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Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children's Tumor Foundation's NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.

Individuals with neurofibromatosis 1 (NF1) may have problems in managing the transition between childhood and adulthood, such as forming a relationship or finding a partner. We aimed to determine the association between NF1 and forming and ending marital or cohabiting relationships by comparing a large Danish population of adults with NF1 with population comparisons. In this population-based cohort study, we compared a population of Danish adults who were hospitalized for or with complications to prior diagnosed NF1 (n = 787) with population comparisons matched on gender and birth year (n = 7787) through nationwide registries with annually updated information on marriage and cohabitation. Discrete-time survival models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the formation and termination of relationships, with adjustment for birth year, gender, and somatic and psychiatric comorbidities at entry. Individuals with NF1 were significantly less likely to form a relationship (HR = 0.65; 95% CI: 0.58-0.73), with the lowest association for individuals ≥33 years (HR 0.40; 95% CI: 0.25-0.63) and the highest for those aged 18-20 years (HR 0.82; 95% CI: 0.70-0.96). No significant difference was found for ending relationships (HR 1.00; 95% CI: 0.86-1.16). In conclusion, individuals who were hospitalized for NF1 are less likely to engage in marital or cohabiting relationships than population comparisons and are older when they form their first relationship. Once a relationship has been established, however, couples with a NF1-individual are not at greater risk of ending the relationship.

Background: Spinal deformities constitute one of the most common types of manifestations of neurofibromatosis type-1 (NF-1), which can lead to either dystrophic or non-dystrophic early-onset scoliosis (EOS). Surgical treatment for EOS with NF-1 is challenging, and the outcomes have rarely been reported. The anterior-posterior procedure is widely used, but posterior-only fusion is theoretically easier and safer to perform. Is it possible that a new surgery that accommodates growth is a better choice? A direct comparison between posterior fusion and growth-friendly surgery in terms of surgical outcomes has not yet been conducted in dystrophic EOS with NF-1 patients., Methods: Baseline information was extracted from the NF-1 database at our institute with approval from the local ethics committee. All enrolled patients were diagnosed with NF-1. Clinical and radiographic data were recorded preoperatively, after the initial surgery, and at the final follow-up. Implant-related, alignment, neurological complication and unplanned revision surgery data were recorded. We compared the outcomes of these two groups in terms of curve correction, growth parameters, complications and unplanned revision surgeries., Results: There were eight patients in the PF group and eight patients in the GR group, with a mean follow-up of 51.0 ± 17.5 months. The main curve size was similar (PF 67.38° ± 17.43° versus GR 75.1° ± 26.43°, P = 0.501), and there were no significant differences in the initial surgery correction rate or the rate of correction. However, the patients in the GR group exhibited more T1-S1 growth during the follow-up overall and per year than did those in the PF group. The operative time was significantly longer for the PF group than for the GR group (PF, 4.39 ± 1.38 vs. GR, 3.00 ± 0.42 h; p = 0.008). Significantly fewer segments were involved in the PF group (8.25 ± 3.20) than in the GR group (13.00 ± 1.60)., Conclusion: For the initial treatment of dystrophic EOS in patients with NF-1, the GR technique is possibly a more appropriate treatment than is the PF technique in terms of trunk growth. However, the repeated procedures required for GR may be a considerable disadvantage. More studies with direct measurement of pulmonary function must be conducted to determine the effect of GR on pulmonary development. More studies with larger sample sizes and longer follow-up periods are needed to fully assess the treatment strategies.

The genetic architecture of neurodevelopmental disorders is largely polygenic, non-specific, and pleiotropic. This complex genetic architecture makes the search for specific etiological mechanisms that contribute to neurodevelopmental risk more challenging. Monogenic disorders provide an opportunity to focus in on how well-articulated signaling pathways contribute to risk for neurodevelopmental outcomes. This paper will focus on neurofibromatosis type 1 (NF1), a rare monogenic disorder that is associated with varied neurodevelopmental outcomes. Specifically, this paper will provide a brief overview of NF1 and its phenotypic associations with autism spectrum disorder, attention-deficit/hyperactivity disorder, and specific learning disorders, describe how variation within the NF1 gene increases risk for neurodevelopmental disorders via altered Ras signaling, and provide future directions for NF1 research to help elucidate the genetic architecture of neurodevelopmental disorders in the general population.

Neurofibromatosis type 1 (NF1) manifests itself in many ways in the spine. This study aims to report the types of spinal lesions, clinical and demographic data in a large cohort from a complex NF1 centre. The characteristics of those with spinal neurofibromatosis, where neurofibromas are present on every spinal nerve root, were sought for comparison with the wider group of NF1 patients. This is a retrospective review of MDT minutes of 303 patients from a UK NF1 centre and the largest reported series of NF1 patients based on radiological data. Prevalence of each symptom and lesion was calculated and statistically significant associations were established. The most reported findings were cutaneous lesions (44.9%) and neurological deficit (27.4%). 28.4% had dural ectasia, 52.5% had some form of spinal deformity. 57.8% had spinal nerve root tumours, the most common of which were at C2. The most progressive lesions were spinal nerve root tumours (29.1%). The only statistically significant association found was between dural ectasia and spinal deformity (P < 0.003), where dural ectasia is associated with a 32.6% increase in spinal deformity incidence. This is the largest descriptive study of spinal lesions in NF1. Spinal tumours and spinal deformity are prevalent in NF1. The predilection of spinal tumours for flexible spinal regions suggests that repetitive movement might be an important factor in pathogenesis. Physicians and patients should be alert to the observation that although many spinal neurofibromatosis patients display no neurological deficit, they often have significant lesions which require monitoring and sometimes surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

