Manifestation Of NF1 Research Articles

Clinical features and surgical treatments of scoliosis in neurofibromatosis type 1: a systemic review and meta-analysis.

Neurofibromatosis type 1 (NF 1) is an autosomal-dominant tumor predisposition genetic disease affecting approximately 1 in 3000 live births. The condition could present various manifestations ranging from skin abnormalities to neurological tumors. The musculoskeletal system could also be frequently affected, and scoliosis is the most common orthopedic manifestation. Characterized by the early-onset and rapid progression tendency, NF 1-related dystrophic scoliosis presented discrepancies from idiopathic scoliosis in terms of natural history, clinical features, and management outcomes and thus required special attention. In the current study, the authors conducted a systemic review to outline the body of evidence of the natural history, clinical characteristics, surgical outcomes, and surgical complications of NF 1-induced scoliosis, aiming to provide an elucidative insight into this condition. Systemic review and meta-analysis were conducted according to the latest Preferred Reporting Items for Systematic Reviews Meta-Analyses (PRISMA) guidelines. The search was performed in Medline, Embase, and Web of Science Core Collection up to December 27, 2022, using related keywords. Clinical features such as frequencies, segmental involvement, and hereditary information were summarized and described qualitatively. Meta-analysis was conducted using R software and the 'meta' package to yield an overall outcome of efficacy and safety of surgical management, precisely, spinal fusion procedure and growing rods procedure. Corrective rate of Cobb angle, sagittal kyphosis angle, and T1-S1 length post-operative and at the last follow-up was used to evaluate the efficacy, and the occurrence of surgery-related complications was used to evaluate the safety. A total of 37 articles involving 1023 patients were included. Approximately 26.6% of the NF 1 patients would present with scoliosis. Patients tend to develop scoliosis at an earlier age. The thoracic part turned out to be the most affected segment. No obvious correlation between scoliosis and genotype or hereditary type was observed. Both spinal fusion and growing rod surgery have shown acceptable treatment outcomes, with spinal fusion demonstrating better performance in terms of effectiveness and safety. The growing rods technique seemed to allow a better lengthening of the spine. The mainstay post-operative complications were implant-related complications but could be managed with limited revision surgery. Severe neurological deficits were rarely reported. Scoliosis, especially the subtype characterized by dystrophic bony changes, is a significant orthopedic manifestation of NF1. It has an early onset, a tendency to persistently and rapidly progress, and is challenging to deal with. The current review outlines the available evidence from the perspective of natural history, clinical features, and the treatment efficacy and safety of the mainstay surgical options. Patients with NF1 scoliosis will benefit from a better understanding of the disease and evidence based treatment strategies.

White matter is increased in the brains of adults with neurofibromatosis 1

BackgroundNeurofibromatosis 1 (NF1) is a rare autosomal dominant disease characterized by increased Schwann cell proliferation in peripheral nerves. Several small studies of brain morphology in children with NF1 have found increased total brain volume, total white matter volume and/or corpus callosum area. Some studies (mostly in children with NF1) also attempted to correlate changes in brain morphology and volume with cognitive or behavioural abnormalities, although the findings were inconsistent. We aimed to characterize alterations in brain volumes by three-dimensional (3D) MRI in adults with NF1 in major intracranial sub-regions. We also aimed to assess the effect of age on these volumes and correlated brain white matter and grey matter volumes with neuropsychometric findings in adults with NF1.MethodsWe obtained brain volume measurements using 3D magnetic resonance imaging for 351 adults with NF1 and, as a comparison group, 43 adults with neurofibromatosis 2 (NF2) or Schwannomatosis. We assessed a subset of 19 adults with NF1 for clinical severity of NF1 features and neurological problems and conducted psychometric testing for attention deficiencies and intelligence quotient. We compared brain volumes between NF1 patients and controls and correlated volumetric measurements to clinical and psychometric features in the NF1 patients.ResultsTotal brain volume and total and regional white matter volumes were all significantly increased in adults with NF1. Grey matter volume decreased faster with age in adults with NF1 than in controls. Greater total brain volume and white matter volume were correlated with lower attention deficits and higher intelligence quotients in adults with NF1.ConclusionOur findings are consistent with the hypothesis that dysregulation of brain myelin production is a cardinal manifestation of NF1 and that these white matter changes may be functionally important in affected adults.

Alterations in brain morphology by MRI in adults with neurofibromatosis 1

ObjectiveNeurofibromatosis 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.MethodsPlanar (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.ResultsFour 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.ConclusionOur findings are consistent with the hypothesis that dysregulation of brain myelin production is an important manifestation of NF1 in adults.

