Publications by authors named "Victor-Felix Mautner"

121 Publications

Alterations in brain morphology by MRI in adults with neurofibromatosis 1.

Orphanet J Rare Dis 2021 11 2;16(1):462. Epub 2021 Nov 2.

Diagnostic and Therapeutic Neuroradiology, University of British Columbia, Vancouver, Canada.

Objective: Neurofibromatosis 1 (NF1) is a rare autosomal dominant disease that causes the dysregulated growth of Schwann cells. Most reported studies of brain morphology in NF1 patients have included only children, and clinical implications of the observed changes later in life remain unclear. In this study, we used MRI to characterize brain morphology in adults with NF1.

Methods: Planar (2D) MRI measurements of 29 intracranial structures were compared in 389 adults with NF1 and 112 age- and sex-matched unaffected control subjects. The 2D measurements were correlated with volumetric (3D) brain measurements in 99 of the adults with NF1 to help interpret the 2D findings. A subset (n = 70) of these NF1 patients also received psychometric testing for attention deficits and IQ and was assessed for clinical severity of NF1 features and neurological problems. Correlation analysis was performed between the MRI measurements and clinical and psychometric features of these patients.

Results: Four of nine corpus callosum measurements were significantly greater in adults with NF1 than in sex- and age-matched controls. All seven brainstem measurements were significantly greater in adults with NF1 than in controls. Increased corpus callosum and brainstem 2D morphology were correlated with increased total white matter volume among the NF1 patients. No robust correlations were observed between the 2D size of these structures and clinical or neuropsychometric assessments.

Conclusion: Our findings are consistent with the hypothesis that dysregulation of brain myelin production is an important manifestation of NF1 in adults.
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http://dx.doi.org/10.1186/s13023-021-02097-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561988PMC
November 2021

Atypical Microdeletions: Challenges and Opportunities for Genotype/Phenotype Correlations in Patients with Large Deletions.

Genes (Basel) 2021 Oct 19;12(10). Epub 2021 Oct 19.

Department of Neurology, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany.

Patients with neurofibromatosis type 1 (NF1) and type 1 deletions often exhibit more severe clinical manifestations than patients with intragenic gene mutations, including facial dysmorphic features, overgrowth, severe global developmental delay, severe autistic symptoms and considerably reduced cognitive abilities, all of which are detectable from a very young age. Type 1 deletions encompass 1.4 Mb and are associated with the loss of 14 protein-coding genes, including and . Atypical deletions, which do not encompass all 14 protein-coding genes located within the type 1 deletion region, have the potential to contribute to the delineation of the genotype/phenotype relationship in patients with microdeletions. Here, we review all atypical deletions reported to date as well as the clinical phenotype observed in the patients concerned. We compare these findings with those of a newly identified atypical deletion of 698 kb which, in addition to the gene, includes five genes located centromeric to . The atypical deletion in this patient does not include the gene but does encompass . Comparative analysis of such atypical deletions suggests that hemizygosity is likely to contribute significantly to the reduced cognitive abilities, severe global developmental delay and facial dysmorphisms observed in patients with type 1 deletions.
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http://dx.doi.org/10.3390/genes12101639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535936PMC
October 2021

Long-term Follow-up and Histological Correlation of Peripheral Nervous System Alterations in Neurofibromatosis Type 2.

Clin Neuroradiol 2021 Oct 15. Epub 2021 Oct 15.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Purpose: To examine long-term alterations of the dorsal root ganglia (DRG) and the peripheral nerve in patients with neurofibromatosis type 2 (NF2) by in vivo high-resolution magnetic resonance neurography (MRN) and their correlation to histology.

Methods: In this prospective study the lumbosacral DRG, the right sciatic, tibial, and peroneal nerves were examined in 6 patients diagnosed with NF2 and associated polyneuropathy (PNP) by a standardized MRN protocol at 3 T. Volumes of DRG L3-S2 as well as peripheral nerve lesions were assessed and compared to follow-up examinations after 14-100 months. In one patient, imaging findings were further correlated to histology.

