Neurofibromatosis tipo 1. Más allá de las manchas café con leche: ¿es necesario actualizar criterios? / Neurofibromatosis type 1. Beyond to café-au-lait spots: necessary update criteria?

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome. Diagnosis is based on clinical findings that meets the criteria developed by the NIH in 1997, which remain highly sensitive and specific in adults, but not in children, in which the manifestations vary with age. In children under 2 years in the pretumoral stage with a negative family history, it would be useful to have additional clinical diagnostic criteria. Genetic testing is not widely available and although café-au-lait spots remain the cardinal and most frequent clinical sign, they cannot make the diagnosis of NF-1 on their own. (AU)

Analysis of genetic variant in a Chinese pedigree affected with neurofibromatosis type I / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with neurofibromatosis type I (NF1).@*METHODS@#Target capture high-throughput sequencing and Sanger sequencing were carried out to detect the pathological variant in a NF1 patient and his parents.@*RESULTS@#The proband and his similarly affected father have both harbored a novel nonsense variant of c.2511G>A (p.trp837x) in the NF1 gene. The same variant was not found in his mother and 200 healthy controls.@*CONCLUSION@#The heterozygous nonsense variant of c.2511G>A (p.trp837x) of the NF1 gene probably underlay the pathogenesis of NF1 in this pedigree.

Analysis of genetic variant in a case of sporadic neurofibromatosis type I with alopecia areata and vitiligo / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient with clinically suspected neurofibromatosis type I, alopecia areata and vitiligo.@*METHODS@#Variant of the NF1 gene was detected by chip capture and high-throughput sequencing. Candidate variant was verified by Sanger sequencing of the family trio.@*RESULTS@#The patient was found to harbor a novel missense c.1885G>A (p.Gly629Arg) variant of the NF1 gene, for which neither parent was carrier. The variant was not recorded in the public database. Based on the guidelines for genetic variation of the American College of Medical Genetics and Genomics, the c.1885G>A missense variant was predicted to be pathogenic (PS1+PS2+PM2+PP3+PP4).@*CONCLUSION@#The c.1885G>A missense variant probably underlay the disease in this child. Above finding has enriched the spectrum of the NF1 gene variants.

Analysis of NF1 gene variants among thirteen patients with neurofibromatosis type 1 / 中华医学遗传学杂志

OBJECTIVE@#To detect variants of NF1 gene among thirteen patients with neurofibromatosis type 1.@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the patients. High-throughput sequencing was employed to detect potential variants of the NF1 and NF2 genes.@*RESULTS@#Thirteen pathogenic variants were identified among the patients, which included one NF1 deletion, three missense variants, three nonsense variants and six frameshifting variants. Among these, 10 variants have been associated with neurofibromatosis type 1. c.4180A>T (p.Asn1394Tyr), c.4217dupT (p.Leu1406fs) and c.1753dupT(p.Leu585Phefs*3) were unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, c.4180A>T (p.Asn1394Tyr) was predicted to be likely pathogenic (PS2+PM1+PM2+PP2), while c.4217dupT (p.Leu1406fs) and c.1753dupT (p.Leu585Phefs*3) were predicted to be pathogenic (PVS1+PS2+PM2).@*CONCLUSION@#Variants of the NF1 gene probably underlay the disease among these children. Above findings have enriched the the spectrum of NF1 gene variants.

Multiple Gastrointestinal Stromal Tumor with Neurofibromatosis Type Ⅰ:Report of One Case / 中国医学科学院学报

Gastrointestinal stromal tumors(GISTs)in the stomach,duodenum,and rectum have low occurrence,and the coexistence GISTs in three parts with neurofibromatosis type Ⅰ(NF-Ⅰ)is even rare.This paper reports a case of GISTs with a family history of NF-Ⅰ.There were multiple nodular masses of different sizes on the patient's face,trunk,and limbs.The patient was admitted due to chest tightness for 5 days and black stools for 1 day.Enhanced CT examination of the abdomen suggested multiple space-occupying lesions in the upper abdomen with multiple small nodules under the abdominal wall,and neurofibromatosis and intestinal stromal tumor cannot be excluded.Finally,surgical pathology confirmed that the multiple tumors in the abdominal cavity were GISTs.The case was confirmed as wild-type GISTs by genetic testing,and the patient recovered well nearly one year after the operation.

