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1.
Pan Afr Med J ; 33: 80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448042

RESUMO

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by formation of central nervous system tumors. They are associated to significant morbidity due to multiple problems such as hearing loss that can lead to many psychiatric disorders.


Assuntos
Transtornos Mentais/diagnóstico , Neurofibromatose 2/diagnóstico , Neuroma Acústico/diagnóstico , Perda Auditiva/etiologia , Humanos , Masculino , Transtornos Mentais/etiologia , Neurofibromatose 2/complicações , Neuroma Acústico/etiologia , Adulto Jovem
2.
Neurology ; 93(10): e964-e967, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31363058

RESUMO

OBJECTIVE: To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children. METHODS: A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed. RESULTS: The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%). CONCLUSIONS: Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.


Assuntos
Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromina 2/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
3.
Graefes Arch Clin Exp Ophthalmol ; 257(7): 1453-1458, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31089872

RESUMO

PURPOSE: To evaluate ophthalmological and molecular findings in eight patients with a clinical diagnosis of neurofibromatosis type 2 (NF2). New pathological mutations are described and variability in the ophthalmic phenotype and NF2 allelic heterogeneity are discussed. METHODS: Eye examination was performed in eight NF2 patients, and it included the measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography, and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual. RESULTS: Ophthalmological features were present in all patients, ranging from subtle retinal alterations identified only using SD-OCT to severe ocular damage present at birth. Six mutations were observed: two patients with stop codon mutation as shown on table 1 and result section, three patients with frameshift mutation as shown on table 1 and result section. Three novel mutations were found among them. CONCLUSIONS: It is a descriptive study of a rare disease, with poor previous literature. Clinical and genetic data are shown, reviving the need to further studies to clarify the genotype-phenotype correlations in NF2.


Assuntos
DNA/genética , Oftalmopatias/etiologia , Genes da Neurofibromatose 2/fisiologia , Mutação , Neurofibromatose 2/diagnóstico , Retina/patologia , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Análise Mutacional de DNA , Oftalmopatias/diagnóstico , Oftalmopatias/metabolismo , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/complicações , Neurofibromatose 2/genética , Fenótipo , Retina/metabolismo , Acuidade Visual , Adulto Jovem
4.
Brain Nerve ; 71(4): 368-372, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-30988223

RESUMO

A large number of genetic neurological disorders are accompanied by dermatological manifestations. Among them, neurofibromatosis 1 (NF1, Recklinghausen disease) is characterized by pigmented macules, such as café au lait macules, freckling and numerous neurofibromas. Neurological complications are also seen in NF1 and it is important to conduct appropriate imaging studies for a correct diagnosis. In this report, I will discuss the differential diagnosis of dermatological manifestations of NF1 compared to those of other neurological disorders, such as Legius syndrome or NF2.


Assuntos
Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Manchas Café com Leite/patologia , Diagnóstico Diferencial , Humanos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/patologia
5.
Medicine (Baltimore) ; 98(5): e14308, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30702605