Results: Follow-up MRN examination showed a non-significant increase of volume for the DRG L3: +0.41% (p = 0.10), L4: +22.41% (p = 0.23), L5: +3.38% (p = 0.09), S1: +10.63% (p = 0.05) and S2: +1.17% (p = 0.57). Likewise, peripheral nerve lesions were not significantly increased regarding size (2.18 mm vs. 2.15 mm, p = 0.89) and number (9.00 vs. 9.33, p = 0.36). Histological analyses identified schwannomas as the major correlate of both DRG hyperplasia and peripheral nerve lesions. For peripheral nerve microlesions additionally clusters of onion-bulb formations were identified.

Conclusion: Peripheral nervous system alterations seem to be constant or show only a minor increase in adult NF2. Thus, symptoms of PNP may not primarily attributed to the initial schwannoma growth but to secondary long-term processes, with symptoms only occurring if a certain threshold is exceeded. Histology identified grouped areas of Schwann cell proliferations as the correlate of DRG hyperplasia, while for peripheral nerve lesions different patterns could be found.
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http://dx.doi.org/10.1007/s00062-021-01102-5DOI Listing
October 2021

Author Correction: Phenotyping spinal abnormalities in patients with Neurofibromatosis type 1 using whole-body MRI.

Sci Rep 2021 Aug 30;11(1):17669. Epub 2021 Aug 30.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

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http://dx.doi.org/10.1038/s41598-021-97577-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405783PMC
August 2021

Phenotyping spinal abnormalities in patients with Neurofibromatosis type 1 using whole-body MRI.

Sci Rep 2021 08 19;11(1):16889. Epub 2021 Aug 19.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Neurofibromatosis Type 1 (NF1) has been reported to be associated with a variety of spinal abnormalities. The purpose of this study was to quantify the prevalence of spinal abnormalities in a collective of NF1 patients that is representative for the general NF1 population, to associate the co-appearance of spinal abnormalities with both NF1 and clinical symptoms and to investigate if different mutations of the NF1 gene affect the prevalence of these abnormalities. Retrospectively, 275 patients with NF1 and an age- and sex-matched collective of 262 patients were analyzed. The prevalence of spinal abnormalities was recorded. Mutational analysis of the NF1 gene was obtained in 235 NF1 patients. Associations between spinal abnormalities, clinical symptoms and genotype were investigated by binary logistic regression analysis. Prevalence of all spinal abnormalities was higher in NF1 patients than in the control group. Six characteristics of spinal abnormalities were significantly associated with NF1 (all p < 0.05). An influence of scalloping on scoliosis (OR 3.01; p = 0.002); of meningoceles (OR 7.63) and neuroforaminal tumors (OR 2.96) on scalloping, and of dural ectasia on neuroforaminal tumors (OR 1.93) was identified. Backpain and loss of motor function were associated with neuroforaminal tumors, spinal tumors and scalloping of vertebral bodies (all p < 0.05). Specific mutations of the NF1 gene were not relevantly associated with the development of spinal abnormalities. These findings can aid clinicians to improve clinical care of NF1 patients by creating awareness for co-appearences of specific spinal abnormalities and associated symptoms.
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http://dx.doi.org/10.1038/s41598-021-96310-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376946PMC
August 2021

Imaging Evaluation of Plexiform Neurofibromas in Neurofibromatosis Type 1: A Survey-Based Assessment.

Neurology 2021 08 6;97(7 Suppl 1):S111-S119. Epub 2021 Jul 6.

The Russell H. Morgan Department of Radiology and Radiological Science (S.A., L.M.F.), Johns Hopkins University, Baltimore, MD; Stephen E. and Catherine Pappas Center for Neuro-Oncology (K.I.L., S.R.P.) and Department of Radiology (G.H.), Massachusetts General Hospital, Boston; Division of Oncology (M.J.F.), The Children's Hospital of Philadelphia, PA; Neurofibromatosis Northeast (A.J.L., D.J.B.), Burlington, MA; Department of Neurology (J.M.S.), University Medical Center Hamburg-Eppendorf; Department of Diagnostic and Interventional Radiology and Nuclear Medicine (V.-F.M.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; Mayo Clinic (D.B.-V.), Rochester, MN; Pediatric Oncology Branch (E.D.), National Cancer Institute, Bethesda, MD; and Department of Neurology (J.B.), Johns Hopkins University, Baltimore, MD.

