RESUMEN
Neurofibromatosis type-1 (NF1) patients suffer from cutaneous and subcutaneous neurofibromas (CNF) and large plexiform neurofibromas (PNF). Whole gene deletions of the NF1 gene can cause a more severe phenotype compared to smaller intragenic changes. Two distinct groups of NF1 whole gene deletions are type-1 deletions and atypical deletions. Our aim was to assess volumes and averaged annual growth-rates of CNF and PNF in patients with NF1 whole gene deletions and to compare these with NF1 patients without large deletions of the NF1 gene. We retrospectively evaluated 140 whole-body MR examinations of 38 patients with NF1 whole gene deletions (type-1 group: n = 27/atypical group n = 11) and an age- and sex matched collective of 38 NF1-patients. Age-dependent subgroups were created (0-18 vs >18 years). Sixty-four patients received follow-up MRI examinations (NF1whole gene deletion n = 32/control group n = 32). Whole-body tumor-volumes were semi-automatically assessed (MedX, V3.42). Tumor volumes and averaged annual growth-rates were compared. Median tumor-burden was significantly higher in the type-1 group (418ml; IQR 77 - 950ml, p = 0.012) but not in the atypical group (356ml;IQR 140-1190ml, p = 0.099) when compared to the controls (49ml; IQR 11-691ml). Averaged annual growth rates were significantly higher in both the type-1 group (14%/year; IQR 45-36%/year, p = 0.004) and atypical group (11%/year; IQR 5-23%/year, p = 0.014) compared to the controls (4%/year; IQR1-8%/year). Averaged annual growth rates were significantly higher in pediatric patients with type-1 deletions (21%/year) compared with adult patients (8%/year, p = 0.014) and also compared with pediatric patients without large deletions of the NF1 gene (3.3%/year, p = 0.0015). NF1 whole gene deletions cause a more severe phenotype of NF1 with higher tumor burden and higher growth-rates compared to NF1 patients without large deletions of the NF1 gene. In particular, pediatric patients with type-1 deletions display a pronounced tumor growth.
Asunto(s)
Eliminación de Gen , Genes de Neurofibromatosis 1 , Estudios de Asociación Genética , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Carga Tumoral/genética , Adolescente , Adulto , Estudios de Casos y Controles , Proliferación Celular , Transformación Celular Neoplásica , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/patología , Prevalencia , Eliminación de Secuencia , Adulto JovenRESUMEN
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.
Asunto(s)
Neurilemoma , Neurofibromatosis , Neurofibromatosis 1 , Neurofibromatosis 2 , Neoplasias Cutáneas , Consenso , Humanos , Neurilemoma/diagnóstico , Neurilemoma/genética , Neurilemoma/patología , Neurofibromatosis/diagnóstico , Neurofibromatosis/genética , Neurofibromatosis 1/genética , Neurofibromatosis 2/diagnóstico , Neurofibromatosis 2/genética , Neoplasias Cutáneas/genéticaRESUMEN
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.
Asunto(s)
Neurofibromatosis 1 , Manchas Café con Leche/genética , Consenso , Pruebas Genéticas , Humanos , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genéticaRESUMEN
INTRODUCTION: The pathophysiological significance of the Fabry-related, non-classical variant p.D313Y still remains to be solved. This study assesses the involvement of the peripheral nervous system with respect to small fiber neuropathy and neuropathic pain in female patients carrying p.D313Y. METHODS: This study examined nine females carrying the Fabry-related p.D313Y variant by obtaining skin punch biopsies above the right lateral malleolus. Intraepidermal nerve fiber density was determined for each patient and compared to reference values matched for the patient's decade of life and sex. Moreover, each patient was characterized by a detailed neurological examination and by pain assessment via questionnaire. RESULTS: Compared to sex-matched lower fifth percentile reference values per decade, intraepidermal nerve fiber density was decreased in seven out of nine patients. Four patients reported acral paresthesias and neuropathic pain with an average visual analogue scale score of 7 out of 10 points. Two patients experienced acute pain crises. Six out of seven patients diagnosed with small fiber neuropathy had a their medical history of hypo- and/or hyperhidrosis. DISCUSSION: The diagnosis of small fiber neuropathy was made in seven out of nine females carrying the non-classical variant p.D313Y. Moreover, neuropathic pain and symptoms indicative of autonomic nervous system dysfunction seem to be common findings that may be of clinical significance and may warrant therapeutic intervention.
