Early childhood diagnosis of acoustic neuromas in presymptomatic individuals at risk for neurofibromatosis 2.

We report on a family in which individuals at risk for NF 2 were investigated with the use of gadolinium-enhanced MRI. This technique has allowed the diagnosis of small (less than 8 mm) acoustic neuromas in two asymptomatic children (age 7 and 11), one of whom had normal audiometric and brainstem-evoked response testing. To our knowledge these are the youngest asymptomatic patients in whom the diagnosis of NF 2 has been demonstrated. It is possible that acoustic neuromas develop at an early age more commonly than recognized previously. The early diagnosis of acoustic neuromas with the use of gadolinium-enhanced MRI may lead to better outcome following surgery. This technique will provide the opportunity to better determine the natural course of this disease.     

Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1

Optic pathway tumors (OPT) occur in about 15% of individuals with Neurofibromatosis Type 1 (NF1) and may effect substantial visual loss. Because their growth is not predictable at the time of discovery, neuroimaging for OPT in asymptomatic NF1 patients remains controversial. We evaluated the outcomes of systematic screening by both MRI and ophthalmic examinations for OPT in young children with NF1 seen at multi-disciplinary clinics for Neurofibromatosis and Genetics at one institution between 1996 and 2001. We report on 84 children who presented with NF1 under age 6 years, of whom 13 children presented with either known OPT or abnormal MRI findings and 11 children had OPTs identified by neuroimaging, including two children with abnormal eye examinations at presentation (one with strabismus and one with optic atrophy). Nine OPTs were detected in asymptomatic subjects with normal ophthalmic examinations. Three children with chiasmal lesions enlarging on subsequent MRI were treated with carboplatin and vincristine. After treatment, the vision in each involved eye was intact. In contrast, the 13 children with OPT diagnosed outside of screening guidelines included five children with substantial visual loss. Our observations suggest that early recognition of NF1 promotes appropriate surveillance and allows early intervention to reduce complications of OPT. This analysis supports prospective studies to compare the outcomes of systematic screening with neuroimaging to screening with ophthalmic examinations alone in children with NF1.     

Frequency of incidental intracranial aneurysms in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is often mentioned among the heritable connective tissue disorders associated with intracranial aneurysms, but the association has not been firmly established. We therefore reviewed a contemporary series of hospitalized patients with NF1, many of whom underwent brain magnetic resonance imaging (MRI). We identified patients with NF1 who were hospitalized at Cedars-Sinai Medical Center, Los Angeles, California, between January 1, 1997 and December 31, 2001 through the hospital's centralized medical records system using DRG codes. The mean age of the 39 patients was 30.4 years, and 22 patients had undergone MRI of the brain for the evaluation of symptoms due to the presence of central or peripheral nervous system tumors. Incidental intracranial aneurysms were detected in 2 (5%) of the 39 patients. Limiting the patient population to the 22 patients who had undergone MRI examination, the detection rate was 9%. This was significantly (P < 0.005) higher than the aneurysm detection rate in a control population (0/526 [0%]) of patients hospitalized for primary or secondary brain tumors, all of whom had undergone MRI examination. Our study suggests that patients with NF1 are at an increased risk of developing intracranial aneurysms.     

Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome

Children with neurofibromatosis type 1 (NF1) may present with optic pathway gliomas (OPG) that can progress to visual loss or other neurologic symptoms. These tumors may become evident either as a result of patient signs or symptoms or as an incidental finding on "baseline" neuroimaging studies. In an attempt to determine if there were differences between symptomatic and asymptomatic children with OPG, a retrospective cohort study of ninety children with NF1 and OPG was performed using data from two large NF1 referral centers. Age at diagnosis, presenting symptoms, tumor location, associated features, and clinical response were assessed for children who were initially symptomatic from their OPG (n = 51) and compared to similar data of asymptomatic children whose tumors were incidentally discovered by MRI (n = 39). There were no differences in age at presentation, tumor location, NF1-associated symptoms, or clinical response between the groups. Initially symptomatic children were much more likely to require treatment (OR: 14.8, 95% CI [1.9-116.7]) than those with incidentally discovered, asymptomatic OPG. Although 36% of OPG were diagnosed in children over the age of 6 years, none received prior neuroimaging and only two children had previously normal eye examinations, suggesting that the vast majority of OPG in this group were longstanding, undiagnosed tumors. Based on these findings, we do not advocate "baseline" MRI in children with NF1, but strongly recommend that all children of the age 10 years and younger with NF1 have complete annual ophthalmologic evaluations.     