RESUMO

RATIONALE: Brain magnetic resonance imaging (MRI) images of atypical teratoid rhabdoid tumor (ATRT) often present heterogeneous signals of various cells without remarkable features of the disease. We describe a unique case of atypical brain MRI images presenting as an type II neurofibromatosis and explore some diagnostic hints. PATIENT CONCERNS: A 1-year-and-7-month-old boy admitted to our department with a 7-day history of drowsiness and 2-day history of emesis, and his presenting complaint was repeated vomit. On physical examination, he had drowsiness, positive sun set sign, slow light reflection, high muscular tension of limbs and 55 cm head circumference. MRI presented masses of bilateral auditory nerve distribution area, the fourth ventricle and right frontal lobe, obstructive hydrocephalus, and amplified cisterna magna. Particularly, dumbbell shape tumor in left cerebellopontine angle area and the fourth ventricle showed iso- or hypo-intensity on T1-weighted image and mix-intensity on T2-weighted image with irregular frontier, obvious mutual high and low signal on T2-weighted image, and growing along cerebrospinal fluid pathway. DIAGNOSIS: The diagnosis of type II neurofibromatosis (NF-II) was considered pre-operatively. After surgery, postoperative histopathology confirmed the diagnosis of ATRT. INTERVENTIONS: After ventriculo-peritoneal (VP) shunt, no evidence of tumor was inspected in cerebrospinal fluid, and enhancement MRI showed heterogeneous contrast signal on dumbbell shape tumor. We executed an incomplete microsurgery for dumbbell shape lesion in left auditory nerve distribution area and the fourth ventricle for differential diagnosis and facilitating further treatment. OUTCOMES: The patient did not recover well postoperatively and suffered from severe pulmonary infection. Refusing further intervention in view of poor prognosis of ATRT, the patient was transferred to another hospital for rehabilitation care. The patient died from progressive tumor and respiratory failure after 2 months. LESSONS: The diagnosis of ATRT can be challenging, in our case due to the disturbance of bilateral auditory nerve distribution area tumors. Under MRI, Irregular frontier, obvious mutual high and low signal on T2-weighted image, growing along cerebrospinal fluid pathway, and heterogeneous contrast enhancement should lead the clinician to strongly consider ATRT.


Assuntos
Neurofibromatose 2/diagnóstico , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/cirurgia , Teratoma/diagnóstico , Teratoma/cirurgia , Diagnóstico Diferencial , Humanos , Lactente , Masculino
6.
Genet Med ; 21(7): 1525-1533, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30523344

RESUMO

PURPOSE: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). METHODS: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. RESULTS: There was no evidence for usefulness of old criteria "glioma" or "neurofibroma." "Ependymoma" had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. CONCLUSIONS: The present study confirms important deficiencies in NF2 diagnostic criteria. The term "glioma" should be dropped and replaced by "ependymoma." Similarly "neurofibroma" should be removed. Dropping "sibling" from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.


Assuntos
Bases de Dados Factuais , Neurofibromatose 2/diagnóstico , Adolescente , Adulto , Criança , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Neurofibromatose 2/fisiopatologia , Terminologia como Assunto , Adulto Jovem
7.
Turk J Pediatr ; 60(1): 107-110, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30102490

RESUMO

Halefoglu AM. Multiple cranial nerve schwannomas and meningiomas as a hallmark sign of neurofibromatosis type 2 in a child. Turk J Pediatr 2018; 60: 107-110. Neurofibromatosis type 2 is a rarely encountered autosomal dominant disorder manifesting with typical radiological findings. These patients have a predilection for development of benign tumors in the central nervous system. Although the presenting symptom is most commonly hearing loss due to acoustic schwannomas, symptoms emanating from other cranial tumors are not uncommon. Herein, we described a 16-year-old male patient presented with multiple meningiomas and cranial nerve schwannomas revealed by magnetic resonance imaging. He fulfilled the diagnostic criteria of neurofibromatosis type 2 and underwent treatment. We emphasized the role of radiology in the early diagnosis of this inherited disorder in order to provide a better prognosis.


Assuntos
Neoplasias dos Nervos Cranianos/etiologia , Imagem por Ressonância Magnética , Neoplasias Meníngeas/etiologia , Meningioma/etiologia , Neurilemoma/etiologia , Neurofibromatose 2/diagnóstico , Adolescente , Neoplasias dos Nervos Cranianos/diagnóstico por imagem , Perda Auditiva Neurossensorial/etiologia , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Neurilemoma/diagnóstico por imagem , Neurofibromatose 2/complicações , Radiografia
8.
Childs Nerv Syst ; 34(9): 1745-1752, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29948132