Asunto(s)
Neuropatía de Fibras Pequeñas/diagnóstico , alfa-Galactosidasa/genética , Adulto , Anciano , Biopsia , Femenino , Humanos , Persona de Mediana Edad , Mutación , Examen Neurológico , Piel/inervación , Piel/patología , Neuropatía de Fibras Pequeñas/genética , Neuropatía de Fibras Pequeñas/patología , Neuropatía de Fibras Pequeñas/fisiopatología , Adulto JovenRESUMEN
We coincidently detected an atypical deletion of at least 1.3-Mb, encompassing the NF1 tumor suppressor gene and several adjacent genes at an apparent heterozygous level in the blood of a 65-year-old female patient. She had multiple subcutaneous tumors that appeared with a certain similarity of subcutaneous neurofibromas, which, however, was revealed as lipomas by histological examination. Comprehensive and exhaustive clinical and radiological examinations did not detect any neurofibromatosis type 1-related clinical symptoms in the patient. Multiplex ligation-dependent probe amplification detected no or only very low level of the 1.3-Mb NF1 deletion in six lipomas and two skin biopsies. Digital polymerase chain reaction estimated the proportion of cells carrying a heterozygous NF1 deletion at 87% in the blood, and 8%, 10%, 13%, 17%, and 20%, respectively, in the five lipomas investigated by this method, confirming our hypothesis of mosaicism. Our findings suggest that de novo cases of genetic disease are potentially mosaic regardless of finding the mutation at an apparently heterozygous level in the blood and that the possibility of mosaicism should be considered in genotype-phenotype studies and genetic counseling.
Asunto(s)
Eliminación de Gen , Mosaicismo , Neurofibromatosis 1/genética , Anciano , Femenino , Genes de Neurofibromatosis 1 , Heterocigoto , Humanos , FenotipoRESUMEN
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare aggressive sarcomas with poor prognosis. More than half of MPNSTs develop from benign precursor tumors associated with neurofibromatosis type 1 (NF1) which is a tumor suppressor gene disorder. Early detection of malignant transformation in NF1 patients is pivotal to improving survival. The primary aim of this study was to evaluate the role of immuno-modulators as candidate biomarkers of malignant transformation in NF1 patients with plexiform neurofibromas as well as predictors of response to immunotherapeutic approaches. METHODS: Sera from a total of 125 NF1 patients with quantified internal tumor load were included, and 25 of them had MPNSTs. A total of six immuno-modulatory factors (IGFBP-1, PD-L1, IFN-α, GM-CSF, PGE-2, and AXL) were measured in these sera using respective ELISA. RESULTS: NF1 patients with MPNSTs had significantly elevated PD-L1 levels in their sera compared to NF1 patients without MPNSTs. By contrast, AXL concentrations were significantly lower in sera of NF1-MPNST patients. IGFBP-1 and PGE2 serum levels did not differ between the two patient groups. IFN-α and GM-CSF were below the detectable level in most samples. CONCLUSION: The immuno-modulator PD-L1 is upregulated in MPNST patients and therefore may provide as a potential biomarker of malignant transformation in patients with NF1 and as a response predictor for immunotherapeutic approaches.