Diagnostic issues in a family with late onset type 2 neurofibromatosis.

We report a family with type 2 neurofibromatosis and late onset tumours. Five members of this family have developed hearing loss late in life, two of whom have only been shown to have the diagnosis in their seventies, and three other obligate gene carriers died undiagnosed at 64, 72, and 78 years of age. A missense mutation at the C-terminal end of the NF2 protein has been identified in this family and segregates with disease. The use of highly polymorphic markers for predictive testing is also shown. There appears to be an autosomal dominant form of spinocerebellar degeneration which is segregating separately to NF2 in this family, which created a diagnostic dilemma.     

Minor disease features in neurofibromatosis type 1 (NF1) and their possible value in diagnosis of NF1 in children < or = 6 years and clinically suspected of having NF1. Neurofibromatosis team of Sophia Children''s Hospital.

OBJECTIVE: To establish the frequency of minor disease features in children with neurofibromatosis type 1 (NF1) and to evaluate the value of minor disease features in children < or = 6 years with a suspected diagnosis of NF1, considering that the disease is virtually 100% penetrant at 6 years of age. DESIGN: During this 10 year, prospective, multidisciplinary, follow up study, 209 children suspected of having NF1 were examined; 150 were diagnosed with NF1 and 59 were not. The present analysis included children in whom NF1 was considered to be present at 6 years of age (n=85) and children without NF1 at 6 years of age (n=42). RESULTS: The minor disease features macrocephaly (52.9%), short stature (24.7%), hypertelorism (63.5%), and thorax abnormalities (37.6%) were highly prevalent in children with NF1 and significantly associated with a diagnosis of NF1 at 6 years of age. In addition, the mean number of minor disease features was significantly higher in children with NF1 at 6 years of age compared to the group without a diagnosis at 6 years of age (mean 1.8 v 0.8, p<0.001). Moreover, children with three or more minor disease features were all diagnosed with NF1 under the age of 6 years. Multivariate analysis using a logistic regression model showed that macrocephaly, short stature, hypertelorism, and thorax abnormalities were all independently associated with the presence of NF1 at 6 years of age. CONCLUSION: In children with insufficient diagnostic criteria aged < or = 6 years, documentation of minor disease features may be a helpful aid in predicting the diagnosis of NF1 in years to come.     

Clinical sensitivity and specificity of multiple T2-hyperintensities on brain magnetic resonance imaging in diagnosis of neurofibromatosis type 1 in children: diagnostic accuracy study

Aim

To determine the prevalence, number, and location of multiple (≥2) T2-hyperintensities on brain magnetic resonance imaging (MRI) in children with neurofibromatosis type 1 (NF1) and their correlation with age, and to establish their sensitivity, specificity, and accuracy for the diagnosis of NF1 in children, especially in the early age (2-7 years).

Methods

We performed a cross-sectional study of 162 patients with NF1 from Croatian Neurofibromatosis Association Database and 163 control children between the ages of 2 and 18 years who underwent brain MRI between 1989 and 2009.