RESUMO

INTRODUCTION: Auditory brainstem implant (ABI), a standard technique in treatment of profound sensorineural hearing loss in patients with neurofibromatosis 2, is now being increasingly employed in children with congenital bilateral sensorineural hearing loss, as in Michele's deformity. A detailed knowledge of the relevant surgical anatomy of the lateral recess and its anatomical landmarks including the flocculus, the choroid plexus and the root entry zones of facial-vestibulocochlear and glossopharyngeal-vagus nerve complexes and their anatomical variants is mandatory, as it is the conduit for electrode array placement. The placement of electrode may be eased or impeded by these variations. MATERIALS AND METHODS: Thirty-two children with congenital bilateral hearing loss underwent surgery through retromastoid suboccipital approach for placement of auditory brainstem implant. The preoperative anatomy was reviewed in detail during procedure and again later in the operative videos. RESULTS: The flocculus was classified into four grades based on its anatomy and relations. Among these, grade II (11 children) was the commonest while grade IV (five children) was least common. Choroid plexus was variable in size across grades of flocculus. Difficulty in defining the anatomy was significantly more (p value = 0.003) in the group with higher grade flocculus (grade III and IV) than in lower grade flocculus (grade I and II). CONCLUSION: The flocculus in these patients is classifiable into one of the four grades and the surgical nuances such as difficulty in defining the anatomy for placement of ABI are dependent on the characteristics exhibited by the floccular anatomy and relations.


Assuntos
Implantes Auditivos de Tronco Encefálico , Tronco Encefálico/anatomia & histologia , Tronco Encefálico/cirurgia , Perda Auditiva/cirurgia , Neurofibromatose 2/cirurgia , Criança , Pré-Escolar , Plexo Corióideo/anatomia & histologia , Plexo Corióideo/cirurgia , Feminino , Perda Auditiva/diagnóstico , Humanos , Lactente , Masculino , Gradação de Tumores/métodos , Neurofibromatose 2/diagnóstico
9.
Am J Med Genet A ; 176(5): 1258-1269, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29681099

RESUMO

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.


Assuntos
Neurilemoma/diagnóstico , Neurilemoma/etiologia , Neurofibromatoses/diagnóstico , Neurofibromatoses/etiologia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/etiologia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/etiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Animais , Gerenciamento Clínico , Modelos Animais de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Técnicas de Diagnóstico Molecular , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , Neurofibromatose 2/terapia , Neoplasias Cutâneas/terapia , Pesquisa Médica Translacional
10.
Arch Dis Child ; 103(5): 463-469, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29535107

RESUMO

OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.


Assuntos
Neurofibromatose 2/diagnóstico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diagnóstico Tardio , Inglaterra/epidemiologia , Oftalmopatias/epidemiologia , Oftalmopatias/etiologia , Feminino , Genes da Neurofibromatose 2 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Neurofibromatose 2/complicações , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Vigilância da População , Dermatopatias/epidemiologia , Dermatopatias/etiologia
11.
Klin Monbl Augenheilkd ; 235(3): 290-300, 2018 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-29534265

RESUMO

BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic condition with an autosomal dominant pattern of inheritance and incomplete penetrance. It is characterized by multiple benign tumors of the central and peripheral nervous system including astrocytomas, ependymomas, meningeomas, and schwannomas, among which bilateral vestibular schwannomas are the most frequent. Among ocular manifestations of NF2, juvenile subcapsular cataract is the most common followed by epiretinal membranes and combined hamartomas of the retina and retinal pigment epithelium. MATERIALS AND METHODS: Multimodal imaging was performed in a female patient and her data were compared to an overview of published cases with retinal hamartoma in NF2. RESULTS: We report on a case of a 14-year-old girl with genetically confirmed NF2 who presented with bilateral, asymptomatic hyperplasia of glia cells within the ganglion cell and the nerve fibre layer by spectral domain optical coherence tomography (SD-OCT). A metaanalysis of 25 published cases revealed combined hamartomas of the retina and retinal pigment epithelium (CHRRPE) as the most common (16 cases) retinal tumors followed by retinal astrocytic hamartomas (RAH, 7 cases). Retinal hamartomas were most often reported bilaterally and observed prior to the clinical diagnosis of NF2 in 11 of 25 cases. No correlation to sex was observed. Reduced visual acuity, cataracts and epiretinal membranes were the leading ocular manifestations. CONCLUSION: There is a large spectrum of ocular-specific findings in NF2. These are seminal, especially at an early age, enabling an early diagnosis and timely therapy of further tumor manifestations. Retinal astrocytic hamartomas may be very discreet and easily missed on routine examination. Fundus infrared imaging is a useful tool allowing to detect even discreet changes rarely seen by ophthalmoscopy in young children. This allows for a more extensive evaluation by SD-OCT.