Asunto(s)
Antígeno B7-H1/sangre , Biomarcadores de Tumor/sangre , Neurofibrosarcoma/sangre , Neurofibrosarcoma/patología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Pronóstico , Carga TumoralRESUMEN
PURPOSE: Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1. METHODS: We included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan-Meier analysis with delayed entry. RESULTS: One hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0-84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8-76.8) and 49.8% (95%CI = 39.3-63.0). Breast cancer-specific 10-year survival was 64.2% (95% CI = 53.5-77.0%) compared with 91.2% (95% CI = 87.3-95.2%) in the non-NF1 age-matched population at increased risk of breast cancer. CONCLUSION: Women with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.
Asunto(s)
Neoplasias de la Mama/genética , Neurofibromatosis 1/complicaciones , Neurofibromina 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Estudios de Cohortes , Detección Precoz del Cáncer , Europa (Continente) , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neurofibromatosis/genética , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibromina 1/metabolismo , Factores de RiesgoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
INTRODUCTION: A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. METHODS: In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. RESULTS: We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2-4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). CONCLUSIONS: Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.
Asunto(s)
Antineoplásicos/uso terapéutico , Glioma/tratamiento farmacológico , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Glioma/patología , Humanos , Lactante , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Nucleares/antagonistas & inhibidores , Complejo Represivo Polycomb 2/deficiencia , Factores de Transcripción/antagonistas & inhibidores , Transcripción Genética , Proteínas ras/metabolismo , Animales , Azepinas/farmacología , Azepinas/uso terapéutico , Proteínas de Ciclo Celular , Muerte Celular/efectos de los fármacos , Cromatina/efectos de los fármacos , Cromatina/genética , Cromatina/metabolismo , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Proteínas de Neoplasias , Neoplasias/patología , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Neurofibromina 1/deficiencia , Neurofibromina 1/genética , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Triazoles/farmacología , Triazoles/uso terapéutico , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas ras/antagonistas & inhibidoresRESUMEN
BACKGROUND: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. METHODS: Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). RESULTS: No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher's exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4-83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3-83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation. DISCUSSION: These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etiología , Genes de Neurofibromatosis 1 , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/genética , Edad de Inicio , Alelos , Sustitución de Aminoácidos , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Incidencia , Fenotipo , Medición de Riesgo , Factores de Riesgo , Eliminación de SecuenciaRESUMEN
We reviewed our experience in managing of NF2-associated vestibular schwannoma (VS) in children and young adults regarding the effect of surgery and postoperative bevacizumab treatment. A total of 579 volumetric and hearing data sets were analyzed. The effect of surgery on tumor volume and growth rate was investigated in 46 tumors and on hearing function in 39 tumors. Long-term hearing follow-up behavior was compared with 20 non-operated ears in additional 15 patients. Sixteen operated VS were treated with bevacizumab. Mutation analysis of the NF2 gene was performed in 25 patients. Surgery significantly slowed down VS growth rate. Factors associated with a higher growth rate were increasing patient age, tumor volume, and constitutional truncating mutations. Immediately after surgery, functional hearing was maintained in 82% of ears. Deterioration of hearing was associated with initial hearing quality, larger tumor volumes, and larger resection amounts. Average hearing scores were initially better in the group of non-operated VS. Over time, hearing scores in both groups worsened with a similar dynamic. During bevacizumab treatment of residual tumors, four different patterns of growth were observed. Decompression of the internal auditory canal with various degrees of tumor resection decreases the postoperative tumor growth rates. Carefully tailored BAEP-guided surgery does not cause additional hearing deterioration. Secondary bevacizumab treatment showed heterogenous effects both regarding tumor size and hearing preservation. It seems that postoperative tumor residuals, that grow slower, behave differently to bevacizumab than reported for not-operated faster growing VS.
