Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation.

PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.

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.

First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics.

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Recent developments in neurofibromatoses and RASopathies: management, diagnosis and current and future therapeutic avenues.

Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues" chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collaborations directed towards the best practices and therapies for individuals with RASopathies.

Cognition in children with neurofibromatosis type 1: data from a population-based study.

AIM: This study aimed to investigate the core cognitive deficits in children with neurofibromatosis type 1 (NF1). METHOD: The study recruited 49 children with NF1 (25 males, 24 females; mean age 11y 9mo [SD 3y 2mo]), 19 healthy siblings of children with NF1 (sibling comparisons; mean age 12y 7mo [SD 2y 7mo], 9 males, 10 females) and 29 healthy children from the community (community comparisons; mean age 11y [SD 2y 7mo], 12 males, 17 females). Participants completed a battery of cognitive tests including tests of intelligence, academic achievement, attention, visuoperceptual functioning, visual learning, executive functioning, and non-verbal working memory tests. RESULTS: Our study, using a population-based sample, confirmed previous findings from studies using variable sampling methods. Children with NF1 had significantly lower Full-scale IQs (p=0.04) and lower academic achievement (p=0.026-0.005) than their siblings. Compared with their siblings, they also had significantly poorer visuospatial processing (p=0.007), visual associate learning (p=0.014), non-verbal working memory (p=0.023), and executive function (p<0.001). Data from the community comparisons were not included because they were subject to significant selection bias. INTERPRETATION: Population-based frequencies for cognitive deficits in children with NF1 are similar to the frequencies in non-population based samples. This study highlights the heterogeneous nature of cognitive problems in children with NF1 and the need for monitoring and support at school.

Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed.

Neurofibromatosis type 1 and autism spectrum disorder.

OBJECTIVE: To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1). METHODS: Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS≥76; n = 32), moderate ASD (SRS ≥ 60<76; n = 29), or non-ASD (SRS <60, n = 48). Twenty-three cases from the significant ASD group, 16 from moderate ASD, and 8 from non-ASD (total n = 47), invited proportionately by random selection, were seen for detailed confirmatory ascertainment. Assessments on Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population. RESULTS: Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%-42.1%) and 20.8% broad ASD (95% confidence interval 10.0%-38.1%); a total of 45.7% showing some ASD spectrum phenotype. CONCLUSIONS: Findings indicate high prevalence of ASD in NF1, with implications for clinical practice and further research into NF1 as a single-gene model for autism.

Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis.

BACKGROUND: Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families. METHOD: Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1. RESULTS: Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed. CONCLUSIONS: Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1.

Spinal bone defects in neurofibromatosis type I with dural ectasia: stress fractures or dysplastic? A case series.

OBJECTIVES: Neurofibromatosis type I (NF1) is a multisystem neurocutaneous disorder with varied musculoskeletal manifestations. Dural ectasia is a known association, whilst pedicular anomalies have been described, although not as frequently as other skeletal manifestations. However, reports of pedicular and other spinal clefts or fractures in combination with dural ectasia in NF1 are scarce. We aimed to identify osseous defects in the posterior elements of NF1 patients with dural ectasia. METHODS: Images of patients with NF1 and back pain were reviewed for osseous defects in the posterior elements. RESULTS: Four patients were identified with NF1, back pain, dural ectasia and bone defects. The imaging appearances of the defects are illustrated. CONCLUSIONS: Defects in the spinal posterior elements of patients with NF1, back pain and dural ectasia may be dysplastic, stress fractures or, most probably, multifactorial in origin. Computed tomography demonstrates these defects most clearly.

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.

Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study.

AIM: To investigate psychopathology in children with neurofibromatosis type 1 (NF1), particularly the prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) symptomatology, using a population-based sampling approach. METHOD: Standard questionnaire screen reports were analysed for ASD (Social Responsiveness Scale, SRS), ADHD (Conners' Parent Rating Scale- Revised, CPRS-R), and other psychiatric morbidity (Strengths and Difficulties Questionnaire, SDQ) from parents and teachers of children aged from 4 to 16 years (112 females, 95 males) on the UK North West Regional Genetic Service register for NF1. RESULTS: Parental response rate was 52.7% (109/207 children; 59 females, 50 males, mean age 9 y 11 mo, SD 3 y 3 mo). The SRS showed that in 29.4% (32/109) of children, autism was in the severe, clinical range (T-score>75) and in 26.6% (29/109) in the mild to moderate range (T-score 60-75). CPRS-R scores showed that in 53.8% (57/106) of children autism was in the clinical ADHD range (ADHD index T-score>65). Based on their scores on the SDQ total difficulties scale, 41.5% (44/106) of children were in the abnormal range and 14.2% (15/106) were in the borderline range. Twenty-five per cent (26/104) of children met criteria for both clinical autism and ADHD. INTERPRETATION: This representative population-based sample of children with NF1 indicates a high prevalence of ASD symptoms associated with NF1 as well as substantial co-occurrence with ADHD symptoms. The findings clarify the psychopathology of NF1 and show the disorder as a potentially important single-gene cause for autism symptoms.

Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence.

AIM: This systematic review aimed to pull together the findings from research into behavioural systems and attention in children with neurofibromatosis type 1 (NF1) and to identify areas that need further study. METHOD: Relevant papers were identified through searches of electronic databases (MEDLINE, PsycINFO, EMBASE) and manual searches through reference lists. In total, 5746 articles were identified and 57 met the inclusion criteria. The data were synthesized using the narrative approach, as the studies varied considerably in terms of participants and measures. RESULTS: The results of the review showed that intelligence, academic skills, visuospatial skills, social competence, and attention are impaired in children with NF1. Evidence of deficits in memory, motor functioning, language, and executive functions was less clear. INTERPRETATION: Research has made marked progress in outlining the behavioural phenotype of NF1. However, although the general areas of impairment are becoming better known, the exact nature of the impairment is still not understood in many areas of behaviour. Care needs to be taken with the way in which behavioural constructs are defined and measured, and the variability of problems in NF1 is a particular challenge. Nevertheless, research is steadily moving towards comprehensive understanding of behaviour in children with NF1.