Assuntos
Astrócitos , Hamartoma/diagnóstico , Neurofibromatose 2/diagnóstico , Doenças Retinianas/diagnóstico , Adolescente , Angiografia , Análise Mutacional de DNA , Diagnóstico Diferencial , Técnicas de Diagnóstico Oftalmológico , Feminino , Angiofluoresceinografia , Fundo de Olho , Hamartoma/genética , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Meningioma/diagnóstico , Meningioma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Doenças Retinianas/genética , Tomografia de Coerência Óptica
12.
Neuro Oncol ; 20(7): 917-929, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29409008

RESUMO

Background: Clinical overlap between neurofibromatosis type 2 (NF2), schwannomatosis, and meningiomatosis can make clinical diagnosis difficult. Hence, molecular investigation of germline and tumor tissues may improve the diagnosis. Methods: We present the targeted next-generation sequencing (NGS) of NF2, SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon-based approach. We analyzed blood DNA from a cohort of 196 patients, including patients with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27 NF2-negative meningiomatosis patients were also evaluated. Results: A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1 variants were identified in 5/40 (12.5%) and 13/40 (∼32%) patients in the schwannomatosis cohort. Potentially pathogenic variants were found in 12/65 (18.5%) patients with no clearly established diagnosis. A LZTR1 variant was identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A SMARCE1 variant was found in 3/39 (∼8%) meningiomatosis patients. No SUFU variant was found in the cohort. NGS was an effective and sensitive method to detect mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we identified a 4-hit mechanism resulting in the complete NF2 loss-of-function combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from NF2 patients. Conclusions: Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a key element in the differential diagnosis of NF2, schwannomatosis, and meningiomatosis. The targeted NGS strategy is suitable for the identification of NF2 mosaicism in blood and for the investigation of tumors from these patients.


Assuntos
Genes Supressores de Tumor , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Mutação , Neurilemoma/diagnóstico , Neurofibromatoses/diagnóstico , Neurofibromatose 2/diagnóstico , Neoplasias Cutâneas/diagnóstico , Biomarcadores Tumorais , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Seguimentos , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Prognóstico , Estudos Prospectivos , Proteínas Repressoras/genética , Estudos Retrospectivos , Proteína SMARCB1/genética , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética
13.
JAMA Dermatol ; 154(3): 341-346, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29322178

RESUMO

Importance: Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing. Objective: To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2. Design, Setting, and Participants: Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NF2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses. Main Outcomes and Measures: Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed. Results: In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype. Conclusions and Relevance: This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.