CO2 Laser Ablation for the Manifestations of Multiple Cutaneous Neurofibromas in an Adult with Neurofibromatosis Type 1(NF1)

Introduction: Neurofibromatosis type 1 is a rare genetic disorder that is characterized by the growth of noncancerous neurocutaneous tumors that form near the spinal cord and along the peripheral nerves in the body. Symptoms NF-1 are usually detected in infancy or early childhood. However, in some cases, children and adults without family history may have a spontaneous genetic mutation of unknown cause. There are several modalities to treat NF-1, which include conventional surgery removal and CO2 laser ablation. The review of literature aims to compare the efficacy and outcomes of these two modalities.
 Case presentation: A 32-year old post-partum Australian woman is presented to the neurosurgery department outpatient clinic. When she was around 20-year old, non-painful multiple noncancerous growth along her spine and peripheral nerves and multiple café-au-lait spots started to appear. The size and numbers of growth and spots are gradually increasing as she aged. The diagnosis of NF-1 was made according to the presence of four of the seven diagnostic criteria of the National Institute of Health Consensus Development Conference. Patient is scheduled to go to NF clinic 2 months after the meeting, in which the patient is planned to undergo a treatment of CO2 laser ablation.
 Conclusions: Studies have shown that CO2 has outperformed conventional surgery in managing the clinical manifestation of NF-1 in term of effectivity and cosmetic outcomes.
 Keywords: neurofibromatosis type I, von Recklinghausen’s disease, adult, post-partum woman, CO2 laser ablation

Cutaneous Lesions Presenting as Recurrent Annular Erythema in a Child with Juvenile Myelomonocytic Leukemia, Coeliac Disease, and CALMs: The Myriad Manifestations of RASopathy

In neurofibromatosis type 1 (NF-1), a Ras-pathway mutation disorder both celiac disease and juvenile myelomonocytic leukemia (JMML) have been found in association. A 3-year-old male child presented to us with annular erythema and cafe-au-lait macules (>6 in number). On investigation, he was found to have JMML and celiac disease. A child with early manifestation of NF1 in association with JMML and celiac disease is an even rarer presentation.

Triple malignancy (NET, GIST and pheochromocytoma) as a first manifestation of neurofibromatosis type-1 in an adult patient

BackgroundNeurofibromatosis type-1 (NF1), also called von Recklinghausen disease, is a rare genetic disease which can lead to the development of benign or even malignant tumors. NF1 is mostly diagnosed in children or early adolescents who present with clinical symptoms. A curative therapy is still missing and the management of NF1 is based on careful surveillance. Concerning tumors which affect the gastrointestinal tract in patients with NF1, the most common is a gastrointestinal stromal tumor (GIST).Case presentationWe present a case of a 58-year-old adult patient with dyspeptic symptoms who was incidentally diagnosed with triple malignancy (pheochromocytoma, multiple GISTs of small intestine and an ampullary NET) as a first manifestation of NF1. The patient underwent surgical treatment (adrenalectomy and pancreaticoduodenectomy) with no complications and after 2 years remains in oncological remission.ConclusionNF1 is a rare genetic disease which can cause various benign or malignant tumors. The coincidence of GIST and NET is almost pathognomonic for NF1 and should raise a suspicion of this rare disorder in clinical practice.

Neurofibromatosis with pulsating exophthalmos

Background: Neurofibromatosis (NF) is a neurocutaneous disorder which involves many organs in the body. There are two types: NF-1 and NF-2. Orbital manifestation is a rarity in NF-1, and it involves dysplasia of the sphenoid bone resulting in herniation of the temporal lobe and subarachnoid space into the orbit culminating in pulsating exophthalmos. Aim: To highlight the clinical presentation and radiological investigation of this rare ocular manifestation of NF-1. Methods: A case report. Results: The case of a 20-year-old male student presenting with a pulsating right eye swelling of about 17-year duration is presented. There was a family history of a first-degree relative with multiple skin swellings. Plain skull radiograph and cranial computed tomography (CT) scan were done and both revealed absence of the right sphenoid bone with herniation of the right temporal lobe and cerebrospinal fluid space into the right orbit. The patient was subsequently lost to follow-up. Conclusion: Pulsating exophthalmos is a complication of sphenoid dysplasia, a rare component of NF-1. Plain skull radiograph and cranial CT scan are two important radiological imaging modalities for investigating patients with such presentation.

