Publications by authors named "Christian Hagel"

145 Publications

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

Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles.

Pituitary 2021 Sep 3. Epub 2021 Sep 3.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Purpose: Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5-1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown.

Methods: Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA).

Results: In accordance with the literature, combinations of GH/prolactin/TSH-FSH/LH adenoma (4/12), GH/prolactin/TSH-ACTH adenoma (3/12), and ACTH-FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern.

Conclusion: Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.
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http://dx.doi.org/10.1007/s11102-021-01164-1DOI Listing
September 2021

[Differential diagnosis of a vasculitic syndrome of the lower limb].

Z Rheumatol 2021 Jul 9. Epub 2021 Jul 9.

Klinik für Rheumatologie und Immunologie, Klinikum Bad Bramstedt, Oskar-Alexander-Str. 26, 24576, Bad Bramstedt, Deutschland.

Vasculitides can present with various clinical signs and symptoms. Besides disease-specific organ manifestations, the skin, peripheral nerves and musculature are frequently involved. The combination of elevated serological inflammatory markers, vasculitic skin lesions, active polyneuropathy and immobilizing myalgia of the lower limb musculature is highly suspicious for muscular polyarteritis nodosa (mPAN). Based on the case of a 63-year-old female patient with a vasculitic syndrome confined to the lower limb due to mPAN, important differential diagnoses of the these disease manifestations are discussed. Magnetic resonance imaging of the affected muscles and subsequent muscle biopsy (including skin and fascia) provide the relevant diagnostic data.
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http://dx.doi.org/10.1007/s00393-021-01044-wDOI Listing
July 2021

Differential expression of stem cell markers in proliferating cells in glioma.

J Cancer Res Clin Oncol 2021 Oct 25;147(10):2969-2982. Epub 2021 Jun 25.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Purpose: The identification of prognostically and therapeutically relevant molecular markers is fundamental to the further development of personalised therapies in brain tumours. Current therapeutic options for the treatment of gliomas rely mainly on surgical resection and the inhibition of tumour cell proliferation by irradiation and chemotherapy. Glioma stem cells are a subpopulation of proliferating tumour cells that have self-renewal capacity and can give rise to heterogeneous cells that comprise the tumour and are thought to play a role in the resistance of gliomas to therapy. The aim of this study was to evaluate the expression of markers of glioma stem cells and differentiated glial cells in proliferating glioma cells in comparison to the overall expression of the respective markers in the tumour tissue.

Methods: Tissue microarrays were assembled from specimen of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, ependymoma, and anaplastic ependymoma. These were immunohistochemically double stained with antibodies against the proliferation-associated antigen Ki67 and marker proteins for glioma stem cells (CD133, Nestin, Musashi, CD15, CD44), and differentiated glioma cells (GFAP, MAP2c).

Results: The expression of both glial and glioma stem cell markers differs between proliferating and non-proliferating glioma cells. Furthermore, the proliferating cells in the different glial tumour entities show a different expression profile.

Conclusion: Further analysis of marker expression in proliferating glioma cells and correlation with clinical outcome and susceptibility to irradiation and chemotherapy might help establish new biomarkers and therapies for glioma.
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http://dx.doi.org/10.1007/s00432-021-03704-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397690PMC
October 2021

Co-occurrence of Pituitary Neuroendocrine Tumors (PitNETs) and Tumors of the Neurohypophysis.

Endocr Pathol 2021 Jun 15. Epub 2021 Jun 15.

Department of Neurosurgery, Johannes Wesling Klinikum, University Hospital of the Ruhr-University Bochum (RUB), Hans-Nolte-Straße 1, D-32427, Minden, Germany.