Results

Multiple T2-hyperintensities were present in 74% of NF1 patients and 1.8% of controls. They were mainly located in the basal ganglia, brainstem, and cerebellum and were significantly decreased in prevalence and number in the older age. T2-hyperintensities had excellent diagnostic accuracy with the area under the receiver operating characteristic (ROC) curve of 0.849 and 95% confidence interval (CI) of 0.805-0.886. The diagnostic sensitivity, specificity, and accuracy rate of T2-hyperintensities for NF1 were highest in the youngest age (2-7 years): 81% (95% CI 71%-89.1%), 99% (95% CI 92.3%-100%), and 85.8 (95% CI 83.3-93.8), respectively.

Conclusion

This study strongly suggests the inclusion of T2-hyperintensities on brain MRI on the list of diagnostic criteria for NF1, especially in children of early age, when the clinical penetration of the NF1 gene has not yet been completely finished.Neurofibromatosis type 1 (NF1) or von Recklinghausen''s disease is one of the most common autosomal dominant inherited diseases in humans with an estimated birth incidence of 1/2500 and a disease prevalence of 1/3000-4000 (1). NF1 gene is located on the pericentromeric region of chromosome 17q11.2 (2). It is a megagene, spaning 350 kb of genomic DNA and consisting of 60 exons encoding an 11-13 kb GTPase activating protein – neurofibromin of 2818 amino acids (3,4). The mutation rate for NF1 gene is high. A half of all NF1 cases are familial, while the other half is caused by a new mutation (5). Genetic molecular testing confirms the disease’s existence but has no predictive value for its severity and course.In the past thirty years, the diagnosis of NF1 was made using a set of clinical criteria developed by the National Institutes of Health Consensus Conference, so called NIH diagnostic criteria (6). The diagnosis of NF1 is based on the presence of two or more of the following: 1) six or more café au lait macules, the greatest diameter of which is more than 0.5 cm in prepubertal patients and more than 1.5 cm in postpubertal patients; 2) two or more neurofibromas of any type, or one plexiform neurofibroma; 3) freckling in the axillary or inguinal region; 4) optic glioma; 5) two or more Lisch nodules; 6) a distinctive osseous lesion such as sphenoid dysplasia or pseudarthrosis; 7) a first-degree relative with NF1 according to the preceding criteria. However, the diagnosis cannot always be made in all children using the above mentioned criteria, especially in early childhood when the penetration of NF1 gene in usually not complete (7,8).The cranial magnetic resonance imaging (MRI) is the best method for showing many features of NF1, including optic pathway gliomas, brain tumors of various locations, brain stem tumors, and orbital neurofibromas. Most frequent brain changes in children with NF1 are areas of increased T2-weighted signal intensity – T2-hyperintensities or “unidentified bright objects,” as they usually cannot be visualized using T1-weighted imaging. T2-hyperintensities are age-related findings on MRI and have been observed in 43%-93% of children who suffer from NF1 (9-11). These lesions do not exert mass effect, contrast enhancement, or surrounding edema. They are most commonly found in the basal ganglia, thalamus, cerebellum, and brainstem (12). Former research on multiple T2-hyperintensities on brain MRI in children as diagnostic criterion for NF1 was contradictory and scarce (13-17).The aim of this cross-sectional study was to determine the prevalence, number, and location of multiple (≥2) brain T2-hyperintensities on MRI, and their correlation with age in children with NF1. A further aim was to determine the indicators of diagnostic accuracy of T2-hyperintensities in children of different ages, especially in the early age (from 2 to 7 years) when the NF1 gene penetration is still not completed.     

Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas

Neurofibromatosis type 2 (NF2) must be suspected in patients presenting with a unilateral vestibular schwannoma at a young age who are therefore at theoretical risk of developing bilateral disease. We identified 45 patients aged 30 years or less at the onset of symptoms of a unilateral vestibular schwannoma. Molecular genetic analysis of the NF2 gene was completed on peripheral blood samples in all 45 and on 28 tumour samples. No pathogenic NF2 mutations were identified in any of the blood samples. NF2 point mutations were identified in 21/28 (75%) tumour samples and loss of heterozygosity (LOH) in 21/28 (75%) tumour samples. Both mutational hits were identified in 18/28 (65%) tumour samples. In one multilobular tumour, one (presumably first hit) mutation was confirmed which was common to different foci of the tumour, while the second mutational event differed between foci. The molecular findings in this patient were consistent with somatic mosaicism for NF2 and the clinical diagnosis was confirmed with the presence of two meningiomas on a follow up MRI scan. A further patient developed a contralateral vestibular schwannoma on a follow up MRI scan in whom neither of the truncating mutations in the vestibular schwannoma were present in blood.