Objective: To assess imaging utilization practices across clinical specialists in neurofibromatosis type 1 (NF1) for the evaluation of symptomatic and asymptomatic children and adults with or without plexiform neurofibromas (PN).

Methods: An institutional review board-exempt survey was administered to medical practitioners caring for individuals with NF1 at the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) meeting in September 2019. The survey included questions on respondent demographic data (9 questions), type of imaging obtained for asymptomatic (4 questions) and symptomatic (4 questions) people with and without PN, and utilization of diffusion-weighted imaging (2 questions).

Results: Thirty practitioners participated in the survey. Most were academic neuro-oncologists at high-volume (>10 patients/week) NF1 centers. Of 30 respondents, 26 had access to whole-body MRI (WB-MRI). The most common approach to an asymptomatic person without PN was no imaging (adults: 57% [17/30]; children: 50% [15/30]), followed by a screening WB-MRI (adults: 20% [6/30]; children: 26.7% [8/30]). The most common approach to a person with symptoms or known PN was regional MRI (adults: 90% [27/30]; children: 93% [28/30]), followed by WB-MRI (adults: 20% [6/30]; children: 36.7% [11/30]). WB-MRI was most often obtained to evaluate a symptomatic child with PN (37% [11/30]).

Conclusions: More than 90% of practitioners indicated they would obtain a regional MRI in a symptomatic patient without known or visible PN. Otherwise, there was little consensus on imaging practices. Given the high prevalence of PN and risk of malignant conversion in this patient population, there is a need to define imaging-based guidelines for optimal clinical care and the design of future clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000012437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594007PMC
August 2021

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

Genet Med 2021 08 19;23(8):1506-1513. Epub 2021 May 19.

Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1038/s41436-021-01170-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354850PMC
August 2021

Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth.

PLoS Genet 2021 05 5;17(5):e1009517. Epub 2021 May 5.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1371/journal.pgen.1009517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099117PMC
May 2021

Risk Stratification for Immediate Postoperative Hearing Loss by Preoperative BAER (Brainstem Auditory Evoked Response) and Audiometry in NF2-Associated Vestibular Schwannomas.

Cancers (Basel) 2021 Mar 18;13(6). Epub 2021 Mar 18.

Department of Neurosurgery and Neurotechnology, University Hospital Tübingen, BW 72076 Tübingen, Germany.

Both brainstem auditory evoked potentials (BAEP) and audiometry play a crucial role in neuro-oncological treatment decisions in Neurofibromatosis Type 2 associated (NF2) vestibular schwannoma (VS) as hearing preservation is the major goal. In this study, we investigated the risk of immediate postoperative hearing deterioration (>15 dB and/or 15% loss in pure-tone average [PTA]/ speech discrimination score [SDS] in a cohort of 100 operated VS (ears) in 72 NF2 patients by retrospective analysis of pre- and postoperative hearing data (PTA, SDS, American Association of Otolaryngology-Head and Neck Surgery [AAO-HNS], and brainstem auditory evoked potential [BAEP] class) taking into account relevant influencing factors, particularly preoperative audiometry and BAEP status and the extent of resection. Immediately after surgery, the hearing was preserved in 73% of ears and approximately ~60% of ears kept their hearing classes. Preoperative BAEP ( = 0.015) and resection amount ( = 0.048) significantly influenced postoperative hearing outcome. The prediction model for postoperative hearing deterioration/loss between preoperative BAEP and AAO-HNS class showed increased risk by increasing BAEP class. Twenty-one tumors/ears were identified with large BAEP and AAO-HNS class discrepancies (≥2 points) and were associated with a high (48-100%) risk of deafness after surgery in ears with preoperative available hearing. Overall, the results were heterogeneous but the better both BAEP and audiometry class before surgery, the higher the chance of hearing maintenance afterwards. Large resection amounts (e.g., 100% risk in near-total resections) exhibit a significant ( < 0.05) higher risk compared to smaller amounts (e.g., 10/20% in laser-coagulated/partially resected tumors). Our results emphasized the indispensable role of both hearing monitoring in form of audiometry and neurophysiology (BAEP) in the pre-and perioperative monitoring of NF2-associated VS. Both BAEP and audiometry are good prognostic markers for the postoperative hearing outcome. The extent of resection should be strictly guided by and adjusted to the intraoperative neurophysiological monitoring.
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http://dx.doi.org/10.3390/cancers13061384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003145PMC
March 2021

Assessment of small fiber neuropathy in patients carrying the non-classical Fabry variant p.D313Y.