Morphological Differences in the Vertebrae of Scoliosis Secondary to Neurofibromatosis Type 1 With and Without Paraspinal Neurofibromas.

A retrospective study. Aim of the study was to investigate morphological differences in the vertebrae of scoliosis secondary to neurofibromatosis type 1 (NF1-S) with and without paraspinal neurofibromas and to identify the relationship between paraspinal neurofibromas and vertebral deformity. Scoliosis is the most common orthopedic manifestation of NF1. Erosion or infiltration of the bone by localized neurofibromas was suggested as one of the primary etiology for the vertebral deformity. One hundred fourteen patients with NF1-S were classified into spinal tumor (ST) group and nontumor (NT) group with respect to the presence of paraspinal neurofibromas. The curve pattern, curve magnitude, the shape and location of paraspinal neurofibromas, and various kinds of morphological changes of vertebrae were evaluated by complete radiographs were compared between the two groups to determine whether the presence of paraspinal neurofibromas could be associated with a more severe vertebral deformity. The ST and NT groups included 54 patients (age, 16.8 ± 5.5 years) and 60 patients (age, 17.3 ± 4.2 years), respectively. The Cobb angles of the main curve were 72.3° ± 20.6° and 65.4° ± 19.4° for the ST and NT groups, respectively. No significant differences were observed between the two groups in age, sex ratio, and Cobb angle. There were significant differences between the ST and NT groups in apical vertebral rotation (36.8° ± 7.2° vs. 27.5° ± 6.8°; P < 0.001) and the prevalence of rotatory subluxation (66.1% vs. 35.0%; P = 0.04). Most of the paraspinal neurofibromas (70.4%) developed within the apical region, with the majority (29/38) located on the concave side. The NF1-S patients with paraspinal neurofibromas had significantly higher prevalence of morphological changes of vertebrae. The paraspinal neurofibromas, most of which were located on the concave side of the apical region, could be associated with more severe vertebral deformities. 3.

Breast Cancer Associated with Von Recklinghausen's Disease: Case Report and Review of Literature.

Breast cancer in association with type- 1 neurofibromatosis (NF1) is a rare clinical entity. Here, we present the case of a 45-year-old woman with typical clinical manifestations of NF1, who presented with a right breast lump, which she had first noticed 8months back but had disregarded, believing it to be another manifestation of her Von Recklinghausen's disease. Clinical examination and diagnostic workup were suggestive of a breast carcinoma. Subsequently, she underwent modified radical mastectomy, followed by postoperative chemotherapy. Histopathological examination revealed high grade invasive duct carcinoma and multiple neurofibromas. After 7.5months, she developed recurrence at the drain site with pulmonary and bony metastasis and died 9months after surgery. Delayed presentation of the patient was the result of her mistaken identification for the breast tumor as a manifestation of NF-1. Early onset, high grade tumor and early recurrence with metastasis place strong emphasis on clinical alertness and to opt for an aggressive treatment option.

Small Bowel Obstruction Due to Gastrointestinal Neurofibromas and Lipomas

The most known manifestation of neurofibromatosis Recklinghausen NF-1 is cafe-au-lait spots on the skin, but up to 25% of patients with NF-1 have gastrointestinal manifestations, and only 5% of the gastrointestinal manifestations of NF-1 will require surgical treatment. We report a rare case of a 73-year-old woman, who five times earlier has undergone bowel resection, due to intussusception and ileus. The patient was admitted to the hospital due to abdominal pain. A computed tomography scan showed progression of the almost disseminated tumor growth of neurofibromas and lipomas of the small intestinal wall. Clinical manifestions showed the ileus required an operative treatment with a sixth small bowel resection. Small bowl obstruction caused by neurofibromas is a rare manifestation of a rare disease. J Med Cases. 2014;5(1):1-3 doi: http://dx.doi.org/10.4021/jmc1579w

Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis

BackgroundConsensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular...

