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At least 19 recordsLinked to original sources
PubMed2026

A 3D in vitro co-culture model to investigate tumor-endothelial interactions in Neurofibromatosis type 2-associated meningiomas.

BACKGROUND: Neurofibromatosis type 2 (NF2)-associated meningiomas and schwannomas are vascular tumors, and while vascular endothelial growth factor (VEGF) inhibition with bevacizumab has benefited some NF2-related schwannomas, most NF2-associated meningiomas remain nonresponsive. METHODS: Leveraging our transcriptomic data, we performed Gene Ontology (GO) analysis comparing NF2-deficient meningioma cells with NF2-expressing arachnoid cells (ACs). We then established a 3D in vitro angiogenesis model by co-culturing NF2-null meningioma cells with human umbilical vein endothelial cells (HUVECs). Endothelial sprouting was assessed by CD31/PECAM immunostaining. Effects of third-generation mechanistic target of rapamycin complex 1 (mTORC1)-selective inhibitor RMC-6272 as well as APLN knock-out using CRISPR-Cas9 gene editing were also examined. RESULTS: GO analysis identified vascular development among the top significantly upregulated pathways in NF2-deficient cells. In 3D co-culture, ECs formed radially sprouting tube-like networks from the spheroid surface, and our data supports an angiogenesis phenotype driven by meningioma cells. Given these results along with hyperactivation of mTORC1 upon NF2-deficiency, we examined whether RMC-6272 disrupts meningioma-driven angiogenesis. RMC-6272 potently suppressed EC sprouting. Cross-referencing baseline transcriptomic data, we identified Apelin (APLN), the ligand for APLN receptor (APLNR), as a basally upregulated angiogenic factor in NF2-deficient meningiomas. Quantitative RT-PCR (qRT-PCR) confirmed increased APLN expression in NF2-null immortalized and patient-derived meningioma lines, with reduced expression upon mTORC1 inhibition. Apelin-13 stimulation enhanced sprouting, whereas APLN deletion reduced endothelial sprouting. CONCLUSIONS: Here we establish a 3D-tumoroid model and implicate tumor-derived Apelin as an important contributor to NF2-associated meningioma angiogenesis. Our data also suggest that APLN expression is regulated, at least in part, by mTORC1. Together, these results provide a preclinical platform for investigating angiogenic vulnerabilities beyond VEGF in NF2-deficient meningiomas.

3D tumoroid model↗
PubMed2025

History and clinical epidemiology of NF2-related schwannomatosis.

NF2-related schwanomatosis (NF2-SWN) (previously Neurofibromatosis 2) as characterised by bilateral vestibular schwannomas (VS) was first described in 1822. However, due to the erroneous conflation of individuals with bilateral eighth nerve tumours with von Recklinghausen disease (currently Neurofibromatosis 1, NF1) in 1917 the literature was confusing for much of the 20th century. Even when the conditions were separated officially in 1987 (with separate localisation of the genes), NF2-SWN remained classified as a neurofibromatosis despite the tumours pathognomonic for NF1, neurofibromas, not being a feature of NF2-schwannomatosis. It is only in 2022 that NF2-SWN was correctly delineated as a schwannomatosis. The epidemiology of NF2-SWN has only been possible to delineate after the separation of NF2-SWN from the much more frequent nerve sheath predisposing tumour condition NF1. Two research groups have published on the birth prevalence and population prevalence of NF2-SWN in the UK and Finland. The most highly ascertained assessment of NF2-SWN cases from the Manchester region of England (population 4.8 million) gave a diagnostic prevalence of 1 in 50,500 and calculated birth prevalences of 1 in 27,956 respectively. However, an updated prevalence across England in 2024 (population 55 million) gave a prevalence of at least 1 in 58,000. NF2-SWN usually presents with bilateral vestibular schwannoma, but can present with meningioma or spinal tumour or ophthalmic features before a VS diagnosis or with a unilateral VS and other tumours and rarely with a unilateral VS alone. Molecular testing is now extremely helpful in confirming the diagnosis of mosaic (present in up to 50% of de novo cases) versus germline NF2 and distinguishing from other tumour predisposition conditions especially in childhood or cases with less common presentation. This chapter summarises the clinical epidemiology of NF2-SWN differentiating the condition from the overlapping non NF2-SWN.