Aim: This study describes the prevalence and severity of perceived fatigue in a young neurofibromatosis type 1 (NF1) population., Methods: Ethical approval was obtained and NF1 affected Individuals aged 2-18 years from the Manchester's NF1 clinic invited along with any unaffected siblings. The PedsQL Multidimensional Fatigue Scale Parental and child report was used. This validated measure explores cognitive, physical and sleep/rest domains on a 0-100 scale. Higher scores indicate less fatigue. Fatigue scores in affected children were compared to unaffected siblings after adjusting for age, sex and Index of Multiple Deprivation and with published population standards using z-scores., Results: A total of 286 families were invited and 75 affected and 16 siblings participated. There were significant differences between NF1 and controls in the aggregated fatigue core (child report 55 ± 19 vs. 75 (14), P < 0.001; parent 54 ± 20 vs. 73 ± 18, P = 0.001) and the three sub-domains: cognitive (child 48 ± 27 vs. 75 ± 23, P < 0.001), physical (child 59 ± 19 vs. 82 ± 14, P < 0.001) and sleep/rest (child 59 ± 19 vs. 71 ± 15, P = 0.018). Similar differences were seen when compared with published controls (aggregated child z-score -1.9 ± 1.4, P < 0.001; parent -3.2 ± 1.8, P < 0.001). Prevalence of severe fatigue indicated by scores <2 standard deviation below published means for healthy controls were also higher for children with NF on both parent and child reports. Agreement between child and parent reports were limited as is frequently seen in the literature., Conclusion: This study suggests that children with NF1 are affected by perceived fatigue when compared with healthy children who do not have NF1., (© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Introduction: Neurofibromatosis Type 1 (NF1) is an autosomal dominant, multisystem, neurocutaneous disorder. This condition has been associated with lower urinary tract dysfunction due to either direct genitourinary organ involvement or spinal cord compression. Based on current literature, there are no reviews examining the relationship between NF1 and lower urinary tract dysfunction (LUTD) in the paediatric population., Methods: A critical review of the literature was conducted using a systematic search of MEDLINE, PubMed and Embase yielding a total of 1285 manuscripts published up to 2019. Two independent reviewers selected studies for screening, eligibility and inclusion into the review. Following title, abstract and full-text review, 46 articles were analyzed., Results: Within these 46 articles, 79 cases were presented. The mean patient age at the time of presentation was 6.97 ± 9.19 years. The most common urologic presentations were irritative lower urinary tract symptoms (30%) and a newly discovered abdominopelvic mass (21%). Diagnostic investigations commonly demonstrated a retrovesical mass with direct invasion of the bladder in 58 cases (73%) and other genitourinary organ involvement in 39 cases (39%). Throughout the total case volume, LUTD was present in 49%. Pathology of malignancy was most commonly malignant peripheral nerve sheath tumour and rhabdomyosarcoma (20% and 14%, respectively). When indicated, surgical management of the lower urinary tract included both radical and partial cystectomy. Conservative management of urinary retention included clean intermittent catheterization (56%), suprapubic catheterization (22%), vesicostomy creation (11%) and mitrofanoff creation (11%)., Conclusion: A complete urologic evaluation including clinical, radiologic, and possibly pathologic investigation is warranted and should be performed for both diagnosis and appropriate management of LUTD in patients with NF1., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome with an incidence of 1:2,000. Patients with NF1 have an increased cancer risk and mortality, but there are no population-based cohort studies specifically investigating the risk of childhood malignancies. We used the Finnish NF1 cohort to analyze the incidence, risk and prognosis of malignancies in NF1 patients <20 years of age. Persons born in 1987-2011 were included, and 524 persons were followed through the files of the Finnish Cancer Registry from birth up to age 20 years. This amounted to 8,376 person years. Fifty-three patients had cancer <20 years of age, yielding a standardized incidence ratio (SIR) of 35.6. The most frequent location of pediatric cancers was the central nervous system (CNS); there were 45 cases and the SIR was 115.7. Exclusion of 22 optic pathway gliomas (OPGs) gave an SIR of 59.1 for the CNS and 21.6 for all cancers. There were nine malignant peripheral nerve sheath tumors (MPNSTs); their cumulative risk was 2.7% by age 20. No cases of leukemia were observed. NF1 patients showed considerable excess mortality with a standardized mortality ratio (SMR) of 73.1. The survival of NF1 patients with CNS tumors other than OPGs did not differ from that of non-NF1 controls (HR 0.64, 95% CI 0.23 to 1.76). In conclusion, brain tumors in childhood and MPNSTs in adolescence are malignancies of major concern in patients with NF1. The risk for myeloid malignancies may not be as high as suggested in the literature., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents., Methods: We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non-NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children's Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures., Results: In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors ( P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children's Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9)., Conclusion: Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

The aim of this study was to assess the prevalence and type of congenital heart disease (CHD) and the associated mutation spectrum in a large series of patients with neurofibromatosis type 1 (NF1), and correlate the mutation type with the presence and subgroups of cardiac defects. The study cohort included 493 individuals with molecularly confirmed diagnosis of NF1 for whom cardiac evaluation data were available. CHD was reported in 62/493 (12.6%) patients. Among these patients, 23/62 (37.1%) had pulmonary valve stenosis/dysplasia, 20/62 (32.3%) had mitral valve anomalies, and 10/62 (16.1%) had septal defects. Other defects occurred as rare events. In this NF1 subcohort, three subjects carried a whole-gene deletion, while 59 were heterozygous for an intragenic mutation. A significantly increased prevalence of non-truncating intragenic mutations was either observed in individuals with CHD (22/59, 37.3%) or with pulmonary valve stenosis (13/20, 65.0%), when compared to individuals without CHD (89/420, 21.2%) ( p = 0.038) or pulmonary valve stenosis (98/459, 21.4%) ( p = 0.002). Similarly, patients with non-truncating NF1 mutations displayed two- and six-fold higher risk of developing CHD (odds ratio = 1.9713, 95% confidence interval (CI): 1.1162-3.4814, p = 0.0193) and pulmonary valve stenosis (odds ratio = 6.8411, 95% CI: 2.6574-17.6114, p = 0.0001), respectively. Noteworthy, all but one patient (19/20, 95.0%) with pulmonary valve stenosis, and 18/35 (51.4%) patients with other CHDs displayed Noonan syndrome (NS)-like features. Present data confirm the significant frequency of CHD in patients with NF1, and provide further evidence for a higher than expected prevalence of NF1 in-frame variants and NS-like characteristics in NF1 patients with CHD, particularly with pulmonary valve stenosis., Competing Interests: The authors declare no conflicts of interest.

