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Human Genomics Oct 2011Somatic gene mutations constitute key events in the malignant transformation of human cells. Somatic mutation can either actively speed up the growth of tumour cells or... (Review)
Review
Somatic gene mutations constitute key events in the malignant transformation of human cells. Somatic mutation can either actively speed up the growth of tumour cells or relax the growth constraints normally imposed upon them, thereby conferring a selective (proliferative) advantage at the cellular level. Neurofibromatosis type-1 (NF1) affects 1/3,000-4,000 individuals worldwide and is caused by the inactivation of the NF1 tumour suppressor gene, which encodes the protein neurofibromin. Consistent with Knudson's two-hit hypothesis, NF1 patients harbouring a heterozygous germline NF1 mutation develop neurofibromas upon somatic mutation of the second, wild-type, NF1 allele. While the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, the classification of NF1 somatic mutations is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, the known somatic mutational spectrum for the NF1 gene in a range of NF1-associated neoplasms - including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, astrocytomas and phaeochromocytomas - have been collated and analysed.
Topics: Genes, Neurofibromatosis 1; Humans; Mutation; Neurofibromatosis 1
PubMed: 22155606
DOI: 10.1186/1479-7364-5-6-623 -
Frontiers in Endocrinology 2023Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which... (Review)
Review
CONTEXT
Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures. To prevent the personal and financial burden of this disabling fatigue, it is crucial to know the causes.
OBJECTIVE
To explore somatic causes and provide practical recommendations for the approach to fatigue in adults with NF1.
DESIGN
Cross-sectional. All adults with NF1 (N = 133) who visited our Endocrinology department underwent a systematic health screening, including a medical questionnaire, structured interview, complete physical examination, biochemical measurements and additional tests if indicated.
MAIN OUTCOME MEASURE
Prevalence of endocrine and non-endocrine health problems between NF1 adults with and without fatigue.
RESULTS
In our cohort, 75% of NF1 adults experienced fatigue. The most frequent endocrine disorders were vitamin D deficiency (28%), obesity (18%) and hypothyroidism (8%). The most frequent non-endocrine internal disorder was high blood pressure (42%). None of the disorders differed significantly between adults with and without fatigue.
CONCLUSIONS
Endocrine and non-endocrine disorders were equally present in our cohort of NF1 adults with and without fatigue. This suggests that the high prevalence of fatigue in NF1 adults is not explained by these somatic disorders. An alternative explanation for fatigue might be deficits in cognitive functioning and other neuropsychological processes in NF1. Based on our results and review of the literature, we provide a clinical algorithm for the approach to fatigue in NF1 adults, including somatic and psychological assessment.
Topics: Adult; Humans; Neurofibromatosis 1; Cross-Sectional Studies; Cognition; Causality; Hypertension
PubMed: 38560379
DOI: 10.3389/fendo.2023.1119159 -
Epilepsy Research May 2024Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study,...
PURPOSE
Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood.
METHODS
Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model.
RESULTS
Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI=6-18%) and point prevalence 7% (CI= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI=3-65) and specificity of 99% (CI=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy.
CONCLUSIONS
In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.
Topics: Humans; Neurofibromatosis 1; Epilepsy; Male; Female; Adult; Prevalence; Young Adult; Electroencephalography; Phenotype; Middle Aged; Genotype; Adolescent; Magnetic Resonance Imaging; Prospective Studies
PubMed: 38471245
DOI: 10.1016/j.eplepsyres.2024.107336 -
European Journal of Human Genetics :... Dec 2022Children with neurofibromatosis 1 (NF1) may have a high burden of somatic disease and cognitive impairments, which can lead to poor academic performance. We evaluated...
Children with neurofibromatosis 1 (NF1) may have a high burden of somatic disease and cognitive impairments, which can lead to poor academic performance. We evaluated school grades from exams ending mandatory schooling (usually around age 15 or 16 years) of children with NF1 in a population-based registry study using a within-school matched design. The study included 285 children with NF1 and 12,000 NF1-free peers who graduated from the same school and year during 2002-2015. We estimated overall and gender-specific grades by subject and compared the grades of children with NF1 with those of NF1-free peers in linear regression models. We also examined the effect of social and socioeconomic factors (immigration status and parental education, income and civil status) on grades and age at finalizing ninth grade. School grades varied considerably by socioeconomic stratum for all children; however, children with NF1 had lower grades by an average of 11-12% points in all subjects. In the adjusted models, children with NF1 had significantly lower grades than their NF1-free peers, with largest negative differences in grades observed for girls with NF1. Finally, children with NF1 were 0.2 (CI 0.1-0.2) years older than their peers on graduating from ninth grade, but only maternal educational modified the age at graduating. In conclusion, students with NF1 perform more poorly than their peers in all major school subjects. Gender had a strong effect on the association between NF1 and school grades; however, socioeconomic factors had a similar effect on grades for children with NF1 and their peers.