It is important when counselling patients with unilateral vestibular schwannomas to identify (1) those at risk of bilateral disease, (2) those at risk of developing other tumours, and (3) other family members at risk of developing NF2. Comparing tumour and blood DNA cannot exclude mosaicism in the index case and cannot, therefore, be used to predict those at risk of developing further tumours. However, identification of both mutations or one mutation plus LOH in the tumour and exclusion of those mutations in the blood samples of the sibs or offspring of the affected case may be sufficient to render further screening unnecessary in these relatives.

     

ERN GENTURIS clinical practice guidelines for the diagnosis,treatment, management and surveillance of people with schwannomatosis

A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70–85% of familial schwannomatosis and 30–40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12–14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients’ psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.Subject terms: Cancer genomics, Whole body imaging     

Age related shift in the mutation spectra of germline and somatic NF2 mutations: hypothetical role of DNA repair mechanisms

It has been suggested that somatic mutations that accumulate due to an age related decline in the efficiency of DNA repair mechanisms might contribute to the increased incidence of cancer in older people. However, there is little direct evidence for this phenomenon. The spectra of germline and somatic mutations can be compared in cancer genes that cause inherited tumour syndromes and sporadic tumours, respectively. In addition, mosaic patients reflect the nature of mutations that occur in early development. Hence, we hypothesised that the "temporal mutation record" of a human cancer gene might provide insight into mechanisms of mutagenesis in the germline, in early development, and in adulthood. We compared the ratio of frameshift to nonsense mutations in three diseases that are related to the NF2 tumour suppressor gene: classic neurofibromatosis 2 (NF2), caused by germline NF2 mutations; mosaic NF2; and unilateral sporadic vestibular schwannoma (USVS), caused by somatic NF2 inactivation. Nonsense mutations predominated in both classic and mosaic NF2, but the ratio of nonsense to frameshift mutations was reversed in USVS. Moreover, in USVS patients, the ratio of somatic frameshift to nonsense mutations increased significantly with increasing age at diagnosis. This pattern is consistent with an age related decline in the efficiency of DNA repair mechanisms. Similar studies for other familial cancer genes may provide further evidence for this hypothesis.     

Aneurysms involving the coronary arteries in a neonate with neurofibromatosis 1

Aneurysmal coronary artery disease (ACAD) has been reported rarely in patients with neurofibromatosis type 1 (NF1), mostly in adults. We report on a female newborn affected by NF1 with ACAD disclosed during investigation for an abnormal prenatal ultrasound along with a review of the previously reported cases. The proposita had multiple café-au-lait spots and had no cardiac symptoms. Echocardiography, and cardiac computed tomography angiography confirmed aneurysms on the left coronary artery, left anterior descending coronary artery, and of the sinus of Valsalva. Molecular analysis detected the pathogenic variant NM_001042492.3(NF1):c.3943C>T (p.Gln1315*). Literature findings on ACAD in NF1 indicated that this mostly occurs in males, showing predilection for the development of aneurysms at the left anterior descending coronary artery, and manifesting predominantly as acute myocardial infarction, inclusively in teenagers, though it may be also asymptomatic as in our case. This report documents the first case of ACAD in a patient with NF1 diagnosed at birth, emphasizing that its early diagnosis is essential to prevent potential life-threatening events attributable directly to coronary lesions.     