Posterior Vertebral Column Resection for the Treatment of Dystrophic Kyphosis Associated With Type-1 Neurofibromatosis

Case report. To describe the use of posterior-only vertebral column resection and postoperative traction for spinal deformity associated with type-1 neurofibromatosis (NF1). Vertebral deformity, namely, thoracic scoliosis, is the predominant orthopedic manifestation of NF1. Patients may present with debilitating pain and rarely, myelopathy. The commonly dystrophic nature of these deformities makes them particularly recalcitrant to surgical correction. Traditionally, circumferential arthrodesis via combined anterior and posterior approaches has been recommended. Clinical and radiographical case review. A 14-year-old adolescent boy with NF1, severe cervicothoracic angular kyphosis, thoracic dislocation, and myelopathy presented status postmultiple anterior and posterior spinal fusions. The patient underwent posterior-only vertebral column resection after 6 weeks of halo-gravity traction. The surgery consisted of thoracic laminectomies, total corpectomies of T3 and T4, circumferential fusion, and posterior instrumentation from the occiput to T11. Autologous rib and iliac crest grafts were used as fusion substrate. Postoperatively, a halo vest was worn for 4 months to support the correction of his chin-on-chest deformity. The patient's neurological status returned to normal by 6 weeks postoperatively, and solid fusion was radiologically evident after 1 year. We think that posterior-only vertebral column resection represents a safe and efficacious but technically challenging option for the treatment of angular kyphotic spinal deformity and associated neurological deficit in patients with NF1.

Four‐year‐ old child with optic nerve glioma revealed by a proptosis

AbstractPurpose Optic pathway gliomas are rare tumors accounting for 3‐5% of brain tumors in children. Our case aims to understand surgical options.Methods We report the case of a 4‐year‐old child with a single optic pathway glioma revealed by a non esthetical proptosis and blindness. Association with NF1 was not found. The MRI showed a tortuous enlargement of the left optic nerve, the glioma extended into the optic canal with a scleral invasion. Considering those results, a treatment consisting of a double team surgery, ophthalmologists and neurosurgeons was performed with enucleation and complete section of the nerve at its optic chiasm root.Results Histology confirmed the diagnosis of glioma, as a pilocytic astrocytoma, with safety margins. Cytogenetic analysis showed an unspecific chromosome 8 deletion. Chemotherapy was avoided because of systemic toxicity and tumor localization.Conclusion Association with NF1 is classical and the incidence of optic nerve glioma is estimated at 15%. In young children the glioma can be the first manifestation of NF1 and the disease should be kept in mind. Cytogenetic mutation must be searched with surgical sample in culture. In children, surgical treatment can be preferred to chemotherapy when excision of the total tumor removal can be performed.

Abstract 4577: Targeting N-glycosylation of tyrosine kinase receptors for preventing tumorigenesis and malignant transformation of neurofibromatosis type I

Abstract Neurofibromatosis type I (NF1) is a dominantly inherited disease affecting 1 in every 2,500 to 3,000 individuals, representing the most common familial cancer predisposition syndrome. The hallmark of clinical manifestation of NF1 is the development of multiple neurofibromas, which are highly heterotypic benign tumors of peripheral nerve sheath mainly composed of immature Schwann cells, fibroblasts, perineurial and inflammatory matrix. NF1 patients are also at high risk for the development of certain maligancies such as pheochromocytomas, childhood myeloid leukemias, neuroblastomas, rhabdomyosarcomas, and malignant peripheral nerve sheath tumors (MPNSTs). Because of the potential involvement of underlying nerves and blood vessels, surgical removal of tumors is not always an option. Once progressing to MPNSTs, although the resection is possible, most patients will eventually relapse locally or systemically. There is no effective treatment for NF1, nor effective approaches for predicting or preventing the occurrence of devastating complications. Thus, to develop agents for preventing or reversing the tumorigenesis and malignant transformation of NF1 are critically needed. In this report, we found HGF, c-MET, EGF and EGFR are aberrantly expressed in clinical specimens of neurofibromas and MPNSTs with NF and that autocrine and/or paracrine HGF/c-MET and EGF/EGFR loops promote MPSNT cell migration and invasion in vitro (Fig1). We also found that the loss of Nf1 in neurofibromas and MPNSTs results in hyperactive of Ras (Fig2). Compared with normal Schwann cells, MPNST cells express more N-glycoproteins and display different N-glycoprotein signatures (Fig3). In order to confirm our hypothesis, we treated cells with Tunicamycin, or 2-DG (N-glycosylation inhibitors) respectively in variable doses for different time. We found that both Tunicamycin and 2-DG inhibited the proliferation and promoted apoptosis of MPNST cell lines but had no effect on normal human Schwann cells (Fig4); inhibited the glycosylation and phosphorylation of EGFR and c-MET and impaired receptor-mediated MEK-ERK1/2 and PI3K-AKT signaling in a dose-dependent manner (Fig5). Moreover, 2-DG inhibited the maturation of c-MET as demonstrated by the intact premature chain, failing to cleave into one mature α-chain and another mature α-chain. In addition, 2-DG inhibited the translocation of the receptors from the cytoplasm onto the cell surface and retained receptors in the ER and Golgi apparatus (Fig6). To date, 2-DG inhibition of N-glycosylation and phosphorylation of tyrosine kinase receptors has not been reported. These novel findings prompted us to explore whether 2-DG disrupts Ras-directed N-glycosylation of tyrosine receptors in Schwann cell progenitors and tumor cells and to evaluate its roles in preventing the tumorigenesis and malignant transformation of NF1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4577. doi:1538-7445.AM2012-4577