Assuntos
Genes da Neurofibromatose 2 , Neurilemoma/genética , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Masculino , Mutação , Neurilemoma/patologia , Células de Schwann , Neoplasias Cutâneas/patologia
14.
Expert Rev Neurother ; 18(1): 29-39, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29088993

RESUMO

INTRODUCTION: Vestibular schwannomas (VS) account for approximately 85% of tumors in the cerebello-pontine angle, with a lifetime incidence of approximately 1 in 1000. Most are sporadic, with approximately 5% related to the tumor predisposition syndrome Neurofibromatosis Type 2 (NF2). The mainstays of management strategies are: observation, surgery, radiosurgery/radiotherapy and, for patients with NF2 and rapidly growing tumors or deteriorating neurologic function the targeted therapy bevacizumab. While morbidity and mortality rates related to treatment of VS have improved dramatically over the last decades, there are still significant improvements that could be made, in particular with regards to long-term facial nerve and hearing outcomes. Areas covered: The epidemiology and diagnosis of VS are discussed, followed by the different management strategies and outcomes of those for both sporadic and NF2 related tumors. An extensive literature review has been performed to inform this review article using PubMed and Google Scholar. Expert commentary: The future direction of VS management lies in obtaining longer-term follow-up data for patients with treated VS, and in improved understanding of cellular pathways and targeted therapies.


Assuntos
Neurilemoma/diagnóstico , Neurilemoma/terapia , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/terapia , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Transtornos da Audição , Humanos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Complicações Pós-Operatórias , Radiocirurgia , Radioterapia , Resultado do Tratamento
15.
Neurochirurgie ; 64(5): 364-369, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26071178

RESUMO

INTRODUCTION: Neurofibromatosis type 2 is characterized by the presence of bilateral vestibular schwannomas. However, other nervous system tumors may also occur. Therefore, the management of NF2 patients is complex and requires a multidisciplinary discussion in a specialized center. MATERIALS AND METHODS: All recent articles concerning tumors other than vestibular schwannoma in NF2 disease were reviewed, using PubMed databases. RESULTS: Intracranial meningiomas occur in 50% of NF2 patients, and are often multiple. Surgery remains the main treatment and should be performed in cases of growing tumors. The role of antiangiogenic therapy is currently under evaluation and the role of radiosurgery still remains to be defined in NF2 disease. Spinal tumors occur in about half of NF2 patients. Surgery should be discussed when radiological tumor progression is demonstrated, even if spinal tumors are asymptomatic, in order to preserve neurological function and good quality of life. As regards lower cranial nerve schwannomas, radiosurgery appears to be a more appropriate treatment for growing tumor with a small volume in order to avoid post-operative complications, especially swallowing disorders. Facial nerve schwannomas may appear, on MRI, like vestibular schwannomas. The diagnosis should be suspected when the facial palsy is an early symptom during cerebello-pontine tumor progression. Trigeminal schwannomas are frequent in NF2 disease and fortunately they are often asymptomatic. Among major neurofibromatosis types, peripheral nerve sheath schwannomas are only present in patients with NF2 disease and schwannomatosis. Surgical resection is required when the cutaneous schwannomas is painful or when tumor progression is observed and causes symptoms. CONCLUSION: Tumors other than vestibular schwannoma are also associated with a poor prognosis in NF2 patients. Surgery remains the main treatment in most cases. Each treatment decision in NF2 disease requires a complete evaluation of all cranial and spinal locations of the disease in order to establish surgical priorities and strategies.


Assuntos
Neurofibromatoses/cirurgia , Neurofibromatose 2/patologia , Neurofibromatose 2/cirurgia , Neoplasias da Coluna Vertebral/cirurgia , Progressão da Doença , Humanos , Imagem por Ressonância Magnética/métodos , Meningioma/diagnóstico , Meningioma/cirurgia , Neurilemoma/diagnóstico , Neurilemoma/cirurgia , Neurofibromatoses/diagnóstico , Neurofibromatose 2/diagnóstico , Complicações Pós-Operatórias/cirurgia , Radiocirurgia/métodos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento
16.
Neurochirurgie ; 64(5): 335-341, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26073919