The epidemiology of heritable traits whose prevalence is determined by a balance between mutation and selection is often explored through deterministic models. Here, the properties are explored by simulation of a model population followed through a sequence of closely spaced time points. Mutation and birth and death occur randomly. The condition neurofibromatosis type 1 (NF1) is used as a point of reference. Critical parameters, such as mutation rates and selection forces, are not known precisely for NF1 so speculative values based on published data from Finland and other studies are proposed.

Background: No study to date has followed disease progression in patients with neurofibromatosis type 1 (NF1), including the incidence of various manifestations, using a national registry. Here we examined the state of NF1 progression using a nationwide registry of patients who submitted claims to receive medical expense subsidies for NF1 in Japan over a five-year period. A total of 342 eligible patients (194 females and 148 males) with NF1 who newly submitted claims for medical expense subsidies in Japan in 2008 were followed until 2012., Results: More than half of the patients were classified as Stage 5 in 2008. Of the eligible patients, 205 (60%) submitted claims to renew the subsidies between 2009 and 2012. During the study period, NF1 stage progressed in 30 patients, yielding an overall stage progression rate of 19% and progression incidence rate per 100 person-years of 12.2. Both stage progression rate and progression incidence rate were the highest in the 0-19 year age group at the time of registration and, as compared to other age groups, progression of neurological and bone manifestations was more prevalent in this age group., Conclusions: The progression of neurological and bone manifestations was more prevalent in the 0-19 year age group compared to other age groups. The registry we used in the present study is useful for understanding the characteristics of patients with uncommon conditions, such as NF1. Our findings also highlight the feasibility of conducting quality research using registries of patients with rare diseases, such as NF1, that were not designed specifically for scientific research.

Purpose: To report the incidence, demographics, and clinical manifestations of neurofibromatosis type 1 among a population-based cohort of patients., Methods: The medical records of all patients diagnosed as having neurofibromatosis type 1 while residing in Olmsted County, Minnesota, from January 1, 1980, through December 31, 2009, were retrospectively reviewed., Results: Fifty patients were diagnosed as having neurofibromatosis type 1 during the 30-year period, yielding an incidence of 1.2 per 100,000 individuals. The mean age at diagnosis was 11.7 years (95% confidence interval [CI]: 0.2 to 47) and 26 (52%) were males. Twenty-eight patients were new mutations, yielding a de novo mutation rate of 56%. During a mean follow-up of 9.8 years (range: 3 weeks to 32 years), café-au-lait macules were diagnosed in 49 individuals (98%), neurofibromas in 26 (52%), and skeletal anomalies in 14 (28%). Three (5.9%) individuals were diagnosed as having glioma of the central nervous system (95% CI: 1.2 to 9.7%) at a mean age of 13 years (range: 5 to 26 years), including 1 patient with optic nerve glioma diagnosed at the age of 26 years. Only 1 (2%) patient was diagnosed as having malignant nerve sheath tumor., Conclusions: Although the prevalence and de novo mutation rate of neurofibromatosis type 1 in this population-based study were similar to prior reports, the occurrence of optic nerve gliomas was much lower. [J Pediatr Ophthalmol Strabismus. 2019;56(4):243-247.]., (Copyright 2019, SLACK Incorporated.)

Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen's disease, is an autosomal dominant dysplasia of the ectoderm and mesoderm with a variable clinical expression, but near-complete penetrance before the age of 5 years. The estimated incidence is 1 in 3000 births. NF-1 is characterized by collections of neurofibromas, café-au-lait spots, axillary and inguinal freckling, and pigmented hamartomas in the iris (Lisch nodules). Pulmonary manifestations of NF-1, which usually include bilateral basal reticulations and apical bullae and cysts, are reported in 10-20% of adult patients. Clinically, neurofibromatosis-associated diffuse lung disease (NF-DLD) usually presents with nonspecific respiratory symptoms, including dyspnea on exertion, shortness of breath, and chronic cough or chest pain, at the time of diagnosis. Computed tomography (CT) is highly accurate for the identification and characterization of NF-DLD; it is the most reliable method for the diagnosis of this lung involvement. Various CT findings of NF-DLD, including cysts, bullae, ground-glass opacities, bibasilar reticular opacities, and emphysema, have been described in patients with NF-1. The typical CT pattern, however, is characterized by upper-lobe cystic and bullous disease, and basilar interstitial lung disease. Currently, the goal of NF-DLD treatment is the earliest possible diagnosis, focusing on symptom relief and interventions that positively alter the course of the disease, such as smoking cessation. The aim of this review is to describe the main clinical, pathological, and imaging aspects of NF-1, with a focus on pulmonary involvement., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Patients with neurofibromatosis type 1 (NF1) have a high predisposition to develop attention-deficit disorder. The aim of this study is to determine the prevalence of NF1 patients with attention-deficit/hyperactivity disorder (ADHD) diagnosis attending our Child Neurology Department. We assess patient adherence and medical treatment outcomes., Patients and Methods: Identification of patients with NF1 being followed up from December 31 2015 to June 31 2017 with ADHD diagnosis. Clinical and treatment data were collected., Results: 56 patients with NF1 were enrolled in the study with a mean age of 9.83 ± 4.17 years. 23 patients (41%) were diagnosed with ADHD, mean age at ADHD diagnosis of 7.53 ± 2.46 years. School-age children with ADHD represented 48.8% of cases. All but one of the children received treatment, mean duration of treatment was 3.85 ± 3.04 years. 19 out of 22 patients (86%) continue medical treatment. Positive effects were reported by eleven patients with a moderate response in eight patients., Conclusions: Prevalence of ADHD in patients with NF1 is high. Early diagnosis and treatment of ADHD in patients with NF1 is highlighted by this study. Our study reveals good patient adherence and medical treatment outcomes in most patients.

