and after treatment. Obstetric ultrasound was used to monitor fetal growth, and clinical surveillance, echocardiography, and brain MRI were used to monitor postnatal growth and development through 6 months of neonatal life. Results Sirolimus was initiated from 28 to 36 weeks of gestation with improvement of cardiac status. During this period, intrauterine growth restriction developed. Postnatally, the infant has had stable rhabdomyomas and cardiac function without reinitiating sirolimus. Brain MRI demonstrated scattered cortical tubers and subependymal nodules, and the infant has not had seizure‐like activity. At 6 months of age, the infant has achieved appropriate developmental milestones. Conclusion In counseling cases of prenatal onset large obstructing rhabdomyomas and cardiac compromise, in utero sirolimus treatment can be considered.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Growth Restrictionmentioning

confidence: 99%

Fetal cardiac rhabdomyomas treated with maternal sirolimus

Pluym

Sklansky

et al. 2020

Prenatal Diagnosis

View full text Add to dashboard Cite

show abstract

“…As such, regardless of the particular feature of the disease that leads to their initiation, therapeutic effects can be expected for multiple aspects of the patient's condition. In fact administering a larger dose of everolimus intermittently, for example weekly or every other day, can be just as effective and better tolerated then daily dosing (Krueger et al, 2018). This is of course not the case for treatment with other modalities for example, resective surgery, traditional anticonvulsants, or other symptomatic treatments.…”

Section: Treating the Patientmentioning

confidence: 99%

“…This means that there is not an immediate loss of efficacy when the drugs are stopped or held. In fact administering a larger dose of everolimus intermittently, for example weekly or every other day, can be just as effective and better tolerated then daily dosing (Krueger et al, 2018). This is particularly useful when treating epilepsy, as abruptly stopping traditional anticonvulsants frequently results in recurrent seizures or status epilepticus.…”

Section: Treating the Patientmentioning

confidence: 99%

mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex

Franz

Krueger

2018

American J of Med Genetics Pt C

Self Cite

View full text Add to dashboard Cite

Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.

show abstract

“…Clinical trials and scientific evidence support the use of sirolimus in TSC patients with specific manifestations, including SEGA and skin lesions [2][3][4]. Darcy AK et al conducted a multicenter clinical investigation on the safety of mTOR inhibitors in TSC patients before the age of 2 years [11]. Sirolimus has been used to treat fetus with TSC and presenting cardiac rhabdomyoma [12].…”

Section: Discussionmentioning

confidence: 99%

Juvenile xanthogranuloma as a new type of skin lesions in tuberous sclerosis complex

Lü

Shi

Wang

et al. 2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

Objective: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions. Methods: A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples. Results: The patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC. Conclusion: This is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment.

show abstract

Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience

Cited by 60 publications

References 52 publications

Fetal cardiac rhabdomyomas treated with maternal sirolimus

Fetal cardiac rhabdomyomas treated with maternal sirolimus

mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex

Juvenile xanthogranuloma as a new type of skin lesions in tuberous sclerosis complex

Contact Info

Product

Resources

About