Between 1996 and 2020, 12,565 cases were enrolled in the German Registry of Pituitary Tumors including 10,084 PitNETs (10,067 adenomas and 19 carcinomas obtained surgically and 193 adenomas diagnosed at autopsy) as well as 69 spindle cell tumors of the neurohypophysis (64 surgical specimens and 5 autopsies). In six patients (1 post mortem and 5 surgical specimens), PitNETs as well as posterior lobe tumors were found in the specimens. Two of the PitNETs were sparsely granulated prolactin-producing tumors, combined in one case with a granular cell tumor and in one case with a pituicytoma. One of the PitNETs revealed that autopsy was a sparsely granulated GH tumor combined with a neurohypophyseal granular cell tumor. Two PitNETs were null cell adenomas combined with a pituicytoma and a spindle cell oncocytoma, respectively. Further, one Crooke cell tumor was combined with a spindle cell oncocytoma. In five cases, the PitNETs were larger than the posterior lobe tumors and accounted for the clinical symptoms. Previously, four cases of co-existing pituitary anterior and posterior lobe tumors were described in the literature, comprising two ACTH PitNETs, one gonadotrophic PitNET and one null cell PitNET, each in combination with a pituicytoma. PitNETs and concomitant granular cell tumor or spindle cell oncocytoma, as observed in our cohort, have not been reported before.
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http://dx.doi.org/10.1007/s12022-021-09677-yDOI Listing
June 2021

Neurofibromatosis Type 1 With Cherubism-like Phenotype, Multiple Osteolytic Bone Lesions of Lower Extremities, and Alagille-syndrome: Case Report With Literature Survey.

In Vivo 2021 May-Jun;35(3):1711-1736

Institute of Human Genetics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

Background/aim: Neurofibromatosis type 1 (NF) is an autosomal dominant hereditary disease. The cardinal clinical findings include characteristic skeletal alterations. Difficulties in diagnosis and therapy can arise if an individual has further illnesses.

Case Report: This is a case report of a 16-year-old patient affected by NF1. She also suffered from Alagille syndrome and the consequences of fetal alcohol exposure. The patient's facial phenotype showed findings that could be assigned to one or more of the known diseases. The patient was referred for treating a cherubism-like recurrent central giant cell granuloma (CGCG) of the jaw. The patient developed bilateral, multilocular non-ossifying fibromas (NOF) of the long bones of the lower extremity. Treatment of the skeletal lesions consisted of local curettage. While NOF regressed after surgery, the CGCG of the jaw remained largely unchanged. Extensive genetic tests confirmed a previously unknown germline mutation in the JAG1 gene, the germline mutation of the NF1 gene, and the somatic mutation in the NF1 gene in the diffuse plexiform neurofibroma, but not in the CGCG.

Conclusion: Assigning facial findings to a defined syndrome is ambiguous in many cases and especially difficult in patients who have multiple diseases that can affect the facial phenotype. Surgical therapy should be adapted to the individual findings.
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http://dx.doi.org/10.21873/invivo.12431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193341PMC
June 2021

Microdont Developing Outside the Alveolar Process and Within Oral Diffuse and Plexiform Neurofibroma in Neurofibromatosis Type 1.

Anticancer Res 2021 Apr;41(4):2083-2092

Private Practice in Orthodontics, Hamburg-Lokstedt, Germany.

Background/aim: Numerical aberrations of permanent dentition and dystopic tooth eruption are part of the phenotype of the tumor predisposition syndrome neurofibromatosis type 1 (NF1). In these cases, surplus tooth germs usually develop in the alveolar processes of the jaw. This report attests to the dystopic development of a dysplastic supernumerary tooth in NF1 arising outside the jaw.

Case Report: The 8-year-old male patient developed a microdont outside the bone and above the occlusal plane of the retained maxillary right second molar. The supernumerary tooth was completely embedded in oral soft tissue. Hyperplastic oral soft tissue in the molar region and microdont were excised. Specimen of the mucosa surrounding the teeth was interspersed with diffuse and plexiform neurofibroma. The retained upper right first molar emerged spontaneously within a few months after surgery. The upper right second molar did not change position.

Conclusion: Odontogenesis can take place within tumorous oral mucosa in NF1. Surgical removal of the tumorous mucous membrane facilitates tooth eruption in some cases.
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http://dx.doi.org/10.21873/anticanres.14979DOI Listing
April 2021

Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study.

Front Neurol 2021 4;12:632535. Epub 2021 Feb 4.