Case report of neurofibromatosis type 1 combined with primary ciliary dyskinesia / 医学前沿

Neurofibromatosis (NF) is a genetic disease in which the lungs are rarely involved. However, in NF cases with lung involvement, chest computed tomography may show bilateral basal reticulations, apical bullae, and cysts without bronchiectasis. Herein, we report a patient diagnosed with NF on the basis of the results of genetic testing who presented with early-onset wet cough and bronchiectasis. Considering the differential diagnosis of bronchiectasis combined with his early-onset wet cough, sinusitis, and sperm quality decline, we considered the possibility of primary ciliary dyskinesia (PCD). Further electron microscopy analysis of cilia and identification of homozygous mutations in the RSPH4A gene confirmed the diagnosis of PCD. Therefore, for patients with NF, when an image change exists in the lungs that does not correspond to NF, the possibility of other diagnoses, including PCD, must be considered.

Neurofibromatosis tipo I. Presentación de un caso / Neurofibromatose tipo I. Apresentação de um caso / Neurofibromatosis type I. Case report

Se presentó un paciente masculino de 25 años de edad con tumoraciones subcutáneas en miembros, región dorsovertebral y dificultad en la marcha. Por este cuadro se ingresó en el Hospital General Docente Dr Agostinho Neto para estudio y tratamiento. Al realizar examen neurológico se constató presencia de marcha antiálgica, atrofia muscular supra e infraclavicular, espinosa, interósea, tenar e hipotenar bilateral, tumoraciones subcutáneas a nivel del cuello, extremidades y tronco, varias manchas color café con leche multiformes, así como disminución de fuerza muscular 4/5 próximo distal de extremidades. Los estudios radiológicos evidenciaron paquete tumoral en área paravertebral e inguinal, se realizó extracción y biopsia, informándose presencia de neurofibromas, diagnosticándose neurofibromatosis tipo I. Por ser una de las enfermedades hereditarias más frecuentes, pero menos estudiadas en nuestro medio se decidió la realización de este estudio(AU)

A 25-year-old male patient presented with subcutaneous tumors in the limbs, dorso-vertebral region and difficulty walking. For this picture, he was admitted to the General Teaching Hospital Dr Agostinho Neto for study and treatment. When the neurological examination was performed, there was presence of antalgic gait, supra and infraclavicular muscular atrophy, spinous, interosseous, tenar and bilateral hypothenar, subcutaneous tumors at the level of the neck, extremities and trunk, several coffee with milk spots, as well as a decrease of muscular strength 4/5 proximal distal of extremities. The radiological studies evidenced tumor bundle in the paravertebral and inguinal area, extraction and biopsy were performed, and neurofibromas were reported, diagnosing neurofibromatosis type I. Because it is one of the most frequent hereditary diseases, but less studied in our environment, it was decided to carry out this study(AU)

Paciente do sexo masculino, 25 anos, apresentava tumores subcutâneos nos membros, região dorso-vertebral e dificuldade para deambular. Para esta foto, ele foi internado no Hospital Geral de Ensino Dr Agostinho Neto para estudo e tratamento. Ao realizar presença exame neurológico da marcha antálgica, supra atrofia muscular e infraclaviculares, espinhosa, interósseo, tenar e hipotenar bilateral, tumores subcutâneos na região do pescoço, tronco e membros, vários pontos coloridos café com leite multiforme foi encontrado, bem como a diminuição de força muscular 4/5 proximal distal de extremidades. Estudos radiológicos mostraram tumores no pacote paravertebral e região da virilha, a remoção e a biópsia, informando a presença de neurofibromas, diagnosticándose neurofibromatosis tipo I. Tal comouma das doenças hereditárias mais comuns, mas pouco estudada no nosso hospital por este motivo decidiu-se realizar este estudo(AU)

