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Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
The MAP kinase pathway is important for many LGAs. It is the driver in tumors in neurofibromatosis type 1 (NF1), where loss of neurofibromin, a negative regulator of the RAS pathway, leads to constitutive activation. LGA arising in NF1 often behave in a more indolent manner and respond better to chemotherapy than sporadic tumors.197
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
Type 1 (neurofibromatosis 1 [NF1], von Recklinghausen's disease) is a relatively common (1 in 3,000) autosomal dominant disease characterized by cutaneous café-au-lait pigmentation and neurofibromas. NF1 is due to mutations in neurofibromin 1, a tumour-suppressor gene. In the central form of the disease (NF2) tumours are common, the most characteristic being bilateral schwannomas of cranial nerve VIII and tumours of the spinal nerve roots. NF2 is due to mutation of the merlin gene, also a tumour-suppressor gene.
Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
This condition affects 1 in 2,000 to 3,000 with up to half arising de novo as new mutations. There is no evidence that particular families with neurofibromatosis are free from serious effects although particular individuals can be more or less severely affected, and some mutations are generally more severe in their effects than others. Most surveys have shown that around one-third of affected individuals have one or more serious medical problems at some stage in life (including benign CNS tumours or extra-CNS malignancies that require active treatment, serious orthopaedic complications, epilepsy, moderate or severe learning disability), while two-thirds are mildly affected; about one-half have mild learning difficulties. The NF1 gene produces an important protein (neurofibromin) regulating cell division and differentiation. A wide variety of different mutations can occur in this large gene, but the clinical utility of molecular confirmation is limited unless there is persistent doubt about the diagnosis, which in practice is usually made on clinical grounds. Molecular diagnosis is likely to become more important as rational treatments are developed.
The importance of suicide risk assessment in patients affected by neurofibromatosis
Published in International Journal of Psychiatry in Clinical Practice, 2021
Isabella Berardelli, Annalisa Maraone, Daniele Belvisi, Massimo Pasquini, Sandra Giustini, Emanuele Miraglia, Chiara Iacovino, Maurizio Pompili, Marianna Frascarelli, Giovanni Fabbrini
Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder due to mutations in the neurofibromatosis type 1 (NF1) gene and the abnormal function of neurofibromin (Bergoug et al. 2020). NF1 is a chronic disorder with variable clinical presentation, and may include neurological, cardiovascular and dermatological features, including disfiguring cutaneous tumours, as well as other medical features (Gutmann et al. 2017). NF1 patients may also complain of psychiatric disorders, including depressive and anxiety symptoms, higher levels of perceived stress and lower levels of self-esteem (Zöller and Rembeck 1999; Wolkenstein et al. 2001; Kessler et al. 2003; Wang et al. 2012; Merker et al. 2014). Some authors have also reported a poorer quality of life when compared with the general population (Page et al. 2006; Kodra et al. 2009; Cohen et al. 2015).
An evaluation of selumetinib for the treatment of neurofibromatosis type 1-associated symptomatic, inoperable plexiform neurofibromas
Published in Expert Review of Precision Medicine and Drug Development, 2021
Laura K. Metrock, Mina Lobbous, Bruce Korf
Neurofibromatosis is a common genetic predisposition syndrome caused by alterations in the NF1 gene, leading to decreased functional neurofibromin. Because neurofibromin is a negative regulator of the RAS proto-oncogene, its inactivation results in increased activation of RAS and RAS downstream pathways including the MEK-ERK pathway and the PI3K-Akt-mTOR pathway. Drugs targeting these pathways have been tried in an attempt to stop or reverse the growth of NF1-related tumors. The most effective treatment to date was found in the phase 1 and phase 2 trials of the MEK inhibitor selumetinib. Extensive research has been undertaken to understand the pharmacokinetics and pharmacodynamics of the drug. A side effect profile has been established, with the most common side effects being creatinine kinase elevation, gastrointestinal side effects, and rash. In the phase 1 and 2 studies of selumetinib in patients of age 2–18 years with NF1-associated symptomatic, inoperable PNs, approximately 70% of patients achieved a partial response in both studies. Furthermore, the response appears to be clinically meaningful as improvement was seen in functional outcomes of strength and range of motion, pain-intensity scores, child-reported, and parent-reported interference of pain in daily functioning and health-related quality of life.
Precision medicine for pediatric central nervous system tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Daniel C. Moreira, Amar Gajjar
Pilocytic astrocytomas are common low-grade gliomas (LGGs) in children and alterations of the MAP kinase pathway is the driving oncogenic stimulus [3]. Inhibition of this pathway with dabrafenib and vemurafenib was demonstrated to be efficacious in clinical trials for patients with the BRAF V600E mutation, while selumetinib and trametinib is efficacious for patients with BRAF fusions. Collaborative trials to provide additional data on the efficacy of targeted therapies for LGGs are ongoing, including testing new agents and drug combinations that inhibit the pathway at different levels. In addition to their use for treating LGGs, MEK inhibitors are beneficial for patients with neurofibromatosis type 1 and plexiform neurofibroma. The lack of functional neurofibromin, a negative regulator of RAS activity, in neurofibromatosis type 1 leads to dysregulation of the RAS pathway and tumorigenesis. In this context, selumetinib is promising for children with inoperable plexiform neurofibroma [4].