Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

AbstractNeurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. Neurofibromin may regulate metabolism, though the underlying mechanisms remain largely unknown. Here we show that neurofibromin regulates metabolic homeostasis in Drosophila via a discrete neuronal circuit. Loss of neurofibromin increases metabolic rate via a Ras GAP-related domain-dependent mechanism, increases feeding homeostatically, and alters lipid stores and turnover kinetics. The increase in metabolic rate is independent of locomotor activity, and maps to a sparse subset of neurons. Stimulating these neurons increases metabolic rate, linking their dynamic activity state to metabolism over short time scales. Our results indicate that neurofibromin regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in neurofibromatosis type 1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

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Isolated premature menarche in two siblings with Neurofibromatosis type 1

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0494 ◽

2020 ◽

Vol 33 (6) ◽

pp. 813-816

Author(s):

James Blackburn ◽

Mohammed Didi ◽

Shivaram Avula ◽

Senthil Senniappan

Keyword(s):

Neurofibromatosis Type 1 ◽

Pubertal Timing ◽

Genetic Disorder ◽

Pubertal Development ◽

Neurofibromatosis Type ◽

Malignant Tumours ◽

Peripheral Tissues ◽

Paediatric Endocrinology ◽

The Central Nervous System

AbstractObjectivesNeurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, caused by mutation in NF1. The condition is typified by the development of benign and malignant tumours in both the central nervous system and peripheral tissues. Isolated menarche is a sub-classification of incomplete isosexual precocious puberty typified by menarche in girls with no other features of pubertal development. The effects of NF1 on pubertal timing are poorly understood, we report two siblings with NF1 and apparent abnormal pubertal development.Case PresentationTwo siblings were referred to the tertiary paediatric endocrinology clinic at 6 and 7 years of age with recurrent, cyclical vaginal bleeding. There was a strong family history of NF1, the mother of the siblings and two brothers were also diagnosed at a young age. On examination both patients were prepubertal at presentation. Both siblings underwent a gonadotrophin releasing hormone test, which revealed a follicle-stimulating hormone dominant (prepubertal) response. The features were suggestive of isolated premature menarche as no other cause was identified. The elder sibling established menarche and developed signs of consonant pubertal development at 12 years of age. The younger sibling remains under regular follow-up.ConclusionsNF1 has previously been associated with alterations in pubertal timing. We report, for the first time, two siblings with NF1 who presented with isolated menarche.

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Pulmonary hypertension associated with neurofibromatosis type 1

European Respiratory Review ◽

10.1183/16000617.0053-2018 ◽

2018 ◽

Vol 27 (149) ◽

pp. 180053 ◽

Cited By ~ 7

Author(s):

Etienne-Marie Jutant ◽

Barbara Girerd ◽

Xavier Jaïs ◽

Laurent Savale ◽

Caroline O'Connell ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Lung Disease ◽

Neurofibromatosis Type 1 ◽

Genetic Disorder ◽

Neurofibromatosis Type ◽

Pulmonary Vascular Disease ◽

Increased Risk ◽

Parenchymal Lung Disease ◽

Parenchymal Lung

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a frequent autosomal dominant genetic disorder with a prevalence of 1 in 3000. Pulmonary hypertension (PH) associated with NF1 (PH-NF1) is a rare but severe complication of NF1 and is classified as Group 5 PH, defined as “PH with unclear and/or multifactorial mechanisms”. A literature review in PubMed on the association between NF1 and PH identified 18 articles describing 31 cases. PH-NF1 was characterised by a female predominance, an advanced age at diagnosis, an association with parenchymal lung disease in two out of three cases and poor long-term prognosis. NF1 is generally associated with interstitial lung disease but some cases of severe PH without parenchymal lung disease suggest that there could be a specific pulmonary vascular disease. There is no data available on the efficacy of specific pulmonary arterial hypertension treatment in PH-NF1. Therefore, these patients should be evaluated in expert PH centres and referred for lung transplantation at an early stage. As these patients have an increased risk of malignancy, careful assessment of the post-transplant malignancy risk prior to listing for transplantation is necessary. Clinical trials are needed to evaluate promising treatments targeting the RAS-downstream signalling pathways.

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Spontaneous Rupture of Multiple Occipital Artery Aneurysms in a Patient With Neurofibromatosis Type 1

Vascular and Endovascular Surgery ◽

10.1177/1538574417742285 ◽

2017 ◽

Vol 52 (1) ◽

pp. 86-88 ◽

Cited By ~ 3

Author(s):

Daniele Bissacco ◽

Maurizio Domanin ◽

Silvia Romagnoli ◽

Edoardo Martelli ◽

Vittorio Civelli ◽

...

Keyword(s):

Nervous System ◽

Neurofibromatosis Type 1 ◽

Spontaneous Rupture ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Neurofibromatosis Type ◽

Occipital Artery ◽

Endovascular Approach ◽

Spontaneous Hematoma

Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder, mainly characterized by skin and peripheral nervous system abnormalities. Uncommonly, NF-1 may be associated with peripheral or supra-aortic trunks artery aneurysms. We report a case of symptomatic multiple occipital artery aneurysms detected in a 53-year-old woman affected by sporadic NF-1. An endovascular approach was performed to exclude aneurysms and to stop laterocervical spontaneous hematoma.

