| 1. |
- Johansson, Edvard, et al.
(author)
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A rare disease and education: Neurofibromatosis type 1 decreases educational attainment.
- 2021
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In: Clinical genetics. - : Wiley. - 1399-0004 .- 0009-9163. ; 99:4, s. 529-539
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Journal article (peer-reviewed)abstract
- Rare heritable syndromes may affect educational attainment. Here, we study education in neurofibromatosis 1 (NF1) that is associated with multifaceted medical, social and cognitive consequences. Educational attainment in the Finnish population-based cohort of 1408 individuals with verified NF1 was compared with matched controls using Cox proportional hazards model with delayed entry and competing risk for death. Moreover, models accounting for the effects of cancer at age 15-30years, parental NF1 and developmental disorders were constructed. Overall, the attainment of secondary education was reduced in individuals with NF1 compared to controls (hazard ratio 0.83, 95%CI 0.74-0.92). History of cancer and developmental disorders were major predictors of lack of secondary education. Individuals with NF1 obtained vocational secondary education more often than general upper secondary education. Consequently, NF1 decreased the attainment of Bachelor's and Master's degrees by 46-49% and 64-74%, respectively. Surprisingly, the non-NF1 siblings of individuals with NF1 also had lower educational attainment than controls, irrespective of parental NF1. In conclusion, NF1 is associated with reduced educational attainment and tendency for affected individuals to obtain vocational instead of academic education. Individuals living with NF1, especially those with cancer, developmental disorders or familial NF1, need effective student counselling and learning assistance. This article is protected by copyright. All rights reserved.
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| 2. |
- Johansson, Edvard, et al.
(author)
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The rare disease neurofibromatosis 1 as a source of hereditary economic inequality: Evidence from Finland.
- 2021
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In: Genetics in medicine : official journal of the American College of Medical Genetics. - : Elsevier BV. - 1530-0366. ; 24:4, s. 870-879
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Journal article (peer-reviewed)abstract
- This study investigated whether individuals with neurofibromatosis 1 (NF1) fare worse than individuals without NF1 in terms of economic well-being. NF1 is relatively common in the population and provides an informative case of a rare hereditary disease.We examined a subset of 692 individuals with verified NF1 from the Finnish total population-based NF1 cohort and compared that with 7407 control individuals matched for age, sex, and municipality during 1997-2014. Economic well-being was operationalized with annual work earnings and total income, including social income transfers.NF1 significantly worsened economic well-being. Low education, increased morbidity, and reduced labor market participation partly explained the effect of NF1. Yet, NF1 was independently associated with lower income even after adjusting for these factors. Furthermore, NF1 had a larger negative effect on income from work than it had on total income, which indicated that the Finnish social security system partly compensated the labor market losses suffered by individuals with NF1. NF1 had a larger impact on economic inequality for men than for women.NF1 contributes to economic inequality. A hereditary disease may convey worse economic well-being over several generations.
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| 3. |
- Kallionpaa, Roope A., et al.
(author)
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Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1
- 2024
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In: LABORATORY INVESTIGATION. - 0023-6837 .- 1530-0307. ; 104:1
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Journal article (peer-reviewed)abstract
- Cutaneous neurofibromas (cNFs) are characteristic of neurofibromatosis 1 (NF1), yet their immune microenvironment is incompletely known. A total of 61 cNFs from 10 patients with NF1 were immunolabeled for different types of T cells and macrophages, and the cell densities were correlated with clinical characteristics. Eight cNFs and their overlying skin were analyzed for T cell receptor CDR domain sequences, and mass spectrometry of 15 cNFs and the overlying skin was performed to study immune-related processes. Intratumoral T cells were detected in all cNFs. Tumors from individuals younger than the median age of the study participants (33 years), growing tumors, and tumors smaller than the data set median showed increased T cell density. Most samples displayed intratumoral or peritumoral aggregations of CD3-positive cells. T cell receptor sequencing demonstrated that the skin and cNFs host distinct T cell populations, whereas no dominant cNF-specific T cell clones were detected. Unique T cell clones were fewer in cNFs than in skin, and mass spectrometry suggested lower expression of proteins related to T cell-mediated immunity in cNFs than in skin. CD163-positive cells, suggestive of M2 macrophages, were abundant in cNFs. Human cNFs have substantial T cell and macrophage populations that may be tumorspecific.
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| 4. |
- Kallionpaa, R. A., et al.