Purpose: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data., Methods: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry., Results: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent., Conclusions: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.

Purpose: The incidence of neurofibromatosis 1 (NF1) is ~1/2,000 live births, but the current estimates of prevalence vary greatly. This retrospective total-population study was aimed at determining the prevalence of NF1 in Finland., Methods: All secondary and tertiary referral centers of Finland were searched for NF1 patients. Patient records were manually reviewed and patients fulfilling the National Institutes of Health diagnostic criteria for NF1 were included. Prevalence on 31 December 2005 was determined. Data on incidence and survival were combined to refine the prevalence estimation., Results: A total of 1,279 patients with NF1 were alive on 31 December 2005, yielding a prevalence of 1/4,088 (95% confidence interval (CI) 1/4,320-1/3,869). The survival of patients with NF1 was inferior compared with the general population (hazard ratio 3.10, 95% CI 2.73-3.53, P < 0.001). When the survival rates of NF1 patients and the Finnish population were combined with an estimate of NF1 incidence, a prevalence of 1/2,052 (95% CI 1/2,176-1/1,941) was estimated for NF1 in a population aged 0-74 years., Conclusion: NF1 is a much more common disorder than previously thought. A large proportion of NF1 patients may not be correctly identified by health-care systems or they do not seek secondary health care for their NF1.

Background: Focal areas of T2 hyperintensity are seen on magnetic resonance imaging (MRI) in patients with neurofibromatosis type 1 (NF1). These lesions are commonly known as "unidentified bright objects" of the brain. We have seen similar lesions in the spinal cord of the same patient population. Our aim was to determine the prevalence and characterize the imaging features of these T2 hyperintense spinal cord lesions in children with NF1., Methods: A search of our hospital's medical imaging database yielded all children with NF1 and MRI of the brain and/or spine between February 2014 and April 2017. Medical imaging was reviewed for T2 hyperintense signal changes and medical records were reviewed of those children with T2 hyperintense spinal cord lesions., Results: During the study period 155 children underwent a brain MRI and 72 had a spine MRI. One hundred twenty-three (79%) showed multiple cerebral T2 hyperintense lesions and six (8%) had non-contrast enhancing spinal cord T2 hyperintensities with five children having had a follow-up scan. The one child without follow-up imaging was not further pursued. Interval scanning showed stable appearance of the spinal cord lesions in four children and signal reduction in one child. All five children with T2 hyperintense changes in the spinal cord had an MRI brain and all (100%) also exhibited cerebral T2 hyperintensities., Conclusions: Focal areas of signal hyperintensity in the spinal cord are the corollary of the better described cerebral T2 hyperintensities in individuals with NF1., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neurofibromatosis 1 has various complications. To elucidate the frequency of neurofibromatosis 1-related major complications requiring medical intervention, a nationwide retrospective study was conducted of 3,530 patients with neurofibromatosis 1 registered from 2001 to 2014 in Japan. The ratio of certified patients requiring medical intervention (>stage 3) was 82%. Patients classified in the most severe grade experienced dermatological complications (71.8% of patients), neurological complications (38.1%) and bone complications (33.3%). In patients with dermatological manifestations, medical treatment was needed for cutaneous neurofibromas (58%), diffuse plexiform neurofibromas (31%) and malignant peripheral nerve sheath tumours (10%). Patients with neurological manifestations needed medical treatment mainly for brain tumours (53%) and intellectual disability (26%). Patients with bone manifestations needed medical treatment for pseudoarthrosis (9%), scoliosis (55%) and bone defects (16%). It is necessary for physicians to be aware of neurofibromatosis 1-related complications requiring medical intervention in order to provide appropriate care for patients with neurofibromatosis 1.

Objective: The main objective of this study was to determine if family history of malignant peripheral nerve sheath tumor (MPNST) increases risk of developing an MPNST in patients with neurofibromatosis-1 (NF-1)., Materials and Methods: Individuals with NF-1 registered with the Children's Tumor Foundation's Neurofibromatosis Registry were emailed an anonymous 15-minute survey with regard to personal and family history of NF-1, MPNST, ages of onset, and symptomatology. Participation was voluntary and information was self-reported., Results: The survey was sent to 4801 registrants, 878 responded. Presence of a family history of MPNST was found to be a risk factor for the development of MPNST; 19.4% of respondents confirming a family history of MPNST developed MPNST compared with 7.5% of respondents with no family history (odds ratio, 2.975; 95% confidence interval, 1.232-7.187; P=0.021). NF-1 patients with a positive family history developed MPNST at a younger age than those with no family history (8.3% vs. 0.5% P=0.003 and 13.9% vs. 2.4% P=0.003, for onset before 10 and 20, respectively). In the MPNST population with a known family history, onset prior to age 10 was significantly more prevalent (42.9% vs. 7% P=0.029)., Conclusions: These results suggest a positive family history of MPNST represents a risk factor for the development and early onset of MPNST in individuals with NF-1.

In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)-and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1.

Objectives: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize NF1 and NF2 variants in patients from Southern Brazil., Methods: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (NF1, RNF135, and SUZ12 genes) and NF2 (NF2 and SMARCB1 genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification., Results: Sixty-eight heterozygous NF1 variants were identified in 75/93 probands (80%) and 3 heterozygous NF2 variants were identified in 3/7 probands (43%). In NF1, 59 (87%) variants were pathogenic (4 large rearrangements - 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In NF2, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort., Conclusion: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ∼1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter- and intrafamilial variability in phenotypic expression which poses disease prediction and management problems. Some NF1 genotype-phenotype correlations have been described. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 52 NF1 patients from 45 families., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (© 2018 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.)