Division of Infectious Disease, I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Progressive multifocal leukoencephalopathy (PML) caused by JCV is a rare but frequently fatal disease of the central nervous system, usually affecting immunocompromised individuals. Our study aims to expand the data on patient characteristics, diagnosis, clinical course, possible PML-directed treatment, and outcome of patients with PML at a German tertiary-care hospital. In this single-center observational cohort study, 37 consecutive patients with a confirmed diagnosis of PML seen at the University Medical Center Hamburg-Eppendorf from 2013 until 2019 were retrospectively analyzed by chart review with a special focus on demographics, risk factors, and clinical aspects as well as PML-directed treatment and survival. We identified 37 patients with definite, probable, and possible PML diagnosis. 36 patients (97%) had underlying immunosuppressive disorders such as HIV/AIDS ( = 17; 46%), previous treatment with monoclonal antibodies ( = 6; 16%), hematological or oncological malignancies ( = 6; 16%), sarcoidosis ( = 5; 14%), solid organ transplantation ( = 1; 3%), and diagnosis of mixed connective tissue disease ( = 1; 3%). In only one patient no evident immunocompromised condition was detected ( = 1; 3%). Treatment attempts to improve the outcome of PML were reported in 13 patients ( = 13; 35%). Twenty seven percent of patients were lost to follow-up ( = 10). Twenty four-month survival rate after diagnosis of PML was 56% ( = 15). This interdisciplinary retrospective study describes epidemiology, risk factors, clinical course, and treatment trials in patients with PML at a German tertiary-care hospital. Acquired immunosuppression due to HIV-1 constituted the leading cause of PML in this monocenter cohort.
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http://dx.doi.org/10.3389/fneur.2021.632535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890249PMC
February 2021

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination.

Acta Neuropathol Commun 2020 12 24;8(1):224. Epub 2020 Dec 24.

Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.

Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2 OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1 oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.
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http://dx.doi.org/10.1186/s40478-020-01105-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761156PMC
December 2020

A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer's disease.

Acta Neuropathol 2021 02 14;141(2):217-233. Epub 2020 Dec 14.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Presenilin-1 (PSEN1) mutations cause familial Alzheimer's disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aβ) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype-phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aβ, there were no relevant differences between groups in generation and deposition of Aβ. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin-proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aβ accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aβ pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD.
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http://dx.doi.org/10.1007/s00401-020-02249-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847436PMC
February 2021

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.

Lancet Neurol 2020 11 5;19(11):919-929. Epub 2020 Oct 5.

Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS.

Methods: In this post-mortem case series, we investigated the neuropathological features in the brains of patients who died between March 13 and April 24, 2020, in Hamburg, Germany. Inclusion criteria comprised a positive test for SARS-CoV-2 by quantitative RT-PCR (qRT-PCR) and availability of adequate samples. We did a neuropathological workup including histological staining and immunohistochemical staining for activated astrocytes, activated microglia, and cytotoxic T lymphocytes in the olfactory bulb, basal ganglia, brainstem, and cerebellum. Additionally, we investigated the presence and localisation of SARS-CoV-2 by qRT-PCR and by immunohistochemistry in selected patients and brain regions.

Findings: 43 patients were included in our study. Patients died in hospitals, nursing homes, or at home, and were aged between 51 years and 94 years (median 76 years [IQR 70-86]). We detected fresh territorial ischaemic lesions in six (14%) patients. 37 (86%) patients had astrogliosis in all assessed regions. Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 34 (79%) patients. SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem. The presence of SARS-CoV-2 in the CNS was not associated with the severity of neuropathological changes.

Interpretation: In general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included.

Funding: German Research Foundation, Federal State of Hamburg, EU (eRARE), German Center for Infection Research (DZIF).
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http://dx.doi.org/10.1016/S1474-4422(20)30308-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535629PMC
November 2020

Co-expression of intermediate filaments glial fibrillary acidic protein and cytokeratin in pituitary adenoma.

Pituitary 2021 Feb 1;24(1):62-67. Epub 2020 Oct 1.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Purpose: To analyze the co-expression of the intermediate filaments GFAP and cytokeratin in 326 pituitary adenomas with regard to the distribution pattern, the subtype of the adenoma and clinical prognostic data.

