The contribution of morbidity and unemployment for the reduced labor market participation of individuals with neurofibromatosis 1 in Finland.

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.

Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1.

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 tumor-specific.

Hypertension in NF1: A closer look at the primacy of essential hypertension versus secondary causes.

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.

Overlap between EEC and AEC syndrome and immunodeficiency in a preterm infant with a TP63 variant.

Pathogenic variants in the transcription factor TP63 gene cause a variety of clinical phenotypes, such as ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome. Historically, TP63-related phenotypes have been divided into several syndromes based on both the clinical presentation and location of the pathogenic variant on the TP63 gene. This division is complicated by significant overlap between syndromes. Here we describe a patient with clinical characteristics of different TP63-associated syndromes (cleft lip and palate, split feet, ectropion, erosions of the skin and corneas), associated with a de novo heterozygous pathogenic variant c.1681 T>C, p.(Cys561Arg) in exon 13 of the TP63 gene. Our patient also developed enlargement of the left-sided cardiac compartments and secondary mitral insufficiency, which is a novel finding, and immune deficiency, which has only rarely been reported. The clinical course was further complicated by prematurity and very low birth weight. We illustrate the overlapping features of EEC and AEC syndrome and multidisciplinary care needed to address the various clinical challenges.

ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1.

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 NIHRBiomedical Research Centre (IS-BRC-1215-20007).

Porokeratosis is one of the most common genodermatoses and is associated with an increased risk of keratinocyte cancer and melanoma.

BACKGROUND: Porokeratosis is a clinically heterogeneous group of keratinization disorders with a genetic background mainly affecting the mevalonate pathway, which is involved in the synthesis of cholesterol, an essential component for the formation of the extracellular lipid lamellae in the stratum corneum. Porokeratosis is reportedly associated with an increased risk of keratinocyte cancer, but to date, no large epidemiological studies have been conducted to further address this association. OBJECTIVES: The first objective was to characterize a cohort of patients diagnosed with porokeratosis at the Department of Dermatology and Venereology, Sahlgrenska University Hospital (SU), Gothenburg, Sweden. The second objective was to conduct a nationwide registry-based cohort study to investigate the association, if any, between porokeratosis and the cutaneous malignancies squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. METHODS: For the SU cohort, the hospital registry was searched for patients with a diagnosis of porokeratosis recorded between 2016 and 2020. Clinical data were extracted from the records of the identified patients. For the nationwide cohort, national registries were searched to identify patients with a diagnosis of porokeratosis between 2001 and 2020. A tenfold control cohort was formed by Statistics Sweden. The data was cross-referenced with the Swedish Cancer Register to study the associations between porokeratosis and SCC, BCC and melanoma. RESULTS: Disseminated superficial actinic porokeratosis was the most common clinical type among the 108 patients in the SU cohort. In the nationwide search, 2277 patients with porokeratosis were identified (prevalence 1/4132). Porokeratosis was associated with an increased risk for SCC, BCC and melanoma with hazard ratios (95% CI) of 4.3 (3.4-5.4), 2.42 (1.97-2.98) and 1.83 (1.18-2.82), respectively, in the patient cohort, compared to the matched control group. CONCLUSION: Porokeratosis is a common genodermatosis, and it is associated with an enhanced risk of skin cancer.

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the most prevalent metastatic skin cancer. Previous studies have demonstrated the autocrine role of complement components in cSCC progression. We have investigated factor D (FD), the key enzyme of the alternative complement pathway, in the development of cSCC. RT-qPCR analysis of cSCC cell lines and normal human epidermal keratinocytes (NHEKs) demonstrated significant up-regulation of FD mRNA in cSCC cells compared to NHEKs. Western blot analysis also showed more abundant FD production by cSCC cell lines. Significantly higher FD mRNA levels were noted in cSCC tumors than in normal skin. Strong tumor cell-associated FD immunolabeling was detected in the invasive margin of human cSCC xenografts. More intense tumor cell-specific immunostaining for FD was seen in the tumor edge in primary and metastatic cSCCs, in metastases, and in recessive dystrophic epidermolysis bullosa-associated cSCCs, compared with cSCC in situ, actinic keratosis and normal skin. FD production by cSCC cells was dependent on p38 mitogen-activated protein kinase activity, and it was induced by interferon-γ and interleukin-1ß. Blocking FD activity by Danicopan inhibited activation of extracellular signal-regulated kinase 1/2 and attenuated proliferation of cSCC cells. These results identify FD as a novel putative biomarker and therapeutic target for cSCC progression.

The rare disease neurofibromatosis 1 as a source of hereditary economic inequality: Evidence from Finland.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: NF1 contributes to economic inequality. A hereditary disease may convey worse economic well-being over several generations.

Mast Cells in Human Cutaneous Neurofibromas: Density, Subtypes, and Association with Clinical Features in Neurofibromatosis 1.

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/mm2, 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.

Treatment of cutaneous neurofibromas with carbon dioxide laser: Technique and patient experience.