Neurofibromatosis type 1 (NF1) is caused, in 4.7-11% of cases, by large deletions encompassing the NF1 gene and its flanking regions within 17q11.2. Different types of large NF1 deletion occur which are distinguishable by their breakpoint location and underlying mutational mechanism. Most common are the type-1 NF1 deletions of 1.4 Mb which exhibit recurrent breakpoints caused by nonallelic homologous recombination (NAHR), also termed unequal crossover. Here, we analyzed 37 unrelated families of patients with de novo type-1 NF1 deletions by means of short tandem repeat (STR) profiling to determine the parental origin of the deletions. We observed that 33 of the 37 type-1 deletions were of maternal origin (89.2% of cases; p < 0.0001). Analysis of the patients' siblings indicated that, in 14 informative cases, ten (71.4%) deletions resulted from interchromosomal unequal crossover during meiosis I. Our findings indicate a strong maternal parent-of-origin bias for type-1 NF1 deletions. A similarly pronounced maternal transmission bias has been reported for recurrent copy number variants (CNVs) within 16p11.2 associated with autism, but not so far for any other NAHR-mediated pathogenic CNVs. Region-specific genomic features are likely to be responsible for the maternal bias in the origin of both the 16p11.2 CNVs and type-1 NF1 deletions.

Background: The aim of this retrospective study was to define clinical and molecular characteristics of a large sample of neurofibromatosis type 1 (NF1) patients, as well as to evaluate mutational spectrum and genotype-phenotype correlation. NF1 is a relatively common neurogenetic disorder (1:2500-1:3000 individuals). It is caused by mutations of the NF1 gene on chromosome 17ql1.2, with autosomal dominant pattern of inheritance and wide phenotypical variability. Café-au-lait spots (CALs), cutaneous and/or subcutaneous neurofibromas (CNFs/SCNFs), skinfold freckling, skeletal abnormalities, Lisch nodules of the iris and increased risk of learning and intellectual disabilities, as well as tumors of the nervous system and other organs are its main clinical features., Methods: The preliminary group collected 168 subjects with clinical suspicion of NF1. They were evaluated following the National Institutes of Health (NIH) criteria for NF1, revised by Gutmann et al. 1997, integrated for 67 of them by molecular testing. According to these references, 112 of 168 patients were diagnosed as NF1. The sample was characterized by an equal sex ratio (57 males, 55 females) and age distribution ranging from 10 days to 60 years of age (mean age, 13 years)., Results: A wide spectrum of clinical features has been observed in our patients. Mutational analysis resulted positive in 51 cases (76%). Twenty-four mutations detected in our cohort have not been reported to date., Conclusions: This study may contribute to a better definition of genotypic and phenotypic features of NF1 patients, with respect to further insights into the clinical characterization of the disease. In addition, an amplification of the spectrum of mutations in the NF1 gene has been documented.

Studies on monogenic diseases are considered valuable because they give insights and expand our knowledge on gene function and regulation. Despite all the current advancement in science and technology, a deep understanding and knowledge as to why only those particular genes are affected in a disease is still vague. We also lack profound illumination as to why only certain mutations are seen in a disease. Though useful from a research perspective, a majority of these diseases are lethal resulting in death of the affected individual. Unfortunately, in the fast - growing land of India, the incidence of monogenic diseases is very high with few counter-measures in place. This article encompasses a list of all monogenic diseases ever to be reported in India with special focus on five diseases which has been stated to have the highest incidence in India. Here, we discuss about the limited research carried out in India on these high incidence monogenic diseases, the other diseases related to those genes, the range of treatments available for these diseases in India in contrast to its availability around the world and the need to develop treatment strategies to reduce the mortality and morbidity due to these rare but daunting diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several skeletal aberrations of the skull have been described for the tumor predisposition syndrome neurofibromatosis type 1 (NF1). Recently, periapical cemental/cemento-osseous dysplasia (COD) has been described in females affected with NF1. This reactive lesion of the hard tissues in tooth-bearing areas of the jaw has been proposed to represent a gender-specific radiological feature of NF1. The aim of this study was to investigate the prevalence of COD in patients with NF1., Patients and Methods: The orthopantomograms (OPGs) of 179 patients with a confirmed diagnosis of NF1 were analyzed for COD. The results were compared to radiographic findings obtained in OPGs of age- and sex-matched controls. The NF1 patient group was further differentiated according to the evidence of facial plexiform neurofibroma., Results: COD was a very rare finding in both groups. The extension of the diagnostic criteria including radiologically-healthy teeth and a widened periodontal gap in the periapical area only marginally increased the number of considered cases. Although there was a somewhat more common occurrence of such changes in the patient group compared to the control group and the number of affected women was greater than the number of men, none of these differences reached statistical significance. Furthermore, COD or widening of the periradicular periodontal space was not found to be associated with facial tumor type in NF1., Conclusion: The investigation revealed that COD is not a diagnostic feature of NF1. There is no clear association of the rare finding of COD with gender. These studies should be compared with patient groups of other ethnic backgrounds., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Neurofibromatosis type 1 (NF1) is related to a generally increased prevalence of seizures. The mechanism underlying the increased predisposition to seizures has not been fully elucidated. The aim of the study was to evaluate the role of NF1 in seizures pathogenesis in a cohort of children with NF1 and seizures., Methods: The medical records of 437 children (0-18 years old) with NF1 were reviewed. All children with at least one afebrile seizure were included. Demographic, clinical, neurological, NF1 mutation status, and EEG data were collected along with brain magnetic resonance imaging. Depending on etiology, structural seizures have been identified and were further classified as NF1 related or not., Results: Nineteen patients (4.3%; 13 males) were included. NF1 was inherited in 7 (37.5%), with 3 maternal forms. Ten children with structural seizures were identified. Seven forms were identified someway related to NF1, two of which were associated to 17q11.2 microdeletion and hypoxic-ischemic encephalopathy. Any brain lesion that could explain seizures was found in nine patients, two third of these patients had a familiar history of epilepsy., Conclusions: Our results suggest seizures are more frequent in NF1 children (4.3%) than in general pediatric population (0.3-0.5%) and that are someway related to NF1 in half of patients. Facing seizures in NF1, the clinician should first exclude brain tumors but also other, and rarer NF1-related scenarios, such as hydrocephalous and vasculopathies. Children with non-structural seizures frequently had a family history of epilepsy, raising questions about the pathogenic role of NF1. They should be approached as for the general population.