Asunto(s)
Neurofibromatosis 2 , Neuroma Acústico , Bevacizumab/uso terapéutico , Niño , Genes de la Neurofibromatosis 2 , Audición , Humanos , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/tratamiento farmacológico , Neurofibromina 2 , Neuroma Acústico/tratamiento farmacológico , Neuroma Acústico/cirugía , Resultado del Tratamiento , Carga Tumoral , Adulto JovenRESUMEN
PURPOSE: An estimated 5-11% of patients with neurofibromatosis type 1 (NF1) harbour NF1 microdeletions encompassing the NF1 gene and its flanking regions. The purpose of this study was to evaluate the clinical phenotype in children and adolescents with NF1 microdeletions. METHODS: We retrospectively analysed 30 children and adolescents with NF1 microdeletions pertaining to externally visible neurofibromas. The internal tumour load was determined by volumetry of whole-body magnetic resonance imaging (MRI) in 20 children and adolescents with NF1 microdeletions. Furthermore, the prevalence of global developmental delay, autism spectrum disorder and attention deficit hyperactivity disorder (ADHD) were evaluated. RESULTS: Children and adolescents with NF1 microdeletions had significantly more often cutaneous, subcutaneous and externally visible plexiform neurofibromas than age-matched patients with intragenic NF1 mutations. Internal neurofibromas were detected in all 20 children and adolescents with NF1 microdeletions analysed by whole-body MRI. By contrast, only 17 (61%) of 28 age-matched NF1 patients without microdeletions had internal tumours. The total internal tumour load was significantly higher in NF1 microdeletion patients than in NF1 patients without microdeletions. Global developmental delay was observed in 28 (93%) of 30 children with NF1 microdeletions investigated. The mean full-scale intelligence quotient in our patient group was 77.7 which is significantly lower than that of patients with intragenic NF1 mutations. ADHD was diagnosed in 15 (88%) of 17 children and adolescents with NF1 microdeletion. Furthermore, 17 (71%) of the 24 patients investigated had T-scores ≥ 60 up to 75, indicative of mild to moderate autistic symptoms, which are consequently significantly more frequent in patients with NF1 microdeletions than in the general NF1 population. Also, the mean total T-score was significantly higher in patients with NF1 microdeletions than in the general NF1 population. CONCLUSION: Our findings indicate that already at a very young age, NF1 microdeletions patients frequently exhibit a severe disease manifestation which requires specialized long-term clinical care.
Asunto(s)
Trastorno del Espectro Autista , Neurofibromatosis 1 , Adolescente , Niño , Humanos , Imagen por Resonancia Magnética , Neurofibromatosis 1/genética , Estudios Retrospectivos , Imagen de Cuerpo EnteroRESUMEN
PURPOSE: The hallmark of neurofibromatosis type 2 (NF2) is the presence of bilateral vestibular schwannomas (VS) which however have not yet developed or grown to large size in children and young adolescents. Therefore, early diagnosis in pediatric patients without family history of NF2 has to be made by signs and symptoms not related to VS which will be reviewed in this study. METHODS: A total of 70 children diagnosed for NF2 at an age of < 18 years were identified from our patient cohort. Age and symptoms, signs and pathology at symptom onset, age at NF2 diagnosis and symptoms leading to diagnosis as well as genetic findings were retrospectively reviewed. RESULTS: The average age at symptom/sign onset was 8 ± 6 (range 0-17) years and 11 ± 5 (range 1-17) years at time of diagnosis. Fifteen children had a positive family history and were diagnosed upon additional clinical symptoms. The most frequent first presenting symptom/signs were ophthalmological abnormalities (49%), followed by cutaneous features (40%), non-VS-related neurological deficits (33%), and symptoms attributable to VS (21%). VS were not only the most common symptomatic neoplasm but also the most frequent pathological evidence for the diagnosis (72%). In 42 patients with available genetic testing results, pathogenic mutations were most frequently identified (n = 27). CONCLUSION: The presenting symptoms in NF2 children appear "unspecific" or less specific for classical NF2 compared with adult NF2 patients, posing a challenge particularly for cases without family history. In children, ophthalmological and cutaneous features should raise clinical suspicion for NF2 and referral to an NF2 specialized center is recommended.