(author)
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Circulating free DNA in the plasma of individuals with neurofibromatosis type 1
- 2021
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In: American Journal of Medical Genetics Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 185:4, s. 1098-1104
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Journal article (peer-reviewed)abstract
- Neurofibromatosis type 1 (NF1) is an autosomal dominant syndrome whose characteristic manifestations include benign neurofibromas, yet NF1 is also associated with a high risk of cancer. Measurements of circulating free plasma DNA (cfDNA) are gaining wider applicability in cancer diagnostics, targeting of therapy, and monitoring of therapeutic response. Individuals with NF1 are likely to be followed up using this method, but the effects of NF1 and neurofibromas on cfDNA levels are not known. We studied peripheral blood samples from 19 adults with NF1 and 12 healthy controls. The cfDNA was isolated from plasma with QIAamp Circulating Nucleic Acid Kit and quantified using the Qubit 2.0 Fluorometer. The cfDNA concentration of each sample was normalized relative to the plasma protein concentration. The normalized median concentration of cfDNA in plasma was 19.3 ng/ml (range 6.6-78.6) among individuals with NF1 and 15.9 ng/ml (range 4.8-47.0) among controls (p = .369). Individuals with NF1 who also had plexiform neurofibroma (pNF) showed non-significantly elevated cfDNA concentration compared to individuals with NF1 and without known pNF (median 25.4 vs. 18.8 ng/ml, p = .122). The effect of NF1 on cfDNA seems to be relatively small and NF1 is therefore unlikely to hamper the use of cfDNA-based assays.
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| 5. |
- Kallionpaa, R. A., et al.
(author)
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Increased risk for dementia in neurofibromatosis type 1
- 2021
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600.
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Journal article (peer-reviewed)abstract
- Purpose To determine the risk for dementia in neurofibromatosis type 1 (NF1) using a Finnish nationwide cohort of individuals with NF1, and data from national registries. Methods A Finnish cohort of 1,349 individuals with confirmed NF1 according to the US National Institutes of Health (NIH) diagnostic criteria was compared with a control cohort of 13,870 individuals matched for age, sex, and area of residence. Dementia-related hospital visits were retrieved from the Finnish Care Register for Health Care using International Classification of Diseases, 10th revision (ICD-10) diagnosis codes G30 and F00-F03. Purchases of antidementia drugs were queried with Anatomical Therapeutic Chemical (ATC) classification code N06D from the drug reimbursement register maintained by the Social Insurance Institution of Finland. The follow-up spanned 1998-2014. Results Totals of 16 and 165 individuals with at least two dementia-related diagnoses or drug purchases were identified in the NF1 and control cohorts, respectively. The hazard ratio for dementia in NF1 was 1.67 (95% confidence interval [CI] 1.00-2.80, P = 0.050). In an analysis stratified by the type of dementia, the risk for Alzheimer disease was increased in NF1 compared to controls with a hazard ratio of 2.88 (95% CI 1.47-5.66, P = 0.002). Conclusion Dementia and especially Alzheimer disease are previously unrecognized neurological complications of NF1.
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| 6. |
- Kallionpaa, R. A., et al.
(author)
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Mast Cells in Human Cutaneous Neurofibromas: Density, Subtypes, and Association with Clinical Features in Neurofibromatosis 1
- 2022
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In: Dermatology. - : S. Karger AG. - 1018-8665 .- 1421-9832. ; 238:2, s. 329-339
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Journal article (peer-reviewed)abstract
- Background: Cutaneous neurofibromas (cNFs) are hallmarks of neurofibromatosis 1 (NF1) and cause the main disease burden in adults with NF1. Mast cells are a known component of cNFs. However, no comprehensive characterization of mast cells in cNFs is available, and their contributions to cNF growth and symptoms such as itch are not known. Methods: We collected 60 cNFs from ten individuals with NF1, studied their mast cell proteinase content, and compared the mast cell numbers to selected clinical features of the tumors and patients. The tumors were immunolabeled for the mast cell markers CD117, tryptase, and chymase, and the percentage of immunopositive cells was determined using computer-assisted methods. Results: The median proportions of positive cells were 5.5% (range 0.1-14.4) for CD117, 4.0% (1.2-7.0) for tryptase, and 5.0% (1.1-15.9) for chymase. The median densities of cells immunopositive for CD117, tryptase, and chymase were 280, 243, and 250 cells/mm(2), respectively. Small tumors, growing tumors, and tumors from patients below the median age of 33 years displayed a high proportion of mast cells. Cells expressing both tryptase and chymase were the predominant mast cell type in cNFs, followed by cells expressing chymase only. Conclusion: The results highlight the abundance of mast cells in cNFs and that their number and subtypes clearly differ from those previously reported in unaffected skin.
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| 7. |
- Kallionpaa, R., et al.
(author)
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The contribution of morbidity and unemployment for the reduced labor market participation of individuals with neurofibromatosis 1 in Finland
- 2024
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In: European Journal of Human Genetics. - 1018-4813. ; 32:1, s. 83-90
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Journal article (peer-reviewed)abstract
- Neurofibromatosis 1 (NF1) is a multisystem disorder associated with, for example, a high risk for cancer, a variety of behavioral and cognitive deficits, low educational attainment and decreased income. We now examined the labor market participation of individuals with NF1. We analyzed the numbers of days of work, unemployment, and sickness allowance among 742 Finnish individuals with NF1 aged 20-59 years using nationwide register data from Statistics Finland and the Social Insurance Institution of Finland. The individuals with NF1 were compared with a control cohort of 8716 individuals matched with age, sex, and the area of residence. Individuals with NF1 had a significantly lower number of working days per year than the controls (rate ratio [RR] 0.93, 95% CI 0.91-0.95). Unemployment (RR 1.79, 95% CI 1.58-2.02), and sickness absence (RR 1.44, 95% CI 1.25-1.67) were more frequent in the NF1 than in the control group. The causes of sickness allowances were highly concordant with the previously reported morbidity profile of NF1 including neoplasms, cardiovascular disease, mental and behavioral diseases, and neurological diseases. In conclusion, NF1 significantly interferes with labor market participation via both unemployment and morbidity. Unemployment seems to cause more days of not working than sickness absence.