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Endocrine Dysfunction in Neurofibromatosis Type 1 – An Update

Acta Medica Marisiensis ◽

10.1515/amma-2016-0003 ◽

2016 ◽

Vol 62 (1) ◽

pp. 155-158

Author(s):

Raluca-Monica Pop ◽

Radu Mircea Neagoe ◽

Melinda Kolcsar ◽

Ionela Paşcanu

Keyword(s):

Neurofibromatosis Type 1 ◽

Genetic Disorder ◽

Parathyroid Tissue ◽

Neurofibromatosis Type ◽

Needle Aspiration ◽

Autosomal Dominant Disorder ◽

Thyroid Lesion ◽

Neurogenic Tumors ◽

Multiple Neoplasms

AbstractBackground: Neurofibromatosis type 1 is an autosomal dominant disorder associated with multiple neoplasms particularly those of ectodermal origin. Various endocrine pathologies are often present, among them, hyperparathyroidism and follicular thyroid lesion are very rare described and their coincidence in the same patient has not been described in the literature reviewed.Subject: A 59-years-old woman with clinical manifestation of neurofibromatosis type 1 developed dysphagia, dysphonia, choking sensation. Physical and imagistic examination revealed a multinodular goiter with microfollicular lesion on fine needle aspiration biopsy (FNAB), elevated parathormone levels and severe osteoporosis. The surgically removed thyroid contained a nodule with follicular architecture of uncertain malignant potential; the parathyroid tissue appeared normal.Discussion and conclusion: This case serves as a reminder to look for non-neurogenic tumors in patients with neurofibromatosis. Clinicians must be aware of the diverse clinical features of this genetic disorder.

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The impact of host immune cells on the development of neurofibromatosis type 1: The abnormal immune system provides an immune microenvironment for tumorigenesis

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz037 ◽

2019 ◽

Vol 2 (Supplement_1) ◽

pp. i33-i39

Author(s):

Cheng-Jiang Wei ◽

Shu-Chen Gu ◽

Jie-Yi Ren ◽

Yi-Hui Gu ◽

Xiang-Wen Xu ◽

...

Keyword(s):

Immune System ◽

Immune Cells ◽

Neurofibromatosis Type 1 ◽

Immune Escape ◽

Genetic Disorder ◽

Neurofibromatosis Type ◽

Complex Interactions ◽

Nf1 Gene ◽

The Impact

Abstract AbstractThe immune system plays an essential role in the development of tumors, which has been demonstrated in multiple types of cancers. Consistent with this, immunotherapies with targets that disrupt these mechanisms and turn the immune system against developing cancers have been proven effective. In neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, the understanding of the complex interactions of the immune system is incomplete despite the discovery of the pivotal role of immune cells in the tumor microenvironment. Individuals with NF1 show a loss of the NF1 gene in nonneoplastic cells, including immune cells, and the aberrant immune system exhibits intriguing interactions with NF1. This review aims to provide an update on recent studies showing the bilateral influences of NF1 mutations on immune cells and how the abnormal immune system promotes the development of NF1 and NF1-related tumors. We then discuss the immune receptors major histocompatibility complex class I and II and the PD-L1 mechanism that shield NF1 from immunosurveillance and enable the immune escape of tumor tissues. Clarification of the latest understanding of the mechanisms underlying the effects of the abnormal immune system on promoting the development of NF1 will indicate potential future directions for further studies and new immunotherapies.

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Mosaic Neurofibromatosis Type 1 in Children: A Single-Institution Experience

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475417708163 ◽

2017 ◽

Vol 21 (5) ◽

pp. 379-382 ◽

Cited By ~ 2

Author(s):

Irene Lara-Corrales ◽

Mitra Moazzami ◽

Maria Teresa García-Romero ◽

Elena Pope ◽

Patricia Parkin ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Cross Sectional Study ◽

Clinical Findings ◽

Loss Of Function ◽

Cross Sectional ◽

Uncommon Presentation ◽

Sick Children

Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by loss-of-function mutation in the NF1 gene. Segmental or mosaic NF1 (MNF) is an uncommon presentation of the NF1 result of postzygotic mutations that present with subtle localised clinical findings. Objectives: Our study’s objectives were to describe the clinical characteristics of children with MNF. Methods: We conducted a cross-sectional study of children diagnosed with MNF at the Hospital for Sick Children in Toronto, Canada, from January 1992 to September 2012. Data were abstracted from health records and analysed using a standardised data collection form approved by our hospital Research Ethics Board. Results: We identified 60 patients with MNF; 32 of 60 (53.3%) were female. Mean ± SD age at first assessment was 10.6 ± 4.6 years. The most common initial physical manifestation in 39 of 60 (65.0%) patients was localised pigmentary changes only, followed by plexiform neurofibromas only in 10 of 60 (16.7%) and neurofibromas only in 9 of 60 (15.0%). Unilateral findings were seen in 46 of 60 (76.7%) patients. Most common associations identified included learning disabilities (7/60; 12%) and bony abnormalities (6/60; 10.0%). Conclusions: MNF is an underrecognised condition with potential implications for patients. Children mostly present with pigmentary anomalies only. Most patients do not develop associated findings or complications before adulthood, but long-term follow-up will help determine outcomes and possible associations. Recognition and confirmation of the diagnosis is important to provide follow-up and genetic counselling to patients.