RESUMO

OBJECTIVE: Neurofibromatosis type 2 (NF2) affects about one in 25,000 to 40,000 people. Most NF2 patients have private loss-of-function mutations scattered along the NF2 gene. Here, we present our NF2 investigation strategy. MATERIAL AND METHODS: We report a comprehensive NF2 mutation analysis of 221 NF2 French patients: 134 unrelated typical NF2 patients fulfilling the Manchester criteria and 87 unrelated patients presenting symptoms that partially fulfilled the Manchester criteria. RESULTS: A NF2 mutation was identified in 56 of the 221 patients, giving a global mutation detection rate of 25%. This rate reached 37% (49/134) for typical NF2 patients fulfilling the Manchester criteria and only 8% (7/87) for patients presenting symptoms suggestive of NF2. Six of these seven patients were under 25 of age. Our approach showed that 77% of NF2 identified variants were detected by coding exons sequencing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements (23% of NF2 identified variants corresponding to complete deletion or partial deletion/duplication of NF2). CONCLUSION: High mutation detection rate can be achieved if well phenotyped NF2 patients are studied with multiple complementary and optimized techniques. NF2 somatic mosaicism detection was improved by frozen tumor samples molecular analysis.


Assuntos
Genes da Neurofibromatose 2/fisiologia , Mutação/genética , Neoplasias/diagnóstico , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Adulto , Estudos de Coortes , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Neoplasias/genética , Neoplasias/metabolismo , Neurofibromatose 2/diagnóstico , Patologia Molecular
19.
J Med Genet ; 54(10): 657-664, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28848060

RESUMO

​BACKGROUND: The clinical severity of disease in neurofibromatosis type 2 (NF2) is variable. Patients affected with a constitutional truncating NF2 mutation have severe disease, while missense mutations or mosaic mutations present with a milder attenuated phenotype. Genotype-derived natural history data are important to inform discussions on prognosis and management. METHODS: We have assessed NF2 clinical phenotype in 142 patients in relation to the UK NF2 Genetic Severity Score to validate its use as a clinical and research tool. RESULTS: The Genetic Severity Score showed significant correlations across 10 measures, including mean age at diagnosis, proportion of patients with bilateral vestibular schwannomas, presence of intracranial meningioma, spinal meningioma and spinal schwannoma, NF2 eye features, hearing grade, age at first radiotherapy, age at first surgery and age starting bevacizumab. In addition there was moderate but significant correlation with age at loss of useful hearing, and weak but significant correlations for mean age at death, quality of life, last optimum Speech Discrimination Score and total number of major interventions. Patients with severe disease presented at a younger age had a higher disease burden and greater requirement of intervention than patients with mild and moderate disease. CONCLUSIONS: This study validates the UK NF2 Genetic Severity Score to stratify patients with NF2 for both clinical use and natural history studies.


Assuntos
Neurofibromatose 2/genética , Neurofibromatose 2/fisiopatologia , Fatores Etários , Feminino , Genes da Neurofibromatose 2 , Perda Auditiva , Humanos , Masculino , Mutação , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Fenótipo , Qualidade de Vida , Índice de Gravidade de Doença
20.
J Assoc Physicians India ; 65(8): 109-110, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28799319

RESUMO

Neurofibromatosis type 2 (NF2) is a genetically inherited disorder characterized by the presence of multiple central nervous system tumours, most pathognomonic being bilateral vestibular schwannomas with or without peripheral manifestations in the form of cataract or cutaneous neurofibromas. NF2 is an uncommon disorder compared to NF1. We describe a classical case of neurofibromatosis type 2 with florid clinical manifestations and characteristic neuroimaging features. We also briefly describe the literature pertaining to this rare disorder. The case also emphasizes the fact that NF2 should be considered in the list of differentials for ataxia especially when it is associated with sensory neural hearing loss.


Assuntos
Ataxia/etiologia , Neurofibromatose 2/diagnóstico , Adulto , Neoplasias dos Nervos Cranianos/patologia , Feminino , Perda Auditiva Neurossensorial/etiologia , Humanos , Neurilemoma/patologia , Doenças do Nervo Vestibulococlear/patologia
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