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Child's Nervous System
Erschienen in: Child's Nervous System 10/2020

29.06.2020 | Annual issue paper

Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism

verfasst von: Eric Legius, Hilde Brems

Erschienen in: Child's Nervous System | Ausgabe 10/2020

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Abstract

Introduction

Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant disorder characterised by café-au-lait maculae (CALM), skinfold freckling, iris Lisch nodules and benign peripheral nerve sheath tumours (neurofibromas).

Mechanism

The NF1 gene is a tumour suppressor gene and NF1 individuals have an increased risk for a long list of tumours, all resulting from a second hit in the normal copy of the NF1 gene. Remarkably, some non-tumour phenotypes such as CALM and pseudarthrosis are also caused by a “second hit”. Germline mutations inactivating the NF1 gene show a large variability in genetic mechanisms ranging from single-nucleotide substitutions and somatic mosaicism to large deletions affecting neighbouring genes. Molecular confirmation of the clinical diagnosis is becoming increasingly more important to differentiate NF1 from other syndromes such as Legius syndrome, to investigate genotype-phenotype correlations relevant in 10% of cases and to detect somatic mosaicism.

Surveillance and therapy

Some degree of learning difficulties, attention deficit and social problems are observed in most children and affect quality of life. There is a large individual variability in complications and the evolution of the disease is difficult to predict. Specialised outpatient clinics for children have been widely established and are important for surveillance and guidance. Regular surveillance is also important for adolescents and adults because many tumour complications can be detected by whole-body MRI and treated even before symptoms develop and irreversible damage occurs. Recent data on nodular plexiform neurofibromas with continued growth in adolescents and young adults show that many of these tumours are premalignant lesions called atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Specific surveillance and timely local resection of these benign peripheral nerve sheath tumours might be important to prevent malignant degeneration. In the last years, targeted therapy with MEK inhibitors has shown promise to treat unresectable and symptomatic plexiform neurofibromas. Many more challenges remain to find the best way to monitor children and adults for potential complications and to find a satisfying cure for many complications in this disorder.
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Metadaten
Titel
Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism
verfasst von
Eric Legius
Hilde Brems
Publikationsdatum
29.06.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
Child's Nervous System / Ausgabe 10/2020
Print ISSN: 0256-7040
Elektronische ISSN: 1433-0350
DOI
https://doi.org/10.1007/s00381-020-04771-8

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