Humans↗
PubMed1979

[Arterial hypertension caused by anomaly of the renal artery or its branches in children].

38 cases of severe hypertension due to a vascular abnormality of the renal pedicle were studied in children under 16 years of age, 18 boys and 20 girls. The most common presentation was at routine clinical examination. The diagnosis of an abnormality of the renal artery was suggested by the appearances of intravenous urography. There were many causes; 4 aneurysms of the renal artery or its branches, 4 fibromuscular dysplasias with one case of bilateral fibromuscular dysplasia, 4 idiopathic stenoses, 2 endarteritis, and 6 thromboses revascularised to variable degrees (2 after umbilical vein catheterisation and one due to DLE). In three cases the hypertension was related to compression of the pedicle by a tumour of haematome, and 14 cases had multiple arterial lesion. In the latter group, 6 cases of neurofibromatosis, 2 cases of William and Beuren's disease, 1 case of generalised Elastorhexia, 2 cases of aortic medio stenosis, probably Takayashu's disease, and 3 unidentified conditions. Surgery was performed on 29 patients, 21 of whom had unilateral lesions and were definitively cured of hypertension. Of the 8 cases with multiple lesions, only 2 were completely corrected with cure of their hypertension.

Adolescent↗
PubMed1975

Optic nerve glioma and cerebellar astrocytoma in a patient with von Recklinghausen's neurofibromatosis.

A 2 and a half year-old boy with neurofibromatosis developed unilateral proptosis, decreased visual acuity, and optic disk edema. After the discovery and removal of an optic nerve glioma, the patient had ten years of excellent health until he began having headaches, nausea, and vomiting. He had papilledema in his remaining eye. At exploration, a cerebellar astrocytoma and a neuroglial hamartoma were removed. The occurrence of a glioma of right anterior visual pathway associated with other primary intracranial lesions in patients with neurofibromatosis was not previously reported.

Adolescent↗
PubMed2026

NF2-related Schwannomatosis Diagnosed Before and After 30 Years of Age: Differences in Disease Presentation and Rates of Positive Genetic Testing.

OBJECTIVE: Characterize pathogenic variants, rates of mosaicism, genetic testing yield, and disease severity among patients with NF2-related schwannomatosis dichotomized by diagnosis before or after the age of 30. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center multidisciplinary NF2 clinic from 2021 to 2024. PATIENTS: Patients with NF2-related schwannomatosis. INTERVENTION: Next-generation sequencing. MAIN OUTCOME MEASURE: Rates of mosaicism, genetic testing rates and yield, and overall disease severity by tumor burden. RESULTS: From 2021 to 2024, there were 32 patients &#x2265;30 years of age and 39 patients diagnosed at younger ages. Patients diagnosed &#x2265;30 years exhibited decreased likelihood of receiving genetic testing (53% vs. 85%; P =0.009) and decreased genetic yield (defined as identification of a pathogenic genetic variant in those undergoing testing; 65% vs. 85%; P =0.20). Both age groups demonstrated similar rates of pathogenic variant type with loss-of-function being the predominant variant detected in 73% vs. 67%, for &#x2265;30 vs. <30 years of age; P =0.90. Those &#x2265;30 years harbored fewer number of average anatomic regions involved by tumor (2.3 vs. 3.4; P <0.001) and decreased total number of tumors (7 vs. 12; P <0.001). CONCLUSIONS: Patients diagnosed with NF2-related schwannomatosis at age &#x2265;30 years exhibited reduced disease severity compared with those diagnosed at a younger age despite harboring similar distributions of genetic pathogenic variants inclusive of loss-of-function pathogenic variants. These observations emphasize the importance of considering patient age in addition to genetic testing for diagnostic framing tailored to patients' biology and clinical context to optimize care in the setting of NF2-related schwannomatosis.

Humans↗
PubMed1979

Neurofibromatous ureteral obstruction relieved by sigmoid conduit cystoplasty.