Asunto(s)
Neurofibromatosis 2 , Adolescente , Adulto , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Mutación , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/diagnóstico , Neurofibromatosis 2/genética , Estudios RetrospectivosRESUMEN
PURPOSE: Neurofibromatosis type 1 (NF1) syndrome is a common rare/orphan disease that manifests itself early in the paediatric age. It imposes a considerable burden upon patients as well as on caregivers. Decisions regarding optimal care often rely on several medical instances working together as a team. METHODS: The authors reviewed the literature and supplied a description of their own clinical work at the NF1 centres. RESULTS: The experience of a multidisciplinary teamwork of three NF centres was summarized in order to enhance awareness for possible multidisciplinary ways of delivery of health and health-related aspects of care to NF1 patients. Both population-focused research centres and family-focused centres were reviewed. CONCLUSIONS: Chronic rare diseases that start in the paediatric age mandate long-term follow-up most often by several disciplines. NF1 syndrome is an example of a multidisciplinary centre in order to enhance the quality of care.
Asunto(s)
Neurofibromatosis 1 , Enfermedades Raras , Niño , Humanos , Neurofibromatosis 1/terapia , Enfermedades Raras/terapiaRESUMEN
INTRODUCTION: Peripheral nerve sheath tumours in children are a rare and heterogeneous group, consisting mostly of benign tumours as well as malignant neoplasms. Especially in the paediatric population, diagnostics and indication for therapy pose relevant challenges for neurosurgeons and paediatric neurologists alike. Most paediatric cases that need surgical intervention are associated to neurofibromatosis type 1 (NF1). METHODS: We retrospectively reviewed all paediatric cases treated at the Department of Neurosurgery in Tübingen between 2006 and 2017 for peripheral nerve sheath tumours. We analysed clinical signs, symptoms, histology, association to an underlying phacomatosis and sensory/motor function. RESULTS: Of the 82 identified patients, the majority had NF1 (76.8%). Nine children bore a sporadic tumour without underlying phacomatosis (11%), 8 had NF2 (9.8%) and 2 schwannomatosis (2.4%), A total of 168 surgical interventions were performed, and 206 tumours were removed. Indication for surgery was in most instances significant tumour growth (45.2%) followed by pain (33.9%). New deficits led to surgery in 12.5% of interventions; malignancy was suspected in 8.3%. Histopathology revealed mostly neurofibromas (82.5%), divided into cutaneous neurofibromas (10.7%), infiltrating plexiform neurofibromas (25.7%) and peripheral nerve-born neurofibromas (46.1%). 12.1% of tumours were schwannomas, 2.9% MPNST, 1.5% ganglioneuroma (n = 3) and 1 hybrid-neurofibroma and perineurinoma each. Leading symptoms, such as pain and motor and sensory deficits, improved after 125/166 interventions (74.4%), remained unchanged following 39 interventions (23.2%) and worsened in 4 occasions (2.4%). CONCLUSION: Surgery is safe and effective for (neurofibromatosis associated) peripheral nerve sheath tumours in the paediatric population; however, management needs a multidisciplinary setting. We propose early surgical resection in paediatric patients with peripheral nerve sheath tumours with significant growth, or pain, or motor deficit, or suspected malignancy.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurilemoma , Neurofibromatosis , Neurofibromatosis 1 , Niño , Humanos , Neoplasias de la Vaina del Nervio/cirugía , Neurilemoma/cirugía , Neurofibromatosis/cirugía , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/cirugía , Estudios RetrospectivosRESUMEN
Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST). Nevertheless, single targeting of this pathway is not sufficient to inhibit MPNST growth. In this report, we demonstrate that combined treatment with the allosteric pan-AKT inhibitor MK-2206 and the mTORC1/mTORC2 inhibitor AZD8055 has synergistic effects on the viability of MPNST cell lines in comparison to the treatment with each compound alone. However, when treating animals bearing experimental MPNST with the combined AKT/mTOR regime, no influence on tumour growth was observed. Further analysis of the MPNST xenograft tumours resistant to AKT/mTOR treatment revealed a reactivation of both AKT and mTOR in several tumour samples. Additional targeting of the RAS/RAF/MEK/MAPK pathway with the allosteric MEK1/2 inhibitor AZD6244 showed synergistic effects on the viability of MPNST cell lines in vitro in comparison to the dual AKT/mTOR inhibition. In summary, these data indicate that combined treatment with AKT and mTOR inhibitors is effective on MPNST cells in vitro but tumour resistance can occur rapidly in vivo by restoration of AKT/mTOR signalling. Our data further suggest that a triple treatment with inhibitors against AKT, mTORC1/2 and MEK1/2 may be a promising treatment option that should be further analysed in an experimental MPNST mouse model in vivo.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Neurofibrosarcoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Bencimidazoles/administración & dosificación , Línea Celular Tumoral , Sinergismo Farmacológico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Humanos , Ratones SCID , Morfolinas/administración & dosificación , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/metabolismo , Neurofibrosarcoma/complicaciones , Neurofibrosarcoma/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.