Adult cerebellar glioblastomas (cGBM) are rare and their characteristics remain to be fully described. We analyzed the characteristics of 17 adult patients with cGBM and compared them to a series of 103 patients presenting a supra-tentorial glioblastoma (stGBM). The mean age at GBMc diagnosis was 53.4 years (range 28-77). A history of neurofibromatosis type I was noted in 3 patients. cGBM were hemispheric in 10 patients (58.8%), only vermian in 4 patients (23.5%), and both vermian and hemispheric in 3 patients (17.7%). A H3 K27M mutation was identified in 3/14 patients, a TERT promoter mutation in 3/14 patients and a methylated MGMT promoter in 3/14 patients. None of the patients (0/14) harbored an EGFR amplification, an IDH or a BRAF mutation. Association with neurofibromatosis type I and H3K27M mutations were mutually exclusive. Compared with stGBM, cGBM occurred in younger patients (53.4 vs. 63.2, p = 0.02), were more frequently associated with neurofibromatosis type I (18 vs. 1%, p = 0.009) and with a H3 K27M mutation (21 vs. 3%, p = 0.02). They also tended to have a more frequent multifocal presentation at diagnosis (21 vs. 4.3%, p = 0.06), more frequently resulted in leptomeningeal or intra-axial metastasis (44.5 vs. 5%, p = 0.002) and were associated with a shorter median overall survival (5.9 vs. 14.2 months, p = 0.004). The present study suggests that adult cGBM differ from their supra-tentorial counterpart and constitute a heterogeneous group of IDH wild-type gliomas with at least two subgroups, one associated with H3K27M mutations and the other with neurofibromatosis type I.

Introducción: La neurofibromatosis tipo 1 (NF1) es una entidad genética con una incidencia de 1 entre 2,500 a 3,500 nacimientos. Por su parte, el complejo esclerosis tuberosa (CET) presenta una incidencia de 1 entre 6,000 a 10,000 nacimientos. Ambas entidades neurocutáneas cursan con un patrón de herencia autosómico dominante, expresividad variable y la morbimortalidad se encuentra asociada a complicaciones multisistémicas. El objetivo de este trabajo fue exponer las características clínicas y epidemiológicas de una serie de pacientes pediátricos con diagnóstico de NF1 y CET atendidos en la Unidad de Genética Médica de la Universidad de Los Andes., Métodos: Este trabajo corresponde a una serie de casos de pacientes menores de 16 años atendidos en un período de 11 años, que cumplan con los criterios diagnósticos de NF1 y CET según los consensos para cada entidad., Resultados: Se estudiaron 89 pacientes, 73 con NF1 y 16 con CET. Presentaron dos criterios para NF1, 58 (79.45%) pacientes, y las máculas café con leche fueron las más frecuentes y presentes en todos los casos; 10 pacientes (62.50 %) presentaron dos criterios mayores para el CET, y las máculas hipocrómicas estuvieron igualmente presentes en todos los casos., Conclusiones: Este estudio muestra la forma de presentación clínica de las dos entidades neurocutáneas más frecuentes. Se discuten los criterios diagnósticos con el objeto de identificarlos a edades más tempranas y poder brindar una evaluación médica interdisciplinaria, tratamiento y un oportuno asesoramiento genético familiar., Background: Neurofibromatosis type 1 (NF1) is a genetic entity with an incidence of 1 in 2,500 to 3,500 births. Tuberous sclerosis complex (TSC) has an incidence between 1 in 6,000 to 10,000 births. Both neurocutaneous entities present an autosomal dominant inheritance pattern, variable expressivity and their morbidity and mortality is associated with multisystemic complications. The aim of this study was to present the clinical and epidemiological characteristics of a series of pediatric patients diagnosed with NF1 and TSC, who were treated in the Medical Genetics Unit of the Universidad of Los Andes., Methods: This work corresponds to a series of cases of patients under 16 years of age served in a period of 11 years, who met the diagnostic criteria of NF1 and CET according to the consensus for each entity., Results: We studied 89 patients, 73 with NF1 and 16 with TSC. 58 (79.45%) of the patients presented two criteria for NF1, with café-au-lait macules being the most frequent and present in all cases. 10 (62.50%) of the patients presented two major criteria for TSC; hypochromic macules were equally present in all cases., Conclusions: This study shows the clinical presentation of the two most frequent neurocutaneous entities. Diagnostic criteria are discussed in order to perform them at younger ages and to provide an interdisciplinary medical evaluation, treatment and timely family genetic counseling., (Copyright: © 2018 SecretarÍa de Salud.)