Cutaneous neurofibromas (cNF) are one of the hallmarks of neurofibromatosis 1 (NF1). The number of cNFs varies between individuals from a few to hundreds or even thousands and increases throughout adult life. cNFs cause a significant disease burden to adult patients and constitute an unmet need for therapy, since they may cause itch and pain and, being conspicuous and unsightly, stigmatize the patient. There is a lack of reports on how the outcome of various treatment options are perceived by the patients. Here we describe a technique for cNF removal using CO2 laser, and report how patients experience the procedure. Questionnaires were sent to patients who had had CO2 laser surgery in the French Referral Center for Neurofibromatoses, and in the Turku University Hospital, Finland, to retrospectively evaluate the patients' global satisfaction of the procedure, treatment indications, and reasons for withdrawal from treatment, if this was the case. The number of returned questionnaires was 233/473 in France and 23/27 in Finland. The results showed that the most important indications for cNF removal were esthetic, and pain and itch caused by the tumors. In general, the procedure was well tolerated, and the degree of satisfaction was 8-10 on a scale from 0 to 10. For those 30% who discontinued the tumor removal program, the main reasons were organizational constraints, a non-satisfactory esthetic result, too many cNFs to treat, or problems with healing. Thus, the CO2 laser method is well tolerated but does not fully answer to the needs of the patients. Since medical treatment is not yet available, we encourage the use of laser removal of cNFs as a feasible method to decrease the tumor burden of the patients.

Increased risk for dementia in neurofibromatosis type 1.

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.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

Signaling pathways in human osteoclasts differentiation: ERK1/2 as a key player.

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.

Circulating free DNA in the plasma of individuals with neurofibromatosis type 1.

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.

A rare disease and education: Neurofibromatosis type 1 decreases educational attainment.

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 15-30 years, 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 counseling and learning assistance.

Haploinsufficiency of the NF1 gene is associated with protection against diabetes.

BACKGROUND: The hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of the NF1 gene. Here, we used a cohort of 1410 patients with NF1 to study the association of the NF1 gene with type 1 (T1D) and type 2 diabetes (T2D). METHODS: A total of 1410 patients were confirmed to fulfil the National Institutes of Health diagnostic criteria for NF1 by individually reviewing their medical records. The patients with NF1 were compared with 14 017 controls matched for age, sex and area of residence as well as 1881 non-NF1 siblings of the patients with NF1. Register-based information on purchases of antidiabetic medication and hospital encounters related to diabetes were retrieved. The Cox proportional hazards model was used to calculate the relative risk for diabetes in NF1. RESULTS: Patients with NF1 showed a lower rate of T2D when compared with a 10-fold control cohort (HR 0.27, 95% CI 0.17 to 0.43) or with their siblings without NF1 (HR 0.28, 95% CI 0.16 to 0.47). The estimates remained practically unchanged after adjusting the analyses for history of obesity and dyslipidaemias. The rate of T1D in NF1 was decreased although statistically non-significantly (HR 0.58, 95% CI 0.27 to 1.25). CONCLUSION: Haploinsufficiency of the NF1 gene may protect against T2D and probably T1D. Since NF1 negatively regulates the Ras signalling pathway, the results suggest that the Ras pathway may be involved in the pathogenesis of diabetes.

Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study.

PURPOSE: Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1. METHODS: We included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan-Meier analysis with delayed entry. RESULTS: One hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0-84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8-76.8) and 49.8% (95%CI = 39.3-63.0). Breast cancer-specific 10-year survival was 64.2% (95% CI = 53.5-77.0%) compared with 91.2% (95% CI = 87.3-95.2%) in the non-NF1 age-matched population at increased risk of breast cancer. CONCLUSION: Women with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.

p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling.

Long noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRECSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.

Correction: Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST).

BACKGROUND: Type 1 neurofibromatosis (NF1) is a genetic tumor predisposing Rasopathy. NF1 patients have an increased risk for developing benign and malignant tumors, but the occurrence of intestinal tumors has not been investigated at the population level. METHODS: In this retrospective register-based total population study, diagnoses of gastrointestinal tract tumors were retrieved from the Finnish Care Register for Health Care for 1,410 NF1 patients and 14,030 reference persons. We also reviewed the death certificates of 232 NF1 patients who died during years 1987-2013, and specifically searched for diagnosis of gastrointestinal stromal tumor (GIST). RESULTS: The register analysis revealed an increased overall hazard ratio (HR) of 2.6 (95% CI 1.9-3.6) for intestinal tumors in NF1 compared to general population. The highest HR of 15.6 (95% CI 6.9-35.1) was observed in the small intestine. The focused analysis of NF1 death certificates and GISTs demonstrated that the GIST was the primary cause of death in seven patients. CONCLUSION: This study emphasizes the need for careful evaluation of NF1 patients with gastrointestinal complaints. The challenge in diagnosis is that the tumors preferably occur at the small intestine, which is difficult target for diagnostic procedures. We also show that the NF1 GISTs may lead to fatal outcome despite of benign histopathological findings at the time of the diagnosis.