Muscle Nerve 2021 05 19;63(5):745-750. Epub 2021 Feb 19.

Department of Neuroradiology, Neurological University Clinic, Heidelberg University Hospital, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1002/mus.27196DOI Listing
May 2021

Supportive care needs of patients with rare chronic diseases: multi-method, cross-sectional study.

Orphanet J Rare Dis 2021 01 22;16(1):44. Epub 2021 Jan 22.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20251, Hamburg, Germany.

Background: In the absence of a cure for the majority of rare diseases, the disease management aims to provide optimal supportive care. The goal of this study was to assess supportive care needs in patients with chronic rare diseases.

Methods: Cross-sectional mixed-method study was conducted using validated self-report scales and open-ended questions to assess supportive care needs. Participants affected by rare diseases across Germany were contacted via patient organizations and centers for rare diseases. N = 304 participants with 81 different rare diseases completed the study, 81.6% were female, mean age was 44.2 years (SD = 12.8, range 16-74). The quantitative results regarding supportive care needs were compared to a reference population of patients affected by cancer (N = 888). Main outcomes were unmet supportive care needs of patients with rare diseases, as assessed by the Supportive Care Needs Survey (SNCS-SF34) and an open-ended question on support wishes.

Results: Patients with rare diseases did not feel sufficiently supported with regard to psychological support, health system and information, physical and daily living, patient care and support, and sexuality needs. The unmet supportive care needs were significantly higher in the patient sample with rare diseases compared to the SCNS-SF34 reference sample of patients with cancer. 60% of patients with rare diseases did not feel sufficiently socially supported.

Conclusions: Patients affected by rare diseases have high unmet support needs in all areas studied. Multidisciplinary care, including psychological support and the provision of information regarding the healthcare system, treatment options, disease course and sexuality, might help address these needs.
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http://dx.doi.org/10.1186/s13023-020-01660-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825171PMC
January 2021

Structural alteration of lung parenchyma in patients with NF1: a phenotyping study using multidetector computed tomography (MDCT).

Orphanet J Rare Dis 2021 01 14;16(1):29. Epub 2021 Jan 14.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Diffuse interstitial lung disease have been described in Neurofibromatosis type 1 (NF1), but its diversity and prevalence remain unknown. The aim of this study was to assess the prevalence and characteristics of (NF1)-associated lung manifestations in a large single-center study using multidetector computed tomography (MDCT) and to evaluate the smoking history, patients' age, genetics, and the presence of malignant peripheral nerve sheath tumors (MPNST) as potential influencing factors for lung pathologies.

Methods: In this retrospective study, 71 patients with NF1 were evaluated for the presence of distinctive lung manifestations like reticulations, consolidations, type of emphysema, pulmonary nodules and cysts. All patients underwent F-18-FDG PET/CT scans, which were reviewed by two experienced radiologists in consensus. Patients' subgroups were formed based on their smoking history (current smokers/previous smokers/never smokers), age (< 12 years, 12-18 years, > 18 years), and presence of MPNST (MPNST/no MPNST). In 57 patients (80%), genetic analysis of sequences coding for the neurofibromin on chromosome 17 was performed, which was correlated with different lung pathologies.

Results: Among all NF1 patients (33 ± 14 years, 56% females), 17 patients (24%) were current smokers and 62 patients (87%) were > 18 years old. Pulmonary cysts, nodules, and paraseptal emphysema were the most common pulmonary findings (35%, 32%, 30%). The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking. Cysts were observed only in adults, whereas no significant correlation between age and all other pulmonary findings was found (p > 0.05). Presence of MPNST was accompanied by higher rates of intrapulmonary nodules and pulmonary metastasis. Neither the presence nor absence of any of the specific gene mutations was associated with any particular lung pathology (p > 0.05).