Topics: Child; Female; Humans; Adolescent; Neurofibromatosis 1; Academic Performance; Schools; Students; Parents
PubMed: 35859011
DOI: 10.1038/s41431-022-01149-z -
American Journal of Medical Genetics.... May 2018Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder associated with lifelong tumor growth propensity and neurocognitive impairments. Although follow-up of adults...
Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder associated with lifelong tumor growth propensity and neurocognitive impairments. Although follow-up of adults with NF1 often focuses on tumor growth, follow-up of cognitive or social problems and other NF1-related comorbidity is often not a part of standardized care. In order to provide optimal care services for these patients, we explored the care needs of adults with NF1. A qualitative study was performed using semi-structured group interviews, exploring worries and care needs in medical, psychological, and socioeconomic domains, also focusing on the transition from pediatric to adult care. Four focus groups were conducted, including young adult patients, patients over age 30, and parents of young adult patients. In total, 30 patients and 12 parents participated. Data were transcribed verbatim and analyzed by computerized thematic analysis. Themes were organized using the World Health Organization International classification of functioning, disability, and health (ICF). Results indicated many and diverse worries and care needs both during the transitional period and in adulthood in medical, mental health, and socioeconomic domains. Worries could be categorized into 13 themes. Parents reported high stress levels and difficulties with their parental role. Participants expressed the need for more information, access to NF1 experts, daily living support, care for mental health and socioeconomic participation, and closer communication between health-care providers. In conclusion, worries and needs of patients and parents underline the importance of multidisciplinary follow-up and continuity of care during and after the transitional period. Additionally, parental stress requires more attention from care providers.
Topics: Activities of Daily Living; Adolescent; Adult; Age Factors; Aged; Anxiety; Disabled Persons; Environment; Female; Focus Groups; Health Services Needs and Demand; Humans; Male; Mental Health; Middle Aged; Neurofibromatosis 1; Parents; Qualitative Research; Young Adult
PubMed: 29681082
DOI: 10.1002/ajmg.a.38680 -
BMC Pediatrics Mar 2023Neurofibromatosis type 1 and pseudoachondroplasia are both rare autosomal dominant disorders, caused by pathogenic mutations in NF1 and COMP genes, respectively. Both...
BACKGROUND
Neurofibromatosis type 1 and pseudoachondroplasia are both rare autosomal dominant disorders, caused by pathogenic mutations in NF1 and COMP genes, respectively. Both neurofibromin 1 and cartilage oligomeric matrix protein (COMP) play a role in the development of the skeleton. Carrying both germline mutations has not been previously reported; however, it can affect the developing phenotype.
CASE PRESENTATION
The index patient, an 8-year-old female presented with several skeletal and dermatologic anomalies resembling the coexistence of multiple syndromes. Her mother had dermatologic symptoms characteristic for neurofibromatosis type 1, and her father presented with distinct skeletal anomalies. NGS-based analysis revealed a heterozygous pathogenic mutation in genes NF1 and COMP in the index patient. A previously unreported heterozygous variant was detected for the NF1 gene. The sequencing of the COMP gene revealed a previously reported, pathogenic heterozygous variant that is responsible for the development of the pseudoachondroplasia phenotype.
CONCLUSIONS
Here, we present the case of a young female carrying pathogenic NF1 and COMP mutations, diagnosed with two distinct heritable disorders, neurofibromatosis type 1 and pseudoachondroplasia. The coincidence of two monogenic autosomal dominant disorders is rare and can pose a differential diagnostic challenge. To the best of our knowledge, this is the first reported co-occurrence of these syndromes.
Topics: Humans; Female; Neurofibromatosis 1; Achondroplasia; Mutation; Phenotype
PubMed: 36890482
DOI: 10.1186/s12887-023-03920-7 -
Genetics in Medicine : Official Journal... Jun 2020The aim was to assess lifetime risk for hospitalization in individuals with neurofibromatosis 1 (NF1).
PURPOSE
The aim was to assess lifetime risk for hospitalization in individuals with neurofibromatosis 1 (NF1).
METHODS
The 2467 individuals discharged with a diagnosis indicating NF1 or followed in a clinical center for NF1 were matched to 20,132 general population comparisons. Based on diagnoses in 12 main diagnostic groups and 146 subcategories, we calculated rate ratios (RRs), absolute excess risks (AERs), and hazard ratios for hospitalizations.
RESULTS
The RR for any first hospitalization among individuals with NF1 was 2.3 (95% confidence interval 2.2-2.5). A high AER was seen for all 12 main diagnostic groups, dominated by disorders of the nervous system (14.5% of all AERs), benign (13.6%) and malignant neoplasms (13.4%), and disorders of the digestive (10.5%) and respiratory systems (10.3%). Neoplasms, nerve and peripheral ganglia disease, pneumonia, epilepsy, bone and joint disorders, and intestinal infections were major contributors to the excess disease burden caused by NF1. Individuals with NF1 had more hospitalizations and spent more days in hospital than the comparisons. The increased risk for any hospitalization was observed for both children and adults, with or without an associated cancer.