Neurofibromatosis 1 (NF1) is characterized by cutaneous, neurological and osseous manifestations. Most NF1 patients develop cutaneous neurofibromas. However, time-dependent change with aging and the predilection site of cutaneous neurofibromas remain unclear. To clarify the natural course and characteristics of cutaneous neurofibromas, a retrospective study was conducted for 57 NF1 patients who were treated at the Department of Dermatology of Tottori University Hospital between January 2007 and April 2016. For each patient, we investigated the time-dependent changes and the numbers of cutaneous neurofibromas in four body surface regions. There was a positive correlation between age and number of cutaneous neurofibromas (r = 0.75, P < 0.001). Cutaneous neurofibromas were located on the trunk (60.2%), lower limbs (16.1%), upper limbs (14.4%), and head and neck (9.2%). There was no significant relationship between each body type (e.g. obese or thin) and cutaneous neurofibromas. With respect to the year-to-year percentage change in cutaneous neurofibromas, the average annual rate of increase was 0.21 (range, -0.71 to 1.2). The number of cutaneous neurofibromas had increased in approximately 61% of the patients 1 year later. Our data will enable physicians to estimate the overall state of cutaneous neurofibromas in NF1 and will be useful for handling cutaneous manifestations before they become a serious condition., (© 2017 Japanese Dermatological Association.)

Background: The aim of this study was to determine the frequency of central nervous system comorbidities in children with neurofibromatosis type 1 (NF1)., Methods: We performed a nationwide survey to investigate neurological comorbidities in 3-15-year-old children with NF1 in Japan by sending questionnaires to pediatricians and pediatric neurologists. A secondary questionnaire was sent to the parents of identified NF1 patients to assess neurological comorbidities including headache, attention deficit-hyperactivity disorder (ADHD) Rating Scale (RS), and the Social Responsiveness Scale 2., Results: The primary survey identified 760 NF1 patients, and the parents of 565 patients were sent the secondary questionnaire. The parental response rate was 25.7% (145; 63 girls, 81 boys, one unspecified). Among the patients, 42.9% (55/128; 35 girls, 20 boys) were reported to exhibit intellectual problems. On the ADHD-RS, 40.2% (47/117) of NF1 patients aged 6-15 had ADHD (RS score >93rd percentile), with a rate of 47.7% in boys and 30.8% in girls. Furthermore, 20.2% of patients had suspected autism spectrum disorder (29/143; 10 girls, 19 boys), with Social Responsiveness Scale score ≥76. Headache was reported by 49.6% (61/123) of children over 5 years old, and 25.2% (31/123; 10 girls, 21 boys) reported migraine. Other neurological comorbidities included 20 cases of epilepsy (13.8%), 11 cases of optic nerve glioma (7.6%), five cases of brain tumor (3.4%), six cases of cerebrovascular disease (4.1%), and two cases of hydrocephalus (1.4%)., Conclusion: Intellectual problems, ADHD, autism spectrum disorder, and migraine are major neurological comorbidities in NF1., (© 2017 Japan Pediatric Society.)

Neurofibromatosis 1 (NF1) is a genetic disease characterized by cutaneous, neurological and osseous complications. Although clinical manifestations of NF1 are variable, there has been no report on evaluation of severity in patients with NF1. To elucidate the grade of severity of NF1, a retrospective study was conducted in 124 NF1 patients at the Department of Dermatology of Tottori University Hospital in 2007-2016. The DNB classification (dermatological, neurological and bone manifestations) in Japan was used for assessment. Based on our current epidemiological data, there were 55 patients (44.3%) in stage 1, 23 (18.6%) in stage 2, three (2.4%) in stage 3, one (0.8%) in stage 4 and 42 (33.9%) in stage 5. The grade of severity in patients with NF1 tended to be higher with aging. Remarkably, 61.8% of the patients in stage 5 had diffuse plexiform neurofibromas with functional disability. We should pay attention to diffuse plexiform neurofibromas that greatly affect quality of life in patients with NF1., (© 2017 Japanese Dermatological Association.)

Over the past several decades, neurofibromatosis type 1 (NF1) has become increasingly recognized as a neurodevelopmental disorder conferring increased risk for several important neurodevelopmental problems. In this review, we summarize the specific neurodevelopmental problems encountered in the context of NF1. These include impairments in general cognitive function, deficits in specific cognitive domains such as executive function and visuospatial processing and risk for specific learning disorders, impairments in attention and social skills and the overlap with attention-deficit-hyperactivity disorder and autism spectrum disorder, and the risk of developing other psychiatric conditions including anxiety and depression. Early recognition of these developmental impairments is important for the effective treatment of children with NF1, and further characterization is essential to improve our understanding of how mutations in the NF1 gene create the diversity of clinical neuropsychiatric symptomatology observed in this at-risk population., (© 2017 Mac Keith Press.)

Background: Neurofibromatosis type 1 (NF1) is a common single-gene disorder. A multidisciplinary approach to the management of NF1 patients is necessitated by the heterogeneity of clinical manifestations. Although multidisciplinary paediatric clinics have been well established, there is a dearth of such resources for adults with NF1. Herein we report our one-year institutional experience with a multidisciplinary adult NF1 clinic., Methods: A multidisciplinary team was assembled, and an NF Patient Registry Initiative questionnaire was adapted to collect patient-reported data during clinics. Multiple databases were searched to identify publications pertaining to the experience of other multidisciplinary NF1 clinics focusing on adult patients. Data on patient epidemiology and clinical staff were compared to our data., Results: A total of 77 patients were scheduled, and 68 attended the clinic, of whom 66 completed the intake questionnaire. The demographic and clinical data from this Canadian population are mostly consistent with previous reports, with some exceptions. Clinical data related to immune system involvement such as asthma, airway/breathing-related difficulties or allergies were striking in our NF1 population. Six relevant published reports of other NF1 clinics were identified. Reports from these studies pertained to periods ranging from 10 to 38 months, and the number of adults assessed ranged from 19 to 177 patients., Conclusions: The structure of our clinic and the patient volume are comparable to those of other established centres found in the literature. Our data offer valuable cross-sectional prevalence statistics in the Canadian population. The patient-reported data concerning involvement of the immune system contribute to an emerging recognized medical concern within the NF1 population and warrant further clinical and basic investigation.

Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.