Conclusions: All pulmonary findings in NF1 patients occurred independently from specific mutation subtypes, suggesting that many NF1 mutations can cause various pulmonary pathologies. The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking, indicating the value of smoking secession or the advice not to start smoking in NF1 patients as preventive strategy for clinicians. For screening of pulmonary manifestations in NF1 patients, an MDCT besides medical history and physical examination is mandatory in clinical routine.
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http://dx.doi.org/10.1186/s13023-021-01672-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809820PMC
January 2021

Assessment of Peripheral Nervous System Alterations in Patients with the Fabry Related -Variant p.A143T.

Diagnostics (Basel) 2020 Nov 30;10(12). Epub 2020 Nov 30.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Background The purpose of this study is to examine alterations of the peripheral nervous system (PNS) in oligo-symptomatic patients carrying the Fabry related -gene variant p.A143T by Magnetic Resonance Neurography (MRN) and skin biopsy. This prospective study assessed dorsal root ganglia (DRG) volume L3 to S2, vascular permeability of the DRG L5, S1, and the spinal nerve L5 in five patients carrying p.A143T in comparison to patients with classical Fabry mutations and healthy controls. Moreover, skin punch biopsies above the lateral malleolus of the right foot were obtained in four patients and intraepidermal nerve fiber density (IENFD) was counted individually. Compared to controls, DRG volumes of p.A143T patients were enlarged by 30% (L3, < 0.05), 35% (L4, < 0.05), 29% (L5, = 0.15), 36% (S1, < 0.01), and 18% (S2, < 0.05), but less pronounced compared to patients carrying a classical Fabry mutation. Compared to healthy controls, vascular permeability was decreased by 40% (L5 right), 49% (L5 left), 48% (S1 right), and 49% (S1) ( < 0.01- < 0.001), but non-significant less than patients carrying a classical Fabry mutation. Compared to sex-matched 5% lower normative reference values per decade, IENFD was decreased in three of four patients. MRN and determination of IENFD is able to detect early alteration of the PNS segment in oligo-symptomatic patients with the disease-modifying -variant p.A143T on an individual basis. This procedure might also help in further -variants of uncertain significance for early identification of patients with single major organ manifestation.
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http://dx.doi.org/10.3390/diagnostics10121027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760340PMC
November 2020

Response to trametinib treatment in progressive pediatric low-grade glioma patients.

J Neurooncol 2020 Sep 7;149(3):499-510. Epub 2020 Oct 7.

Hopp Children's Cancer Center (KiTZ), Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1007/s11060-020-03640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609413PMC
September 2020

Age at Onset and Presenting Symptoms of Neurofibromatosis Type 2 as Prognostic Factors for Clinical Course of Vestibular Schwannomas.

Cancers (Basel) 2020 Aug 20;12(9). Epub 2020 Aug 20.

Department of Neurosurgery, University Hospital Tübingen, 72076 Tübingen, Germany.

The presenting symptoms of the tumor suppressor gene syndrome neurofibromatosis type 2 (NF2) are often non-specific and unrelated to the disease hallmark bilateral vestibular schwannomas (VS). However, age at onset and presenting symptoms may have predictive values for the clinical course of VS. In this retrospective single-center study, we addressed this issue by reviewing 106 patients with 194 VS. Presenting symptoms attributable to VS commonly occur in 87% of adults and 31% of children. Age at onset significantly correlates with tumor volumes at presentation ( = 0.034). In addition, age at onset significantly correlates with pure-tone average ( = 0.0001), speech discrimination scores ( = 0.001), age at beginning of hearing loss ( = 0.0001), age at deafness ( = 0.0001), and age at first surgery ( = 0.0001). Patients presenting with VS related symptoms had significantly ( < 0.05) worse hearing values at presentation and after surgery. These patients also exhibited higher growth rates and tumor volumes compared to patients with non-VS related presenting symptoms, but this difference did not reach the significance level of < 0.05. Due to the late appearance of these symptoms, the time of beginning hearing loss, surgery and deafness is significantly delayed ( < 0.05) compared to patients not presenting with VS. In summary, age at onset and type of presenting symptom provide excellent prognostic parameters for predicting VS- and hearing-related clinical course.
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http://dx.doi.org/10.3390/cancers12092355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563356PMC
August 2020

MRI based volumetric measurements of vestibular schwannomas in patients with neurofibromatosis type 2: comparison of three different software tools.