Malignant peripheral nerve sheath tumours in inherited disease.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNST) are rare tumours known to occur at high frequency in neurofibromatosis 1 (NF1), but may also occur in other cancer prone syndromes. METHODS: The North West Regional Genetic Register covers a population of 4.1 million and was interrogated for incidence of MPNST in 12 cancer prone syndromes. Age, incidence and survival curves were generated for NF1. RESULTS: Fifty two of 1254 NF1 patients developed MPNST, with MPNST also occurring in 2/181 cases of schwannomatosis and 2/895 NF2 patients. Three cases were also noted in TP53 mutation carriers. However, there were no cases amongst 5727BRCA1/2 carriers and first degree relatives, 2029 members from Lynch syndrome families, nor amongst 447 Familial Adenomatous Polyposis, 202 Gorlin syndrome, nor 87 vHL cases. CONCLUSION: MPNST is associated with schwannomatosis and TP53 mutations and is confirmed at high frequency in NF1. It appears to be only increased in NF2 amongst those that have been irradiated. The lifetime risk of MPNST in NF1 is between 9-13%.

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

Life expectancy in hereditary cancer predisposing diseases: an observational study.

BACKGROUND: Neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), familial adenomatous polyposis (FAP), von Hippel-Lindau syndrome (VHL), and Gorlin syndrome (GS) are single gene diseases that predispose to early onset tumours. Few studies have assessed the effect of these diseases on life expectancy. This study's aim was to assess this effect, and to test the hypothesis that genetic registers increase survival. METHOD: NF1, NF2, VHL, FAP, and GS patients were identified through the North West Regional Genetic Register Service and the North West Cancer Intelligence Service. Information on benign and malignant tumours, and deaths were obtained. Kaplan-Meier curves were used to show actuarial survival rates for each disease, compared to the local population, and in patients diagnosed pre/post the regional genetic register. Log rank (Mantel-Cox) tests were used to compare survival between groups. RESULTS: Life expectancies were significantly reduced for all diseases investigated compared with the local population (80.0 years) (p=0.05). GS had the longest life expectancy at 73.4 years, followed by NF1 at 71.5 years, NF2 at 69.0 years, FAP at 63.6 years, and VHL at 52.5 years. Patients diagnosed after establishment of the genetic register had an increase in survival compared to those diagnosed pre-1990: NF2 (14.7 years), FAP (13.9 years), VHL (16.3 years), and GS (11.2 years). CONCLUSION: Life expectancy for all five diseases was less than normal, although in recent years this reached the level of the local population in GS. Although there have been improvements in all conditions which may in part be attributable to better targeted care through the genetic register service, more needs to be done to address the very poor life expectancy in VHL.

Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas, and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro-oncology patients afflicted with these tumors.

Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989.

Neurofibromatosis 1 (NF1) is a comparatively common autosomal dominant disorder. However, relatively few studies have assessed lifetime risk; and information about the effect of NF1 on mortality remains uncertain. NF1 patients were identified using The North West regional family Genetic Register, which covers the 4.1 million people living in North West England, including the regions of Greater Manchester, Cheshire and Cumbria. Data relating to tumours and malignancies were obtained from The North West Cancer Intelligence Service. Death data for the general North West population were obtained from the Office of National Statistics. We identified 1186 individuals with NF1, of whom 1023 lived within the strict regional boundaries (constituting a region of North West England bound by The Pennines to the east and Irish Sea to the west, but excluding the conurbation of Liverpool (Merseyside) and the Wirral peninsula) and 131 had died. MPNST and glioma were found to be the two most common causes of reduced life expectancy among NF1 patients. In Kaplan-Meier analyses the median survival for NF1 patients was shown to be 71.5 years, with women living ∼7.4 years longer than men. On average both men and women lived ∼8 years less than their counterparts in the general population. Reduction in life expectancy for NF1 patients was found to be much lower (8 years) than the previously estimated 15-year decrease. Limitations relating to the underreporting of NF1 on death certificates were once again highlighted and should be considered in future investigations.

Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNST) are the main soft tissue malignancy associated with neurofibromatosis 1. These uncommon tumours are known to occur at high frequency and lead to poor survival. Our aim was to determine risk of MPNST in NF1 patients, and survival rates. METHODS: The incidence of MPNST in NF1 was identified through the NF1 genetic register and The North West Cancer Intelligence Service (NWCIS). Data were used to generate incidence and survival curves. Strict regional boundaries were adhered to avoid ascertainment bias. Kaplan-Meier curves were used to determine five and ten-year survival. RESULTS: Of the 1059 NF1 patients 52 developed MPNST (30 cases in females and 22 in males), 43 cases were resident within the strict regional boundary. The risk of MPNST was 10.2% in males and 12.7% in females by age 70 years (p=0.9), with a statistically better survival in females than males (5 and 10 year survival 46% and 41.5% versus 22% and 8.2%; p=0.05). Survival was also significantly improved for patients diagnosed in the last 14 years compared to the previous 13-year period (p=0.03). CONCLUSION: With fifteen strict regional MPNSTs in the fourteen years since our previous population study an annual incidence of above 1 per 1000 NF1 patients has now been maintained over a 27-year period. No significant increase in risk of MPNST in females compared to males was found, though the difference in survival is intriguing. Male survival is particularly poor with <10% alive at 10 years.