A Case of Persistent Foot Pain in a Neurofibromatosis Type I Patient

Introduction. This is the case of a young male patient who presented to his family physician with atypical left foot pain, which was extremely resistant to analgesia and caused significant disability. Despite extensive investigations, the cause of his pain was not identified until 18 months after his initial symptoms, when the official diagnosis of malignant peripheral nerve sheath tumour (MPNST) was made. Detailed review of the patient's past history established the diagnosis of type I neurofibromatosis (NF-1), previously undetected. Discussion. NF-1 is an autosomal dominant genetic disorder caused by loss of function mutations of the NF1 gene in chromosome 17. Patients with this condition are at increased risk for developing MPNSTs which, however, are treatable only in early stages. Conclusion. Although monitoring NF-1 patients for the development of MPNSTs is common practice, the index of clinical suspicion in patients without an established NF-1 diagnosis is low. Any atypical pain in young adults should raise the possibility of this malignancy, and this case illustrates the fact that MPNSTs can be the first manifestation of NF-1 in patients previously undiagnosed with the disease.

Recurrent abdominal complaints caused by a cecal neurofibroma: A case report

Gastrointestinal involvement of neurofibromatosis type 1 (NF1, Von Recklinghausen's disease) is generally associated with the upper gastrointestinal tract. Abdominal manifestation of NF1 includes several tumors such as malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors and ampulla of vater tumors. However, colonic involvement in NF1 patients is rare. We report a case of a patient presenting with dysphagia, weight loss, intermittent abdominal pain and constipation caused by a single cecal neurofibroma obstructing the ileocecal valve. Also gastrointestinal involvement of the lower tract should be considered in patients with NF1 presenting with abdominal complaints.

Gastric Outlet Obstruction due to Submucosal Neurofibromatous Proliferation of Duodenal Bulb in Neurofibromatosis Type 1 Patient

Neurofibromatosis type 1 (NF1; also known as von Recklinghausen’s neurofibromatosis) is inherited in an autosomal dominant fashion, although it can also arise due to spontaneous mutation. Gastrointestinal involvement of NF1 is seen in 10% to 25% and causes symptoms in fewer than 5%. Histologically, the gastro intestinal (GI) manifestation of NF1 occurs in three forms: hyperplasia of the gut neural tissue, stromal tumors, and duodenal or periampullary endocrine tumors. A 31-year-old female, diagnosed with NF1, presented with poor oral intake and vomiting for 10 days prior to admission. Preoperative gastrofiberscopic finding was gastric outlet obstructing polypoid duodenal bulb lesion. The patient underwent hemigastrectomy with antecolic gastrojejunostomy due to gastric outlet obstruction. The final pathologic report was submucosal neurofibromatous proliferation with Brunner’s gland hyperplasia located at the duodenal bulb in the NF1 patient. We report this case with a review of literatures. (J Korean Surg Soc 2010;79:S31-36)

Solitary neurofibroma of the Mesentery: Report of a Case and review of the literature

Neurofibromas of the gastrointestinal tract are usually associated with neurofibromatosis type 1 (Nfl), or they are exclusive manifestations of the so-called "familial intestinal neurofibromatosis". Gastrointestinal neurofibromas can rarely occur as sporadic lesions in the jejunum and stomach, and only exceptionally in the mesentery. A critical review of the literature revealed that only seven cases of solitary neurofibromas (SNFs) of the mesentery (six in the ileal mesentery; one in the gastrocolic mesentery) have been reported in patients without stigmata of Nf1. We report the clinicopathologic features of an additional case of SNF of the ileal mesentery, incidentally found in a patient with an advanced gastric carcinoma. Since there is increasing evidence that some patients may have some features of Nf1, including dermal or nodular SNFs alone - limited to one or more body segments - (segmental Nf1), the possibility that SNFs of the mesentery may also represent a segmental manifestation of Nf1 is postulated.