Methods: Tissue from 326 pituitary adenomas and 13 normal anterior pituitaries collected in the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, between 2006 and 2009 was investigated by immunohistochemistry, immunofluorescence and electron microscopy.

Results: Co-expression of intermediate filaments GFAP and cytokeratin was associated with hormone expression in 62/278 cases (22%), but only found in 2/48 (4%) of null cell adenomas (p < 0.01). Simultaneous co-expression of GFAP and cytokeratin in the same cells was demonstrated in 26 out of 326 pituitary adenomas and in all 13 pituitaries. In pituitary intermediate filaments were demonstrated in a larger area of the cytoplasm than in adenoma (p < 0.01), however, overlapping expression was seen in 2.6% of the total area in both, pituitary and adenoma. Congenially, cells with overlapping expression were found near vessels and in follicles. Furthermore, adenomas with cellular co-expression of GFAP and cytokeratin were associated with a lower recurrence rate (7.7%) compared to adenomas without co-expression of intermediate filaments (17.8%).

Conclusions: Cellular co-expression of the intermediate filaments GFAP and cytokeratin in pituitary adenomas and the pituitary was demonstrated and shown to be associated with hormone expression and low recurrence rate. The results are discussed with regard to the biology of folliculostellate cells, neural transformation and tumor stem cells. This study may complement the understanding of pituitary adenoma biology.
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http://dx.doi.org/10.1007/s11102-020-01087-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864846PMC
February 2021

Lingual Mandibular Bone Depression.

In Vivo 2020 Sep-Oct;34(5):2527-2541

Department of Oral and Craniomaxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.

Background/aim: In the area of the jaw angle, osteolytic lesions can occur, the differential diagnosis of which can be difficult and require very different therapeutic measures. One of these lesions is lingual mandibular bone depression (LMBD). The aim of this study was to present the characteristics of the lesion in a group of LMBD patients and to differentiate it from other lesions.

Patients And Methods: Radiological images of 21 patients with LMBD were examined.

Results: The majority of LMBDs were located in the jaw angle. On cross-sectional images, the lesion could be distinguished from salivary tissue (n=2). One case of LMBD had an impact on the course of the fracture line in the mandibular trauma.

Conclusion: LMBD is a developmental disorder of the mandible and only rarely of pathological importance. Imaging the lesion with cross-sectional images is preferable to using plain X-ray projections. In some cases, surgical exploration is essential for diagnosis.
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http://dx.doi.org/10.21873/invivo.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652515PMC
June 2021

Mosaic Neurofibromatosis Type 1 With Multiple Cutaneous Diffuse and Plexiform Neurofibromas of the Lower Leg.

Anticancer Res 2020 Jun;40(6):3423-3427

Institute of Human Genetics, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease with complete penetrance and a very variable phenotype. Recent research has shown that postzygotic NF1 gene mutations occur to a far greater extent than previously thought. The phenotype of affected individuals reflects the time of somatic mutation and the phenotype is correspondingly diverse. This report describes histological and genetic findings in a case of mosaic NF1, the clinical control of which documents almost stationary skin findings over a period of 9 years.

Case Report: The 55-year-old female first presented for advice on a strip of nodular skin tumours of the calf skin. She had no hallmarks of NF1. It was only 9 years later that she had the skin tumours removed, all of which were partially diffuse and partially plexiform neurofibroma. The genetic examination showed an atypical large deletion of the NF1 gene in the skin tumours, but not in overlying skin or blood.

Conclusion: Segmental NF1 is a distinct type of mosaic/somatic NF1 mutation. The phenotype of diffuse and plexiform skin neurofibromas can resemble cutaneous neurofibroma. Surgical therapy for segmental neurofibromatosis does not differ from the concepts for treating nerve sheath tumours in NF1 patients with a germline NF1 mutation.
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http://dx.doi.org/10.21873/anticanres.14327DOI Listing
June 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

Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis.