CONCLUSION
NF1 causes an overall greater likelihood of hospitalization, with frequent and longer hospitalizations involving all organ systems throughout life.
Topics: Adult; Child; Denmark; Hospitalization; Humans; Longevity; Neurofibromatosis 1; Registries
PubMed: 32107470
DOI: 10.1038/s41436-020-0769-6 -
Orphanet Journal of Rare Diseases Apr 2021The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should... (Review)
Review
BACKGROUND
The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should be clinically examined and undergo follow-up in accordance with the standard NF1 guidelines, as MNF1 patients more often may develop more benign phenotypes and thereby less disease-associated complications including cognitive impairment. We discussed the need for a specific MNF1 follow-up guideline with focus on frequency of plexiform neurofibromas and NF1-associated complications.
METHOD
A systematic retrospective data collection in a MNF1 cohort from one of two Danish national centers of NF1 Expertise was completed. Data collected included demographics, clinical features including NF1 diagnostic criteria and NF1-associated complications. Recent literature in the field was reviewed.
RESULTS
We identified 17 patients with MNF1 with a median age of 37 years [4; 66]. Eleven (65%) were females. Five patients (30%) had a plexiform neurofibroma. The median age at detection of plexiform neurofibroma was 30 years [14; 60]. Nine (53%) had at least one NF1-related complication; scoliosis, hypertension, ADHD, learning disability, language delay, autism and delay in gross and fine motor function development. We reviewed nine articles. In total, 126 cases were described within three case-series. Nineteen (15%) had a plexiform neurofibroma and in total, 23 NF1-associated complications were reported including language delay, learning disability and skeletal abnormalities. Furthermore, from the literature it was evident that the diagnosing of MNF1 varies among physicians and across countries.
CONCLUSION
Patients with MNF1 present with plexiform neurofibromas and other NF1-related complications with a frequency requiring that follow-up of MNF1 patients should be in accordance with the standard NF1 guideline in both childhood and adulthood. Physicians should be aware of cognitive impairment as a complication to MNF1. To develop a specific MNF1 follow-up guideline, there is a need for an international consensus on the diagnostic criteria for MNF1 and a follow-up study conducted in a larger MNF1 cohort.
Topics: Adult; Child; Female; Follow-Up Studies; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Retrospective Studies; Severity of Illness Index
PubMed: 33853649
DOI: 10.1186/s13023-021-01796-3 -
Developmental Medicine and Child... Aug 2020To describe the cognitive development of children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas, and identify predictors of cognitive development. (Clinical Trial)
Clinical Trial
AIM
To describe the cognitive development of children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas, and identify predictors of cognitive development.
METHOD
Participants included 88 children with NF1 and plexiform neurofibromas (50 males, 38 females, aged 6-18y, mean=12y, SD=3y 7mo) on a natural history study at the National Cancer Institute. Neuropsychological assessments (e.g. IQ, academic achievement, attention, and executive functioning) were administered three times over 6 years.
RESULTS
Relative to normative peers, the total sample of children with NF1 and plexiform neurofibromas demonstrated significantly lower scores in most cognitive domains and decreasing z-scores over time in math, writing, inhibitory control, and working memory. Children who had parents with (vs without) NF1 were more likely to experience decreased z-scores in performance IQ, reading, writing, attention, and working memory. Higher (vs lower) parental education was related to higher levels of IQ, math, reading, and cognitive flexibility and a slower decrease in math z-scores. Children's sex and the number of NF1 disease-related complications were not related to most cognitive outcomes.
INTERPRETATION
Children with NF1 and plexiform neurofibromas are at high risk for cognitive difficulties and declining z-scores in various domains of cognitive functioning over time. The findings highlight the need for a better understanding of the within-group differences in these children and their need for individualized educational plans.
WHAT THIS PAPER ADDS
Math, writing, inhibitory control, and working memory scores decreased over time. The proportion of children with clinically significant cognitive deficits increased over time. Parental neurofibromatosis type 1 and low education were related to greater cognitive difficulties in children.
Topics: Adolescent; Child; Child Development; Cognition; Female; Humans; Longitudinal Studies; Male; Neurofibroma, Plexiform; Neurofibromatosis 1; Neuropsychological Tests
PubMed: 32052421
DOI: 10.1111/dmcn.14489 -
The New England Journal of Medicine May 2021
Topics: Adult; Biopsy; Chest Pain; Coronary Aneurysm; Coronary Angiography; Coronary Stenosis; Diagnosis, Differential; Electrocardiography; Female; Humans; Mutation, Missense; Myocardial Infarction; Neurofibromatosis 1; Skin
PubMed: 33951365
DOI: 10.1056/NEJMcps2034360