Sci Rep 2020 07 14;10(1):11541. Epub 2020 Jul 14.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Neurofibromatosis type 2 is a neurogenetic disorder with an incidence of about 1:33.000. Hallmarks are bilateral benign vestibular schwannomas, which can lead to deafness or brainstem compression. Volumetric tumor measurements are essential to assess the efficacy of new therapies. We present a statistical and methodical comparison of three volumetric image analysis tools. We performed volumetric measurements on phantoms with predefined volumes (0.1 to 8.0 ml) and tumors seen on 32 head MRI scans from eight NF2 patients with BrainLab, ITK-Snap, or OsiriX. The software was compared with regard to accuracy and reproducibility of the measurements and time required for analysis. The mean volume estimated by all three software programs differed significantly from the true volume of the phantoms, but OsiriX and BrainLab gave estimates that were not significantly different from each other. For the actual tumors, the estimated volumes with all three software tools showed a low coefficient of variability, but the mean volume estimates differed among the tools. OsiriX showed the shortest analysis time. Volumetric assessment of MRI images is associated to an intrinsic risk of miscalculation. For precise volumes it is mandatory to use the same volumetric tools for all measurements.
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http://dx.doi.org/10.1038/s41598-020-68489-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360562PMC
July 2020

The Neurofibromatoses.

Dtsch Arztebl Int 2020 May;117(20):354-360

Neurofibromatosis Center, Department of Neurosurgery, Helios Hospital Erfurt

Background: Neurofibromatosis of types 1 and 2 (NF1, NF2) and schwannomatosis are the diseases that make up the neurofibromatosis spectrum. With respective incidences of 1 in 3000, 1 in 33 000, and 1 in 60 000 births, they form part of the group of rare tumor-suppressor syndromes. They give rise to a greater tumor burden for the nervous system than any other type of neoplastic disease. New approaches to symptomatic treatment are emerging.

Methods: This review is based on articles retrieved by a selective literature search on the pathogenesis, diagnosis, and treatment of the neurofibromatoses.

Results: NF1 and NF2 are monogenic diseases, while the genetics of schwannomatosis is complex. The three entities are clinically and pathophysiologically distinct. An important aspect of their tumor biology is the alternation of growth phases and growth pauses. Correlations between genotypes and phenotypes are variable, while new mutations and genetic mosaics are common. Ninety-nine percent of patients with NF1 have six or more café-au-lait spots by the age of 12 months; 90-95% of patients with NF2 develop bilateral vestibular schwannomas. In schwannomatosis, pain is the most prominent symptom; two-thirds of those affected develop spinal schwannomas. The severity and prognosis of these disorders are not closely correlated with the radiological findings; rather, neurologic deficits, malignant transformation, and psychosocial stress are of greater clinical importance. Advances in knowledge of pathophysiology have led to the development of targeted treatment approaches. Examples include the off-label treatment of vestibular schwannomas with bevacizumab and of plexiform neurofibromas with MEK inhibitors.

Conclusion: Patients with neurofibromatoses need individualized care. They should be treated in centers of expertise where interdisciplinary consultation is available and new types of pharmacotherapy can be provided.
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http://dx.doi.org/10.3238/arztebl.2020.0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373809PMC
May 2020

Managing NF2-associated vestibular schwannomas in children and young adults: review of an institutional series regarding effects of surgery and bevacizumab on growth rates, tumor volume, and hearing quality.

Childs Nerv Syst 2020 10 16;36(10):2471-2480. Epub 2020 Jun 16.

Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany.

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.
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http://dx.doi.org/10.1007/s00381-020-04728-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575489PMC
October 2020

Presenting symptoms in children with neurofibromatosis type 2.

Childs Nerv Syst 2020 10 15;36(10):2463-2470. Epub 2020 Jun 15.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1007/s00381-020-04729-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575472PMC
October 2020

Clinical characterization of children and adolescents with NF1 microdeletions.

Childs Nerv Syst 2020 10 12;36(10):2297-2310. Epub 2020 Jun 12.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1007/s00381-020-04717-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575500PMC
October 2020

Role, function and challenges of multidisciplinary centres for rare diseases exemplified for neurofibromatosis type 1 syndrome.

Childs Nerv Syst 2020 10 8;36(10):2279-2284. Epub 2020 Jun 8.