Background: Although isolated cafe-au-lait macules (CALMs) are a common skin finding, they are an early feature of neurofibromatosis type 1 (NF1)., Objective: We sought to develop an algorithm determining the risk of children with CALMs to have constitutional NF1., Methods: We conducted a retrospective study of patients with isolated CALMs. Diagnosis of NF1 was based on detecting NF1 mutation in blood or fulfilling clinical criteria., Results: In all, 170 of 419 (41%) and 21 of 86 (24%) children with isolated CALMs who underwent molecular testing and clinical follow-up, respectively, were given a diagnosis of NF1. Presence of fewer than 6 CALMs at presentation or atypical CALMs was associated with not having NF1 (P < .001). An algorithm based on age, CALMs number, and presence of atypical macules predicted NF1 in both cohorts. According to the algorithm, children older than 29 months with at least 1 atypical CALM or less than 6 CALMs have a 0.9% (95% confidence interval 0%-2.6%) risk for constitutional NF1 whereas children younger than 29 months with 6 or more CALMs have a high risk (80.4%, 95% confidence interval 74.6%-86.2%)., Limitations: The study was designed to detect constitutional NF1 and not NF1 in mosaic form., Conclusions: A simple algorithm enables categorization of children with isolated CALMs as being at low or high risk for having NF1., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1)., Methods: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed., Results: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups., Conclusions: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only., (© 2017 American Academy of Neurology.)

Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers., Methods: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls., Results: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P=0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population., Conclusions: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive group of soft tissue sarcomas that can arise sporadically, in the context of neurofibromatosis Type 1 (NF1) or at a site of prior irradiation. Large series profiling the features and outcomes of sporadic, NF1-associated, and radiation-associated MPNSTs are limited. The goal of this study was to elucidate differences between MPNST etiologies in a large single-institution retrospective study. METHODS Patients (n = 317) were identified through the tumor registry of The University of Texas MD Anderson Cancer Center. Clinicopathological features were retrospectively collected. Features were compared among MPNST subtypes for patients who had sufficient clinical history (n = 289), and clinicopathological features were used to identify adverse predictors of recurrence and survival outcomes. RESULTS Five-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and disease-specific survival (DSS) estimates were 56.6%, 49.6%, and 53.6%, respectively, for the high-grade MPNST cohort. Five-year DSS was lower in NF1-associated and radiation-associated MPNST than in sporadic MPNST (52%, 47%, and 67%, respectively, p = 0.140). Patients with radiation-associated MPNST had worse 5-year LRFS than those with the sporadic and NF1-associated subtypes (RT-associated vs sporadic, p = 0.010; RT-associated vs NF1-associated, p = 0.232). Truncally located tumors, positive surgical margins, local recurrence, and metastasis were predictors of adverse DSS in multivariate analysis. CONCLUSIONS Radiation-associated MPNSTs are associated with poorer local recurrence-free and disease-specific survival than sporadic and NF1-associated tumors. NF1-associated MPNSTs may have worse survival outcomes owing to large tumor size, compromising truncal location, and lower rate of negative resection margins compared with sporadic tumors.

Background/aims: Children with optic pathway glioma (OPG) face sequelae related to tumour location and treatment modalities. We aimed to assess the prevalence of hypothalamic-pituitary dysfunctions in children with neurofibromatosis type 1 (NF1) and OPG who did not receive radiotherapy or surgical resection. The causative role of tumour location on endocrinopathy development is investigated., Methods: A retrospective follow-up study of 40 children with NF1 and OPG evaluated between August 1996 and May 2015 was undertaken. Patients who underwent radiotherapy or surgical resection were excluded and 36 patients were studied. Tumour location was classified according to the Dodge criteria: stage I, optic nerve alone; stage II, optic chiasm with or without optic nerve involvement; and stage III, involvement of the hypothalamus or other adjacent structures., Results: Endocrinopathies were diagnosed in 20/36 (55.6%) children during a mean follow-up of 9.1 (0.2-13.6) years: 0/4 OPGs were Dodge stage I, 12/21 (57.1%) stage II, and 8/11 (72.7%) stage III. The first endocrinopathy was found at a mean age of 7.4 (5.0-13.2) years, 2.4 (0-6.7) years after tumour diagnosis. We found growth hormone deficiency (GHD; 36.1%), central precocious puberty (33.3%), obesity with insulin resistance/impaired glucose tolerance (11.1%), early puberty (5.5%), GH excess (5.5%), ACTH deficiency (5.5%), hypogonadotropic hypogonadism (2.7%), and thyrotropin deficiency (2.7%). GHD was transient in all of those who were retested., Conclusion: This population is at high risk of endocrinopathies due to tumour location. Lifelong endocrine follow-up is recommended.
., (© 2017 S. Karger AG, Basel.)

Neurofibromatosis Type 1 (NF1) plexiform neurofibromas (pNFs) are associated with a variety of symptoms and concerns that affect patients' quality of life (QOL), highlighting the value of incorporating the patients' perspective when evaluating treatment outcomes. To better conceptualize the experience of patients with pNFs, this qualitative study sought to identify the most important outcomes to assess from the perspective of patients, families, and clinicians. Clinicians, patients age 5 years old and above, and parents of patients aged 5-17 years participated in semi-structured interviews to elicit the pNF symptoms/concerns considered most important to assess. The data were analyzed using an iterative coding procedure and the frequency with which symptoms/concerns emerged was tabulated. Eight clinicians, 31 patients, and 17 parents of patients participated in semi-structured interviews. The most frequently reported concerns raised by patients across all age groups included pain, appearance/disfigurement, social activity/role participation, stigma, and anxiety. For parents, physical functioning was the primary concern, followed by pain, social activity/role participation, appearance/disfigurement, and social relationships. The resulting conceptual framework included five domains to represent the most important identified symptoms/concerns: pain, social functioning, physical function impact, stigma, and emotional distress. This conceptual framework describing the symptoms/concerns of patients with pNF can help investigators create a measurement system to improve assessment of aspects of QOL only patients can report on. It may also provide the ability to identify symptoms/concerns that might warrant referrals to various clinical disciplines. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)