Two sporadic spinal neurofibromatosis patients with malignant peripheral nerve sheath tumour

We analyzed two unrelated male patients in whom neurofibromatosis type 1 (NF1) was not suspected until they presented with malignant peripheral nerve sheath tumours (MPNSTs) in their thirties and forties, respectively. Patient A presented with progressive peroneus paresis due to a rapidly growing MPNST in the thigh. MRI examination revealed multiple symmetrical spinal neurofibromas in this patient as well as in patient B who presented at the age of 42 with paraparesis and an MPNST at spinal level L4. Dermal features in both patients were strikingly mild, therefore both patients were considered belonging to the NF1-subform of spinal neurofibromatosis (SNF). The novel NF1 mutations identified, i.e. splice mutation, c.7675+1G > A, in patient A and two alterations, p.Cys1016Arg and p.2711delVal, located in trans in patient B support the notion that the phenotype of SNF may be related to mutations with possible residual functionality. The MPNSTs of both patients showed LOH affecting chromosome 17 including the NF1 locus. Furthermore, a truncating TP53 mutation was identified in the tumour of patient A. Both alterations are frequent findings in NF1-associated MPNSTs. To our knowledge these are the first MPNST patients with the clinical phenotype of SNF. The clinical course observed in these two patients suggests that nodular plexiform neurofibromas and spinal-nerve-root neurofibromas which may be asymptomatic for a long time and, hence, unrecognized in SNF patients bear the risk for malignant transformation.     

A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling.

The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied. The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations. A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.     

Immotile cilia syndrome: A recombinant family at HLA-linked gene locus

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families. Work-up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age-at-onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype. Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long-term prognosis and in formulating individualized guidelines for medical surveillance. © 1994 Wiley-Liss, Inc.

1 This article is a U.S. Government work and, as such, is in the public domain in the United States of America

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Phenotypic variability in monozygotic twins with neurofibromatosis 2

Mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene on chromosome 22q12 cause a clinically variable autosomal dominant syndrome characterized by bilateral vestibular schwannomas (VSs), other nervous system tumors, and early onset lenticular cataracts. We studied three pairs of monozygotic (MZ) twins with NF2, all with bilateral VSs, to separate genetic from nongenetic causes of clinical variability. The evaluation included gadolinium-enhanced high-resolution magnetic resonance imaging of the head and spine, neuro-ophthalmic examination with slit lamp, physical examination, and zygosity testing with microsatellite markers. Each MZ pair was concordant for general phenotypic subtype (mild or severe) and often for the affected organ systems. However, the MZ pairs were discordant for some features of disease presentation or progression. For example, all three pairs were discordant for presence or type of associated cranial tumors. We hypothesize that phenotypic differences between NF2 MZ twins are at least partly due to stochastic processes, such as the loss of the second NF2 allele or alleles of other genes. © 1996 Wiley-Liss, Inc.     

Unique Intracerebral Tumor with Divergent Differentiation in a Patient Presenting as NF2: Report of a Case with Features of Astrocytoma, Ependymoma, and PNET

Patients with neurofibromatosis 2 (NF2) are predisposed to a variety of neoplastic and dysplastic lesions, including schwannomas, neurofibromas, meningiomas, astrocytomas, and ependymomas, as well as entities such as meningioangiomatosis, schwannosis, and hamartomas. This study reports a unique intracerebral frontotemporal tumor in a 6-year-old boy with presumed NF2, on the basis of bilateral cerebellopontine tumors consistent with acoustic neuromas. The intracerebral tumor revealed a variety of histological patterns, including foci of primitive neuroectodermal tumor (PNET), low-grade astrocytoma and ependymoma, as well as neuroepithelial rests with immature ganglion cells and hamartomatous areas. The MIB-1 labeling index ranged from 63% in the foci of PNET to 4-7% in other foci. The PNET component revealed immunopositivity for synaptophysin and neurofilament and showed cells with delicate intercellular junctions, profiles of rough endoplasmic reticulum, mitochondria, and dense core granules, and cell processes with microtubules and neurofilaments. The glial and ependymal components showed bundles of glial filaments and prominent cell junctions, cilia, and microvilli. The hamartomatous component also included aggregates of cells with hyaline eosinophilic cytoplasm. By EM these cells contained abundant amorphous flocculent material. This constellation of pathologic findings, especially the finding of PNET, is unique and not previously reported in the setting of NF2.     

Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.

Blood samples from 125 unrelated families with classical type 2 neurofibromatosis (NF2) with bilateral vestibular schwannomas have been analysed for mutations in the NF2 gene. A further 17 families fulfilling modified criteria for NF2 have also been analysed. Causative mutations have been identified in 54 (43%) classical families and six (35%) of those fulfilling modified criteria. Forty-two cases from 38 families with truncating mutations had an average age at onset of symptoms of 19 years and diagnosis at 22.4 years. Fifty-one cases from 16 families with splice site mutations (15 from six), missense mutations (18 from six), and large deletions (18 from five) had an average age of onset of 27.8 years and at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001). There were also significantly fewer multigenerational families with truncating mutations. Four further truncating mutations were in mosaic form and were associated with milder disease than other similar mutations. This large study has confirmed the previous impression that truncating mutations are associated with severe disease, but caution has to be exercised in using mutation type to predict disease course.     

Automated gamma knife radiosurgery treatment planning with image registration, data-mining, and Nelder-Mead simplex optimization

Gamma knife treatments are usually planned manually, requiring much expertise and time. We describe a new, fully automatic method of treatment planning. The treatment volume to be planned is first compared with a database of past treatments to find volumes closely matching in size and shape. The treatment parameters of the closest matches are used as starting points for the new treatment plan. Further optimization is performed with the Nelder-Mead simplex method: the coordinates and weight of the isocenters are allowed to vary until a maximally conformal plan specific to the new treatment volume is found. The method was tested on a randomly selected set of 10 acoustic neuromas and 10 meningiomas. Typically, matching a new volume took under 30 seconds. The time for simplex optimization, on a 3 GHz Xeon processor, ranged from under a minute for small volumes (<1000 cubic mm, 2-3 isocenters), to several tens of hours for large volumes (>30,000 cubic mm, >20 isocenters). In 8/10 acoustic neuromas and 8/10 meningiomas, the automatic method found plans with conformation number equal or better than that of the manual plan. In 4/10 acoustic neuromas and 5/10 meningiomas, both overtreatment and undertreatment ratios were equal or better in automated plans. In conclusion, data-mining of past treatments can be used to derive starting parameters for treatment planning. These parameters can then be computer optimized to give good plans automatically.     

Neurofibromatosis type 1 and malignancy in childhood

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary neurocutaneous syndrome characterized by multi‐system involvement and an increased incidence of both benign and malignant tumors. In this study, we evaluated the clinical presentation and prognosis of NF1 and malignancy. Between 1975 and 2013, 26 (5%) of the 473 patients with NF1 at our center developed non‐neurofibroma neoplasms. The patient files of 26 subjects with tumors, other than optic glioma, were analyzed retrospectively to evaluate clinical features and treatment results. The age at diagnosis of NF1 ranged from 3 months to 16 years (median 5.5 years). The age range at tumor diagnosis was 1.5–33 years (median 8 years) in these 26 patients. The tumor histological subtypes included the following: 12 soft‐tissue tumors (6 malignant peripheral nerve sheath tumors (MPNST), 5 rhabdomyosarcomas (RMS) and 1 malignant fibrous histiocytoma), 11 brain tumors (6 low‐grade gliomas, 3 high‐grade gliomas, and 2 medulloblastoma), 2 neuroblastomas and 1 non‐Hodgkin's lymphoma. Twelve of 26 patients were alive at the time of the study. Although benign brain tumors with NF1 are more common, high‐grade brain tumors also occur. Thus, careful and regular follow‐up is crucial for early detection of malignancy in NF1 patients.