Centre of Neurofibromatosis at the Centre of Rare Diseases, Tuebingen University Hospital, Tuebingen, Germany.

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.
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http://dx.doi.org/10.1007/s00381-020-04708-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276654PMC
October 2020

Surgical management of peripheral nerve sheath tumours in children, with special consideration of neurofibromatoses.

Childs Nerv Syst 2020 10 6;36(10):2433-2442. Epub 2020 Jun 6.

Division of Paediatric Neurosurgery, Department of Neurosurgery, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

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.
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http://dx.doi.org/10.1007/s00381-020-04703-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272701PMC
October 2020

C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis.

Int J Mol Sci 2020 May 18;21(10). Epub 2020 May 18.

Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

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.
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http://dx.doi.org/10.3390/ijms21103569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278954PMC
May 2020

Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism.

Hum Mutat 2020 07 13;41(7):1226-1231. Epub 2020 Apr 13.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1002/humu.24022DOI Listing
July 2020

Upregulated immuno-modulator PD-L1 in malignant peripheral nerve sheath tumors provides a potential biomarker and a therapeutic target.

Cancer Immunol Immunother 2020 Jul 19;69(7):1307-1313. Epub 2020 Mar 19.

BIH Center for Regenerative Therapies, Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

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.
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http://dx.doi.org/10.1007/s00262-020-02548-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303069PMC
July 2020

Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo.

Int J Mol Sci 2020 Feb 24;21(4). Epub 2020 Feb 24.

Laboratory for Tumor Genetics, Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

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.
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http://dx.doi.org/10.3390/ijms21041548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073166PMC
February 2020

Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors.

J Clin Invest 2020 05;130(5):2488-2495

Heidelberg Center for Personalized Oncology (HIPO), DKFZ, Heidelberg, Germany.

BACKGROUNDNeurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking.METHODSWe used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTSWhole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns.CONCLUSIONThese findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDINGThis work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.
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http://dx.doi.org/10.1172/JCI130787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190903PMC
May 2020

Attention Deficit Predicts Intellectual Functioning in Children with Neurofibromatosis Type 1.

Int J Pediatr 2019 10;2019:9493837. Epub 2019 Dec 10.

University Children's Hospital Tübingen, Department of Pediatric Neurology, Hoppe-Seyler-Straße 1, 72076 Tübingen, Germany.

Aims: Attention deficit hyperactivity disorder (ADHD) is one of the most frequent neurocognitive impairments in neurofibromatosis type 1 (NF1) and a well-known risk factor for intellectual dysfunction in general. Since NF1 is per se associated with intellectual difficulties, this comorbidity may be crucial for the cognitive development of affected patients. In our study, we investigated if attention deficits are associated with intellectual functioning in NF1 and if children with NF1 plus ADHD differ in their intellectual and attention profiles from children affected by NF1-only or ADHD only.

Methods: 111 children aged between 6 and 12 years (53 NF1 plus ADHD, 28 NF1-only, 30 ADHD-only) performed the German version of the intelligence test WISC-IV and a continuous performance test (T.O.V.A.) to assess attention functions. Parents completed questionnaires about everyday attention and executive functions (Conners 3®, BRIEF).

Results: Children with NF1 plus ADHD showed significantly lower intelligence test scores (full-scale IQ: 89.39 [1.40]) than patients with NF1-only (full-scale IQ: 101.14 [1.98]; < .001), and intellectual functioning correlated significantly with attention performance in NF1 ( < .001). As compared to NF1-only, attention, and executive functioning were impaired on several dimensions (T.O.V.A., Conners 3® and BRIEF) in NF1 plus ADHD. ADHD-only was associated with significantly higher problem scores regarding hyperactivity/impulsivity and inattention (Conners 3®). NF1-only was associated with inattentiveness when compared to the normative sample of the T.O.V.A.

Conclusion: NF1 is associated with variable attention problems. Severe attention deficits appear to be a risk factor for intellectual dysfunction in NF1, more than NF1 without attention deficit. NF1 plus ADHD presents a specific cognitive profile, which differs from that of NF1 and from neurotypical ADHD.
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http://dx.doi.org/10.1155/2019/9493837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930769PMC
December 2019
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