Neurofibromatosis is a neural disease of hereditary nature affecting both sexes of all races. Visceral and central nervous system involvement can cause serious interference with normal function of affected structures. Under these circumstances, lifelong observation and individualized treatment of the patient are essential to proper management. This report is an account of nearly 2 decades of conservative management of neurofibromatosis of the pelvis in a young woman. Progressive, bilateral ureteral obstruction developed but normal function of the urinary tract has been maintained for the last 10 years with a sigmoid conduit cystoplasty. It is anticipated that continued progression of the disease will require cutaneous transfer of the sigmoid conduit. Also, a colostomy might become necessary because of recent evidence of rectal obstruction noted on computed tomography.

Adult↗
PubMed1977

[Central nervous manifestations of neurofibromatosis in children (author's transl)].

Serious central nervous manifestation of neurofibromatosis have been reported in 11 children aged 1,5-12 years. According to the present literature we conclude: 1. Central nervous lesions of neurofibromatosis are common even in childhood. 2. About two thirds of these patients suffer from brain tumors. 3. The tumors involve the suprasellar region in many cases. 4. By this localisation endocrine manifestations, especially precocious puberty, are frequent.

Astrocytoma↗
PubMed1979

Localization of pheochromocytoma by selective venous catheterization and assay of plasma catecholamines.

The diagnosis of pheochromocytoma rests primarily on determination of the 24-hour urinary excretion of catecholamines and their metabolites. In most cases nephrotomography and selective arteriography or venography, or both, are sufficient to localize the tumour. Selective venous catheterization and the assay of plasma catecholamines should be considered for pheochromocytoma localization in: (a) patients in whom standard techniques fail to localize the tumour; (b) patients who exhibit idiosyncratic reactions to the angiographic contrast materials; (c) young patients or patients with familial pheochromocytoma, including those with multiple neurofibromatosis or multiple endocrine adenomatosis, type 2; (d) patients with recurrent, malignant, or suspected multicentric or extra-adrenal tumours; and (e) patients excreting only norepinephrine in the urine. The validity of the results is particularly dependent on the skill with which venous catheterization is carried out.

Adrenal Gland Neoplasms↗
PubMed1976

Intrathoracic meningocele: a report of two cases.

Two cases of intrathoracic meningocele are reported: their association with neurofibromatosis is stressed. The likelihood of a posterior mediastinal mass occurring in a patient with neurofibromatosis being a meningocele is emphasised. A review of the literature is presented. In view of the relatively few cases of intrathoracic meningocele with neurofibromatosis documented since 1933, we feel justified in reporting these 2 cases.

Adult↗
PubMed1976

Studies on café au lait spots in neurofibromatosis and pigmented macules of nevus spilus.

Café au lait spots from 14 Japanese patients with neurofibromatosis and nevus spilus from 9 Japanese patients were subjected to the studies on the differences in nature of their melanocytes. When the number of melanocytes of the pigmented lesions was compared with that of the surrounding normal skin, the former was always increased and that of café au lait spot was higher than that of nevus spilus. Giant pigment granules were recognized only in 6 patients out of 14 with neurofibromatosis but not in nevus spilus examined. 2 days after UV irradiation at 4 MED, the number of melanocytes was increased in both surrounding normal skin and pigmented lesion, and the rates of increase were lower in the pigmented lesion. Under the electron microscope, melanocytes in café au lait spots which received an ultraviolet light irradiation showed various changes in their cytoplasm; a development of dendrites containing many mature melanosomes, an increased number of cytoplasmic vacuoles and mitochondria, a development of Golgi apparatus in their cytoplasm, appearances of some dense-bodies and of autophagosomal melanosome-complexes. In nevus spilus, the same kind of changes occurred, but they were moderate compared with those developed in café au lait spots. Melanosomes in the keratinocytes of café au lait spots tended to come together around the nucleus and to form melanosome-complexes; while, melanosomes in the keratinocytes of nevus spilus seemed to be single-dispersed after irradiation. The causative factors of the hyperpigmentation and the different reactivity of melanocytes against UV irradiation in these two pigmented macules were discussed.

Adult↗
PubMed1976

Gastric lesions in generalized neurofibromatosis.

A patient with dyspepsia and multiple gastric polyps associated with generalized neurofibromatosis is described, and the English literature on generalized neurofibromatosis with gastric involvement is reviewed. Nine patients with gastric neurofibromas have been reported and 2 with one and two gastric polyps respectively, but none with multiple gastric polyps. The commonest presentation has been dyspepsia suggestive of a peptic ulcer.