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| 8. |
- Loponen, Niina, et al.
(author)
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Hypertension in NF1: A closer look at the primacy of essential hypertension versus secondary causes
- 2024
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In: Molecular Genetics and Genomic Medicine. - 2324-9269. ; 12:1
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Journal article (peer-reviewed)abstract
- Background: We aimed to analyze hypertension in neurofibromatosis type 1 (NF1) in a Finnish population-based cohort in 1996–2014. Methods: A cohort of 1365 individuals with confirmed NF1 was compared with a control cohort of 13,923 individuals matched for age, sex, and area of residence. Diagnoses of hypertension were retrieved from the Finnish Care Register for Health Care. These registered data were separately analyzed for secondary and essential hypertension. Purchases of antihypertensive drugs were queried from the Finnish Register of Reimbursed Drug Purchases. Results: We identified 115 NF1 patients with hospital diagnosis of hypertension. Our findings revealed a hazard ratio (HR) of 1.64 (95% CI 1.34–2.00, p < 0.001) in NF1 versus controls. NF1 patients presented with a significantly increased hazard for both secondary hypertension (n = 9, HR 3.76, 95% CI 1.77–7.95, p < 0.001) and essential hypertension (n = 98, HR 1.73, 95% CI 1.39–2.14, p < 0.001). No difference in the HR of hypertension was observed between men and women, while NF1 patients with essential hypertension were, on average, younger than the controls. The proportions of individuals with antihypertensive medication did not differ between NF1 patients and controls (OR 0.85). Conclusion: NF1 is a risk factor for hypertension. Despite the recognized risk for secondary hypertension, essential hypertension is the predominant type in NF1.
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| 9. |
- Pennanen, P., et al.
(author)
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Signaling pathways in human osteoclasts differentiation: ERK1/2 as a key player
- 2021
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In: Molecular Biology Reports. - : Springer Science and Business Media LLC. - 0301-4851 .- 1573-4978. ; 48, s. 1243-1254
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Journal article (peer-reviewed)abstract
- Little is known about the signaling pathways involved in the differentiation of human osteoclasts. The present study evaluated the roles of the Ras/PI3K/Akt/mTOR, Ras/Raf/MEK1/2/ERK1/2, calcium-PKC, and p38 signaling pathways in human osteoclast differentiation. Mononuclear cells were isolated from the peripheral blood of control persons and patients with neurofibromatosis 1 (NF1), and the cells were differentiated into osteoclasts in the presence of signaling pathway inhibitors. Osteoclast differentiation was assessed using tartrate-resistant acid phosphatase 5B. Inhibition of most signaling pathways with chemical inhibitors decreased the number of human osteoclasts and disrupted F-actin ring formation, while the inhibition of p38 resulted in an increased number of osteoclasts, which is a finding contradictory to previous murine studies. However, the p38 inhibition did not increase the bone resorption capacity of the cells. Ras-inhibitor FTS increased osteoclastogenesis in samples from control persons, but an inhibitory effect was observed in NF1 samples. Inhibition of MEK, PI3K, and mTOR reduced markedly the number of NF1-deficient osteoclasts, but no effect was observed in control samples. Western blot analyses showed that the changes in the phosphorylation of ERK1/2 correlated with the number of osteoclasts. Our results highlight the fact that osteoclastogenesis is regulated by multiple interacting signaling pathways and emphasize that murine and human findings related to osteoclastogenesis are not necessarily equivalent.
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| 10. |
- Carton, C., et al.
(author)
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ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1
- 2023
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In: Eclinicalmedicine. - : Elsevier BV. - 2589-5370. ; 56
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Journal article (peer-reviewed)abstract
- Background Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is important in patients with NF1. Proposals for NF1 care and its specific manifestations have been developed, but lack integration within routine care. This guideline aims to assimilate available information on NF1 associated tumours (based on evidence and/ or expert opinion) to assist healthcare professionals in undertaking tumour surveillance of NF1 individuals.Methods By comprehensive literature review, performed March 18th 2020, guidelines were developed by a NF1 expert group and patient representatives, conversant with clinical care of the wide NF1 disease spectrum. We used a modified Delphi procedure to overcome issues of variability in recommendations for specific (national) health care settings, and to deal with recommendations based on indirect (scarce) evidence.Findings We defined proposals for personalised and targeted tumour management in NF1, ensuring appropriate care for those in need, whilst reducing unnecessary intervention. We also incorporated the tumour-related psychosocial and quality of life impact of NF1. Interpretation The guideline reflects the current care for NF1 in Europe. They are not meant to be prescriptive and may be adjusted to local available resources at the treating centre, both within and outside EU countries.Funding This guideline has been supported by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union. DGE is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). 2023;56: Published January https://doi.org/10. 1016/j.eclinm.2022. 101818
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