Sensory neuronopathy in a patient with neurofibromatosis type 1: A case report.

RATIONALE: Neurofibromatosis type 1 (NF-1) can manifest with various neurological symptoms. However, sensory ataxia has not been reported. PATIENT CONCERNS: A 44-year-old man with NF-1 presented with several weeks of unsteady gait. He was diagnosed with gastric neuroendocrine tumor with multiple hepatic metastases 6 years ago and received palliative chemotherapy. Neurological examination revealed ataxia veering to the right side with no motor weakness. DIAGNOSES: Clinical manifestations and electrodiagnostic studies suggested the dysfunction of the thoracic dorsal column (DC). Initial magnetic resonance imaging showed a lateral thoracic meningocele (LTM) located in the right paravertebral area at the T3-T4 vertebral level, but the spinal cord was unremarkable. Gait disturbance worsened after 9 months, and follow-up magnetic resonance imaging showed high signal intensity involving the right DC at the level adjacent to the LTM and spinal cord atrophy distal to the DC lesion. Tests for well-characterized paraneoplastic antibodies were negative. Ultimately, the patient was assumed to have sensory neuronopathy due to compressive damage to the dorsal root ganglia within the intervertebral foramina by LTM. INTERVENTIONS: Empirical treatment with vitamin B12 supplementation and corticosteroids failed to improve his condition. The patient underwent decompressive laminectomy and excision of the meningocele with dura repair. OUTCOMES: The patient temporarily improved to walk with assistance postoperatively. However, he developed dyspnea and hypotension 5 weeks later. Carcinoid heart disease confined the patient to the bed. The patient died of pneumonia 3 months after the operation. LESSONS: This case with NF-1 shows asymmetric sensory ataxia of subacute progression. LTM may contribute to the development of sensory neuronopathy by damaging sensory neurons of the dorsal root ganglia. The comorbidities of the patient, including gastric neuroendocrine tumor and LTM, made it challenging to investigate the pathomechanism.

Speech difficulties and patient health communication mediating effects on worry and health-related quality of life in children, adolescents, and young adults with Neurofibromatosis Type 1.

The objective was to investigate the serial mediating effects of speech difficulties, patient health communication, and disease-specific worry in the relationship between neurofibromatosis (NF) symptoms (pain and skin symptoms) and total generic health-related quality of life (HRQOL) in children, adolescents, and young adults with NF Type 1 (NF1) from the patient perspective. The Speech, Communication, Worry, Pain, Skin Itch Bother, and Skin Sensations Scales from the Pediatric Quality of Life Inventory (PedsQL) NF1 Module and the PedsQL 4.0 Generic Core Scales were completed in a multi-site national study by 305 patients ages 5-25 years. A serial multiple mediator model analysis was conducted to test the hypothesized sequential mediating effects of speech difficulties, health communication, and worry as intervening variables in the association between NF1 symptoms and HRQOL. Symptoms predictive effects on total generic HRQOL were serially mediated by speech difficulties, patient health communication, and worry. In predictive analytics models utilizing hierarchical multiple regression analyses with age and gender demographic covariates, the pain, skin itch bother, and skin sensations multiple mediator models accounted for 61%, 59%, and 56% of the variance in generic HRQOL (p < .001), reflecting large effect sizes. Speech difficulties, patient health communication, and disease-specific worry explain in part the mechanism of symptoms predictive effects on total generic HRQOL in pediatric patients with NF1. Identifying NF1-specific predictors and serial mediators of total generic HRQOL in pediatric patients with NF1 from the patient perspective enables a patient-centered comprehensive care approach for children, adolescents, and young adults with NF1.

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report.

BACKGROUND In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. CASE REPORT We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7-15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment. CONCLUSIONS This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment.

Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients.

BACKGROUND: Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition? METHODS: We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls. FINDINGS: NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase. INTERPRETATIONS: Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work.

Neurofibromatosis, pathological fracture and hypervitaminosis-D.

Pathologic fractures in children may be due to various causes. Rarely, it may be the presenting symptom of neurofibromatosis. A misdiagnosis of Rickets and Vitamin D supplementation in such a case may wreak havoc in the form of iatrogenic hypervitaminosis D. We report one such case.

Generalized metabolic bone disease in Neurofibromatosis type I.

Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1) but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical and pathological level the bone involvement in NF1 patients. Using dual energy X-ray absorptiometry (DXA) we analyzed bone status in 73 unselected NF1 subjects, 26 males and 47 females, mainly children and adolescents (mean age: 16.6 years). In a subgroup of subjects with low bone mass, we measured indices of calcium-phosphate metabolism, bone turnover, and bone density before and after vitamin D and calcium treatment. We found statistically significant and generalized reduction in bone mass with the mean lumbar bone mineral density (BMD) z-score being -1.38+/-1.05 (CI 95% -1.62 to -1.13), and whole body bone mineral content (BMC) z-score -0.61+/-1.19 (CI 95% -0.94 to -0.29), both significantly reduced compared to normal controls (p<.001). PTH was moderately elevated and after 4 months of supplemental therapy with calcium and vitamin D, it decreased to the normal range. However, BMD z-scores did not significantly improve after 2 years of follow-up. Histological analysis of bone samples from NF1 patients revealed substantial alteration of bone microarchitecture due mainly to reduced trabecular bone. Our observations are consistent with a generalized bone metabolic defect due to loss of the function of neurofibromin. Early identification of patients with osteoporosis may permit more timely and aggressive treatments to prevent the likely substantial morbidity associated with increased fracture risk later in life.

Neurofibromatosis type 1: diffusion weighted imaging findings of brain.

PURPOSE: The purposes of this study were to evaluate the differences in apparent diffusion coefficient (ADC) values between infra and supratentorial unidentified bright objects (UBOs), between UBOs and normal appearing side (NAS, contralateral regions of the UBOs and/or normal appearing region without UBOs) in the neurofibromatosis type 1 patients (NF1) and control group and also to investigate correlation between age and ADC values. METHODS: A total of 30 patients and 26 healthy controls were included. The MRI examination consisted of routine imaging and diffusion weighted imaging (DWI). Seven distinct locations (frontal, parieto-occipital and cerebellar white matter, globus pallidum, thalamus, hippocampus, and midbrain) were selected for the analysis. The ADC values were calculated directly from these automatically generated ADC maps with ROI. RESULTS: The ADC values of UBOs were significantly increased in cerebellar white matter, hippocampus, globus pallidum, midbrain, and thalamus when compared with NAS and control group. There were statistically significant differences between NAS and control group in the ADC values obtained from hippocampus and thalamus. There were statistically significant differences between supra and infratentorial UBOs in ADC values. There was a negative correlation between age and the ADC values obtained from normal appearing midbrain, hippocampus, thalamus, and globus pallidum. CONCLUSION: ADC values both in UBOs and in the normal appearing locations as hippocampus and thalamus were detected to be higher in the patients with NF1. The detection of lesions might be independent of MRI appearance in NF1, i.e. although the brain is affected, MRI appearance may be normal. Therefore, DWI and ADC values should also be utilized in the delineation of brain involvement of NF1 patients.

T2-weighted hyperintensities (unidentified bright objects) in children with neurofibromatosis 1: their impact on cognitive function.

The impact of magnetic resonance imaging (MRI)-identified T2-weighted hyperintensities (unidentified bright objects) on the cognitive function of children with neurofibromatosis 1 is controversial. We recruited 32 right-handed children with neurofibromatosis 1 (22 boys, 10 girls) aged between 5 and 16 years (mean age 10.2 years) for magnetic resonance imaging examinations and neuropsychologic evaluation. Statistical analysis was performed to evaluate the significance of the hyperintensities. Twenty-four children had unidentified bright objects, whereas eight children did not. Using the t-test, thalamic lesions were associated with lower intellectual function (P = .031). Left globus pallidus hyperintensities were associated with a lower attention score (P = .04), and right middle cerebellar peduncle hyperintensities were associated with a lower sensorimotor score (P = .05). The size of the thalamic lesions correlated with cognitive function (P < .05). Among the group with unidentified bright objects, there was a significant association between more involved sites on the dominant hemisphere and impaired verbal function (r = -.55; P = .005). Unidentified bright objects in the thalamus, globus pallidus, and middle cerebellar peduncles and the laterality of the lesions had an impact on cognitive function.

A corneal diffuse neurofibroma as a manifestation of von recklinghausen disease.

PURPOSE: To report a case of a primary corneal diffuse neurofibroma in a patient with von Recklinghausen disease (NF-1). METHODS: Case report. A physical examination and histopathology were performed. The immunohistochemical studies were performed using an avidin-biotin-peroxidase complex technique on formalin-fixed and paraffin-embedded tissue. Histologic sections from corneal tissue were incubated with primary antibodies against vimentin and S-100 protein. A complementary ultrastructural study of the same formalin-fixed and paraffin-embedded tissue was made. RESULTS: The ophthalmologic examination revealed a yellowish-white elevated mass that involved the supratemporal cornea but not the limbus. Histologic study showed a tumor of the peripheral nerve sheath, a diffuse neurofibroma in the corneal stroma, and proliferation of spindle cells with markedly elongated nuclei. Cells comprising the tumor reacted with vimentin and S-100 protein, and the ultrastructural studies revealed myelinated nerve fibers confirming the diagnosis. CONCLUSION: The development of a primary diffuse neurofibroma in the cornea of patients with von Recklinghausen disease is possible. The present case supports the statement that neurofibromas arising from the peripheral nerve sheath may involve any part of the body.