Sci Rep 2020 04 15;10(1):6455. Epub 2020 Apr 15.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma N2a cells. We examined early signs of stress in different conditions: endoplasmic reticulum (ER) stress, calcium overload, oxidative stress, and Aβ 1-42 oligomers toxicity. Additionally, we induced autophagy via serum starvation. PS1 mutations did not have an effect in ER stress but PS1E280A mutation affected autophagy. PS1 overexpression influenced calcium homeostasis and generated mitochondrial calcium overload modifying mitochondrial function. However, the opening of the mitochondrial permeability transition pore (MPTP) was affected in PS1 mutants, being accelerated in PS1E280A and inhibited in PS1Δ9 cells. Altered autophagy in PS1E280A cells was neither modified by inhibition of γ-secretase, nor by ER calcium retention. MPTP opening was directly regulated by γ-secretase inhibitors independent on organelle calcium modulation, suggesting a novel direct role for PS1 and γ-secretase in mitochondrial stress. We identified intrinsic cellular vulnerability to stress in PS1 mutants associated simultaneously with both, autophagic and mitochondrial function, independent of Aβ pathology.
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http://dx.doi.org/10.1038/s41598-020-63254-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160112PMC
April 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

Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.

Eur J Immunol 2020 07 20;50(7):1078-1080. Epub 2020 Apr 20.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.

AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.
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http://dx.doi.org/10.1002/eji.201948504DOI Listing
July 2020

Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis.

Cancers (Basel) 2020 Jan 10;12(1). Epub 2020 Jan 10.

Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen Stuttgart, 72076 Tübingen, Germany.

The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.
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http://dx.doi.org/10.3390/cancers12010177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016954PMC
January 2020

The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration.

Acta Neuropathol Commun 2019 12 5;7(1):199. Epub 2019 Dec 5.

Research Institute Children's Cancer Center Hamburg, Martinistrasse 52, N63 (HPI), 20251, Hamburg, Germany.

CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBP, mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system.Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses.In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients' quality of life.
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http://dx.doi.org/10.1186/s40478-019-0849-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896766PMC
December 2019

Cerebral cavernomas in adults and children express relaxin.

J Neurosurg Pediatr 2019 Nov 22:1-7. Epub 2019 Nov 22.

2Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Objective: To shed light on the role of relaxin in cerebral cavernous malformations (CCMs) in adults and children, the authors investigated endothelial cell (EC) expression of relaxin 1, 2, and 3; vascular endothelial growth factor receptor-1 and -2 (VEGFR-1 and -2); Ki-67; vascular geometry; and hemorrhage, as well as the clinical presentation of 32 patients with surgically resected lesions.

Methods: Paraffin-embedded sections of 32 CCMs and 5 normal nonvascular lesion control (NVLC) brain tissue samples were immunohistochemically stained with antibodies to relaxin 1, 2, and 3; angiogenesis growth factor receptors Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2); and proliferation marker Ki-67. For morphometric analysis, Elastica van Gieson stain was used, and for hemorrhage demonstration, Turnbull stain was used. Data from the pediatric and adult CCMs were compared with each other and with those obtained from the NVLCs. Statistical analyses were performed with Fisher's exact test, the chi-square test, the phi correlation coefficient, and the Student t-test. A p value < 0.05 was considered significant.

Results: Pediatric and adult cavernoma vessels did not significantly differ in diameter. Hemorrhage was observed in CCMs but not in NVLC samples (p < 0.05). There was no difference in expression of Ki-67, VEGFR-1 and -2, and relaxin 1, 2, and 3 in the ECs of pediatric and adult CCMs. The ECs of CCMs were largely negative for relaxin 3 compared to NVLCs (p < 0.05), whereas CCMs, compared to control brain tissue samples, more frequently expressed Flt-1 and relaxin 2 (p < 0.05). Ki-67 was not expressed in the NVLCs, but the difference was not statistically significant. Relaxin 1 and 2 expression and increased expression of VEGFR-1 were associated with a supra- versus infratentorial location (p < 0.05).

Conclusions: Relaxin 1 and 2 and VEGFR-1 play a role in supratentorial cavernomas. Relaxin 3 may play a physiological role in normal brain vasculature. Relaxin 1 and 3 are also found in normal cerebral vasculature. Relaxin 1, 2, and 3 are associated with increased VEGFR-1 expression.
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http://dx.doi.org/10.3171/2019.9.PEDS19333DOI Listing
November 2019

Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype.