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Oral Manifestations of Neurofibromatosis Type 1 in Children with Facial Plexiform Neurofibroma: Report of Three Cases

Journal of Clinical Pediatric Dentistry ◽

10.17796/jcpd.39.2.972220046g774534 ◽

2015 ◽

Vol 39 (2) ◽

pp. 168-171 ◽

Cited By ~ 6

Author(s):

KS Cunha ◽

RE Rozza-de-Menezes ◽

RM Andrade ◽

LMS Almeida ◽

MER Janini ◽

...

Keyword(s):

Trigeminal Nerve ◽

Neurofibromatosis Type 1 ◽

Soft Tissues ◽

Genetic Disorder ◽

Plexiform Neurofibroma ◽

Neurofibromatosis Type ◽

Oral Manifestations ◽

Plexiform Neurofibromas ◽

Organ Systems

Neurofibromatosis type 1 (NF1) is a common autosomal genetic disorder with a prevalence of 1 in 3,000 births. NF1 is a complex syndrome characterized by many abnormalities and may affect all organ systems. Oral manifestations of NF1 occur frequently, but reports including NF1 children with facial plexiform neurofibromas and oral alterations are scant. Facial plexiform neurofibroma may cause asymmetry, disfigurement and usually arises from the trigeminal nerve. The aim of this paper is to to report three pediatric NF1 cases with facial plexiform neurofibroma presenting with oral manifestations, which were evaluated clinically and radiographically, and also to briefly review the literature. Patients presented with changes in the oral soft tissues, jaws, and teeth ipsilateral to the tumor.

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The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: An Evolutive Approach

Genes ◽

10.3390/genes10110839 ◽

2019 ◽

Vol 10 (11) ◽

pp. 839

Author(s):

Larissa Brussa Reis ◽

Andreia Carina Turchetto-Zolet ◽

Maievi Fonini ◽

Patricia Ashton-Prolla ◽

Clévia Rosset

Keyword(s):

Positive Selection ◽

Neurofibromatosis Type 1 ◽

Mammalian Species ◽

Ring Finger ◽

Purifying Selection ◽

Neurofibromatosis Type ◽

Evolutionary Constraint ◽

Loss Of Function ◽

Cancer Predisposition Syndrome

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the NF1 gene. Large rearrangements are present in 5–10% of affected patients, generally encompass NF1 neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype–phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with NF1 microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes. Fourteen genes were analyzed in twelve mammalian species. Of these, four and ten genes showed positive selection and purifying selection, respectively. The protein, RNF135, showed three sites under positive selection at the RING finger domain, which may have been selected to increase efficiency in ubiquitination routes in primates. The phylogenetic analysis suggests distinct evolutionary constraint between the analyzed genes. With these analyses, we hope to help clarify the correlation of the co-deletion of these genes and the more severe phenotype of NF1.

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Neurofibromatosis Type 1 Complicated by Atypical Coarctation of the Thoracic Aorta

Case Reports in Pediatrics ◽

10.1155/2013/458543 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4

Author(s):

Masato Kimura ◽

Shuhei Kakizaki ◽

Kengo Kawano ◽

Shinichi Sato ◽

Shigeo Kure

Keyword(s):

Thoracic Aorta ◽

Neurofibromatosis Type 1 ◽

Aortic Coarctation ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Neurofibromatosis Type ◽

Lisch Nodules ◽

Atypical Coarctation ◽

Graft Interposition

Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic disorder with a prevalence of 1 in 3,000 (0.03%) at birth. Clinical features are café-au-lait macules, intertriginous freckling, dermal neurofibroma, iris hamartoma (Lisch nodules), and learning disability. NF1 vasculopathy is a serious but underrecognized complication involving the cerebrovascular and cardiovascular systems. The incidence of hypertension in patients with NF1 is around 1% and is associated mainly with renal artery stenosis in children. Only a few cases of thoracic aortic coarctation in association with hypertension and neurofibromatosis have been reported. Here we describe the case of a 4-year-old girl who presented with NF1 and hypertension due to atypical coarctation of the thoracic aorta. The diagnosis of coarctation of the thoracic aorta at the Th5-to-Th6 level was made following catheterization with a pressure gradient of 40 mmHg. The patient underwent surgery comprising resection of the coarctation of the thoracic aorta and graft interposition. On the basis of our findings, annual assessment of blood pressure is advised for patients with NF1.

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