Lesiones vasculares múltiples y precoces en la neurofibromatosis. Descripción de un caso clínico y revisión bibliográfica / Multiple premature vascular lesions in neurofibromatosis. Description of a clinical case and a review of the literature

Introducción. La neurofibromatosis tipo I de von Recklinghausen es un síndrome neurocutáneo que, con escasa frecuencia, tiene alteraciones vasculares, y éstas pueden ser muy variadas. La afectación más frecuente es la estenosis de aorta pararrenal, asociada a estenosis proximal de arteria renal, que produce hipertensión vasculorrenal. La afectación típica de las arterias cerebrales es la estenosis de la porción terminal de la carótida interna, o de la porción proximal de las arterias cerebrales anterior o media; es menos frecuente que afecte a la mitad posterior del círculo de Willis. Puede haber lesiones estenóticas o aneurismáticas (saculares) de arterias viscerales y de arterias de miembros inferiores. Caso clínico. Presentamos el caso de una paciente con afectación vascular multifocal, muy grave y precoz, en la que se decidió una actitud conservadora en espera de la evolución clínica durante el seguimiento; también se realiza una revisión bibliográfica del tema (AU)

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[Decreased bone mineral density as a risk factor in the development of spinal deformities in neurofibromatosis]. / Csökkent csontdenzitás, mint lehetséges tényezó a neurofibromatosist kíséró gerincdeformitások kialakulásában.

Neurofibromatosis-1 is a here-do-familiar disorder that is associated with a variety of skeletal anomalies, mostly with spinal deformities in 10-50% of the patients. Intraoperatively, a poor vertebral bone quality has been observed. Efforts have been made to identify factors preventing curve progression, to optimize operational planning and to explain the pathomechanism. As part of the preoperative evaluation, the authors used a dual X-ray absorptiometry to assess the bone mineral density of the lumbar spine in 12 non operated patients with neurofibromatosis-1, supplemented by laboratory blood/urine investigations. A significant decrease in bone mineral density of lumbar spine was measured. An inverse relation was suggested between the severity of scoliosis and the lumbar spine Z-scores. No pivotal alterations were identified in the laboratory measurements. The bony tissue abnormality observed intraoperatively in neurofibromatosis-1 patients may be described as a diminution of the axial bone mineral density. The evaluation of bone mineral density in the course of the preoperative planning is proposed in neurofibromatosis-1.

Spontaneous regression of low-grade astrocytomas in childhood.

An 8-year-old boy with neurofibromatosis type 1 (NF1) and a biopsy-proven juvenile pilocytic astrocytoma of the hypothalamic/chiasmatic region was followed with serial MRIs over 4 years. Spontaneous tumor regression was followed by progression and biopsy; 6 months later, the tumor regressed again. This bimodal regression is rare, but highlights the variable natural history of low-grade gliomas in children with NF1 and the difficulty in evaluating response of such tumors to therapy.

Initial management of children with hypothalamic and thalamic tumors and the modifying role of neurofibromatosis-1.

Diencephalic gliomas may be grouped into 2 clinical categories. Optic pathway/hypothalamus gliomas (OPG) arise primarily from a slower-growing juvenile pilocytic astrocytoma, and thalamic gliomas arise primarily from a fibrillary astrocytoma which can become clinically and histologically more aggressive. Children with OPG have an excellent long-term prognosis with a 10-year survival of over 85%. The major therapeutic challenge for these patients is to maximize their quality of life by preserving visual and endocrine function while minimizing treatment-related morbidity. Treatment is often initiated at diagnosis in infants and toddlers who have a major visual impairment or the diencephalic syndrome. The judicious application of chemotherapy may serve to forestall the need for radiotherapy or surgery. Children with neurofibromatosis-1 (NF-1) usually have a more indolent course. Tumors may grow more slowly or occasionally regress spontaneously. However, over 90% of children with OPG without NF-1 will require some form of therapy. Patients with thalamic gliomas present with a shorter history, often with hydrocephalus. Surgical intervention is often required to relieve intracranial pressure and establish the histologic identity of the tumor. Over 75% of these tumors will become locally aggressive. Current multimodality therapy is relatively ineffective. The bithalamic variant behaves similarly to a pontine glioma.

Spontaneous involution of pilocytic astrocytoma in a patient without neurofibromatosis type 1: case report.

Serial magnetic resonance imaging findings are described in a patient with a sporadically occurring pilocytic astrocytoma that underwent spontaneous regression over 6 years. To the authors' knowledge, this is the first report in which spontaneous involution of a pilocytic astrocytoma not associated with neurofibromatosis type 1 has been described. A literature review regarding sporadic and syndrome-associated pilocytic astrocytoma was undertaken, with particular reference to treatment and natural history.