Sci Rep 2019 Oct 2;9(1):14185. Epub 2019 Oct 2.

Department of Ophthalmology, Experimental Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is a neurodegenerative storage disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients suffer from brain atrophy, mental and motor retardation, seizures, and retinal degeneration ultimately resulting in blindness. Here, we performed an in-depth analysis of the retinal phenotype of a PPT1-deficient mouse, an animal model of this condition. Reactive astrogliosis and microgliosis were evident in mutant retinas prior to the onset of retinal cell loss. Progressive accumulation of storage material, a pronounced dysregulation of various lysosomal proteins, and accumulation of sequestosome/p62-positive aggregates in the inner nuclear layer also preceded retinal degeneration. At advanced stages of the disease, the mutant retina was characterized by a significant loss of ganglion cells, rod and cone photoreceptor cells, and rod and cone bipolar cells. Results demonstrate that PPT1 dysfunction results in early-onset pathological alterations in the mutant retina, followed by a progressive degeneration of various retinal cell types at relatively late stages of the disease. Data will serve as a reference for future work aimed at developing therapeutic strategies for the treatment of retinal degeneration in CLN1 disease.
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http://dx.doi.org/10.1038/s41598-019-50726-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775149PMC
October 2019

Distinctive low epidermal nerve fiber density in schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis.

Brain Pathol 2020 03 12;30(2):386-391. Epub 2019 Sep 12.

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

Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P < 0.0001). In addition, the difference between the IEND of our patients and the 5% lowest normative reference IEND was highly significantly larger in schwannomatosis patients than in NF2 patients (P < 0.0001). IEND of our patients did not correlate with neither the presence nor types of germline mutations in neither the NF2 nor the LZTR1 gene. In conclusion, schwannomatosis patients have marked low IEND which provides a major parameter for diagnosis and differential diagnosis.
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http://dx.doi.org/10.1111/bpa.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018006PMC
March 2020

Early-onset stroke in two siblings with Neurofibromatosis type 1.

Eur J Med Genet 2019 Oct 4;62(10):103710. Epub 2019 Jul 4.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, characterized by cafe-au-lait macules, benign neurofibromas as well as malignant peripheral nerve sheath tumours, freckling in the axillary or inguinal regions, optic glioma and Lisch nodules (iris hamartomas) and further manifestations like bone deformities etc. Additionally, NF1 patients are at increased risk of early-onset cerebrovascular diseases, the pathogenesis of which has not been clarified yet. Here we report the first case of two siblings with NF1 who suffered an acute ischemic stroke. Professionals treating NF1 patients should be aware of the elevated risk of stroke in this population. Large prospective studies are needed to establish optimal guidelines for diagnosis, monitoring and treatment of cerebrovascular disease in patients suffering from NF1, as well as to achieve a consensus on routine vascular screening in NF1.
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http://dx.doi.org/10.1016/j.ejmg.2019.103710DOI Listing
October 2019

Driver mutations in USP8 wild-type Cushing's disease.

Neuro Oncol 2019 10;21(10):1273-1283

Department of Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg (UKW), Würzburg, Germany.

Background: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.

Methods: Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.

Results: Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.

Conclusions: USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
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http://dx.doi.org/10.1093/neuonc/noz109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784271PMC
October 2019

Painful Vater-Pacini neuroma of the digit in neurofibromatosis type 1.

GMS Interdiscip Plast Reconstr Surg DGPW 2019 8;8:Doc03. Epub 2019 Feb 8.

Institute of Neuropathology, Eppendorf University Hospital, University of Hamburg, Germany.

Vater-Pacini neuromas are rare causes of severe pain in the phalanges. The cause of this change in the tactile corpuscles is unknown. A traumatic cause has been plausibly demonstrated, at least in some cases. Here, the rare occurrence of a Vater-Pacini neuroma in a patient with neurofibromatosis type 1 is reported. The discussion addresses the difficulties of terminology and current diagnostic procedures for differentiating small nodular masses of the palm and digits. The surgical treatment leads to rapid relief of the symptoms.
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http://dx.doi.org/10.3205/iprs000129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441816PMC
February 2019
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