Asunto(s)
Fibras Nerviosas/patología , Neoplasias del Sistema Nervioso/etiología , Neuralgia/patología , Neurilemoma/complicaciones , Neurofibromatosis/complicaciones , Neoplasias Cutáneas/complicaciones , Adulto , Anciano , Dolor Crónico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Neoplasias del Sistema Nervioso/diagnóstico por imagen , Neuralgia/etiología , Neoplasias del Sistema Nervioso Periférico/diagnóstico por imagen , Neoplasias del Sistema Nervioso Periférico/etiología , Factores de Transcripción/genética , Imagen de Cuerpo EnteroRESUMEN
Different types of large NF1 deletion are distinguishable by breakpoint location and potentially also by the frequency of mosaicism with normal cells lacking the deletion. However, low-grade mosaicism with fewer than 10% normal cells has not yet been excluded for all NF1 deletion types since it is impossible to assess by the standard techniques used to identify such deletions, including MLPA and array analysis. Here, we used ultra-deep amplicon sequencing to investigate the presence of normal cells in the blood of 20 patients with type-1 NF1 deletions lacking mosaicism according to MLPA. The ultra-deep sequencing entailed the screening of 96 amplicons for heterozygous SNVs located within the NF1 deletion region. DNA samples from three previously identified patients with type-2 NF1 deletions and low-grade mosaicism with normal cells as determined by FISH or microsatellite marker analysis were used to validate our methodology. In these type-2 NF1 deletion samples, proportions of 5.3%, 6.6% and 15.0% normal cells, respectively, were detected by ultra-deep amplicon sequencing. However, using this highly sensitive method, none of the 20 patients with type-1 NF1 deletions included in our analysis exhibited low-grade mosaicism with normal cells in blood, thereby supporting the view that the vast majority of type-1 deletions are germline deletions.
Asunto(s)
Biomarcadores/análisis , Eliminación de Gen , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Neurofibromatosis 1/genética , Neurofibromina 1/sangre , Neurofibromina 1/genética , Humanos , Neurofibromatosis 1/sangre , Neurofibromatosis 1/patología , PronósticoRESUMEN
Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes, and peripheral neuropathy has been reported in both. We prospectively applied in vivo morphometric measurement of dorsal root ganglia volume in 16 schwannomatosis patients, 14 neurofibromatosis type 2 patients, and 26 healthy controls by magnetic resonance neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3, + 267%; L4, + 235%; L5, + 241%; S1, + 300%; S2, + 242%; Bonferroni-adjusted p < 0.001) but not in schwannomatosis. Dorsal root ganglia may be a vulnerable site in origination of areflexia and sensory loss and a useful diagnostic marker in neurofibromatosis type 2. Ann Neurol 2018;83:854-857.