Aged↗
PubMed1977

Chromosome complement and SV40 transformation of cells from patients susceptible to malignant disease.

A comparative study has been made of fibroblasts obtained from patients with differing susceptibilities to malignant disease, both with respect to their chromosome complements and their transformation with SV40 virus. Fibroblasts from 2 Bloom's syndrome patients were found not to have raised SV40 transformation rates and no correlation was found between chromosome abnormality per se and transformation. Of 2 cell types with greatly increased rates, one was derived from a neurofibromatosis patient and the other from an A-T heterozygote. When SV40 DNA was employed as the transforming agent for the latter, the transformation rate was no longer raised.

Antigens, Viral↗
PubMed1977

Congenital pseudarthrosis of long bones: a clinical, radiographic, histologic and ultrastructural study.

Sixteen patients with pseudarthrosis of the tibia and one of the radius were evaluated clinically, radiograpically, and microscopically and separated into 3 groups; 8 had neurofibromatosis clinically, 3 had fibrous dysplasia histologically, and 6 had no evidence of either neurofibromatosis or fibrous dysplasia. Prognosis and therapy were determined by correlated clinical, radiographic, and histological observations. Fracture before age 2 years carried a poor prognosis. Electron microscopy allowed neither differentiation among these fibrous lesions, nor any clue to their origin, nor did it support the concept of a neural or vascular derivation.

Adolescent↗
PubMedDate not supplied

Forearm pseudarthrosis--neurofibromatosis: case report.

A 3 1/2-year-old white girl with neurofibromatosis sustained left radius and ulna fractures. The radius was sclerotic with no medullary canal at the fracture site, and the ulna was hypoplastic distal to the fracture. The fractures failed to unite when immobilized in a long arm plaster cast for 5 months and pseudarthrosis developed. Three subsequent operative attempts to obtain union of the pseudarthrosis by means of internal fixation and bone grafting over the next 30 months were also unsuccessful, and the pseudarthrosis persisted. The forearm was supported in a custom molded leather brace until the child was 13 1/2 years old and had reached skeletal maturity. Osseous union was then operatively obtained using dual onlay tibial cortical and cancellous bone grafts. There has been no recurrence of the pseudarthrosis 3 years and 2 months after bone grafting. The author recommends postponing surgical attempts to achieve union of the forearm bone pseudarthrosis associated with neurofibromatosis until the patient reaches skeletal maturity.

Bone Neoplasms↗
PubMed1978

[The problem of malignant degeneration in case of multiple neurofibromatosis (author's transl)].

Within less than one year, our hospital received three cases of malignant manifestation in case of multiple neurofibromatosis. If the histological findings and the neurogenic origin of the malignant tumor are evaluated very critically, the malignant suppression of the differentiation of one or more neurofibromas in case of multiple neurofibromatosis must be considered as occuring very rarely. If in case of a neurofibromatosis a malignant manifestation is found, it has to be examined very carefully by tissue specimens of numerous spots (Loehr and Willebrand), furthermore the neurogenic origin must be ensured (Zuelch). There are three clinical possibilities: 1. Sarcomatous degeneration of a neurofibroma with demonstrable neurogenic origin. 2. Histological appearence of a malignant suppression of the differntiation of a neurofibroma with benign clinical course. 3. Independent sarcoma as second disease without original connection to an existing multiple neurofibromatosis.--A critical evaluation of our cases showed that there was only one case of malignant tumor with neurogenic origin, namely a neurofibrosarcoma originating from a multiple neurofibromatosis.

Adult↗
PubMed1977

Massive subperiosteal hemorrhage in neurofibromatosis.

Neurofibromatosis is seen in association with elephantiasis neuromatosa and overgrowth of abnormal bones, but rarely with subperiosteal hemorrhage. This is a secondary finding after severe or minor trauma to the periosteum, which is abnormally loose from mesodermal dysplasia. The clinical, plain radiographic, and angiographic findings of 2 cases of massive subperiosteal hemorrhage are presented, and the literature reviewed.

Bone Diseases↗