Massive Plexiform Neurofibroma of the Neck and Larynx

Introduction Laryngeal neurofibromas are extremely rare, accounting for only 0.03 to 0.1% of benign tumors of the larynx. Objectives To report the first case of massive neck plexiform neurofibroma with intralaryngeal (supraglottic) extension in a 5-year-old boy with neurofibromatosis type 1 and to describe its treatment. Resumed Report This massive plexiform neurofibroma was surgically removed, relieving its significant respiratory obstructive symptoms without recurrence to date. Conclusion Massive neck plexiform neurofibroma with supraglottic part was found in a child with neurofibromatosis type 1; it should be included in differential diagnosis of stridor and neck mass in children. It was diagnosed and removed in early in childhood without recurrence.(AU)

Neurofibromatosis tipo 1 (NF1) y su diagnóstico molecular como estrategia del diagnóstico diferencial y a edades tempranas / Molecular diagnosis as a strategy for differential diagnosis and at early ages of neurofibromatosis type 1 (NF1)

Neurofibromatosis type 1 (NF1), is a haploinsufficient and multisystemic disease, caused by inherited or sporadic mutations in the NF1 gene. Its incidence is one in 2,500 to 3,000 individuals, it has an autosomal dominant pattern of inheritance, high clinical variability, complete penetrance and age-dependent complications. Neurofibromin is the product of the NF1 gene and is believed to act as a tumor suppressor since the loss of its function has been associated with benign and malignant tumors in neural crest-derived tissues. Only two correlations between clinical phenotype and mutant alleles in the NF1 gene have been observed. The established criteria for disease diagnosis are very efficient in adults and children older than 3 years of age, but not for children under this age. Mutational analysis is therefore recommended to confirm the disease in young children with a negative family history. A pathogenic mutation in the NF1 should be added to the list of diagnostic criteria. Mutational analysis is also recommended for differential diagnosis and for prenatal or pre-implantation genetic diagnosis, taking into consideration the family history and the type of method to be applied. Molecular studies of this disease using different complimentary molecular techniques and bioinformatics tools have characterized NF1 gene mutations at both the DNA and mRNA levels, increasing the mutational spectrum. Consequently, about 1,289 defects have been reported to date, mainly nonsense/missense mutations, deletions and splice site defects.

Neurofibromatosis tipo I: Mutación de splicing detectada por MLPA y secuenciación en la Argentina

La neurofibromatosis tipo 1 (NF1) es un desorden genético autosómico dominante, con una prevalencia de 1 en 2500-3000 nacidos vivos. La dificultad diagnóstica se debe al tamaño extenso del gen NF1 con pocos sitios hot-spot, la ausencia de una clara relación genotipo-fenotipo y rasgos clínicos con un espectro muy heterogéneo. Un caso sospechoso de NF1 procedente de la provincia de Jujuy fue analizado por MLPA (multiplex ligation-dependent probe amplification) en nuestro laboratorio. Mujer, adolescente mestiza (Amerindia/Europea), con un osteoma maxilar, lordosis lumbar, neurofibromas cutáneos y manchas café con leche. Por MLPA se detectó una alteración en el exón 13 del gen NF1. Por secuenciación del exón 13 se identificó una mutación "missense" en la posición 1466 del ARNm (NM_000267.3:c.1466A>G) que introduce un sitio de splicing aberrante. La patogenicidad de la mutación fue corroborada en la base de datos de variantes clínicas del National Center for Biotechnology Information. En nuestro conocimiento, este es el primer registro de una mutación NF1 en un paciente proveniente de poblaciones mestizas del Noroeste Argentino. La alteración ha sido reportada en individuos de otras poblaciones de origen muy disímil al del caso presentado, como la europea, sugiriendo que el sitio podría considerarse un sitio hot-spot del gen. Donde exista baja disponibilidad de diagnósticos moleculares, como en nuestro caso, se puede aplicar un algoritmo que comience por el estudio del gen NF1 por MLPA, metodología relativamente sencilla y de costo accesible. Con ella se evita enviar muestras al extranjero para análisis genéticos.

Neurofibromatosis type 1 (NF1) is a dominant autosomic genetic disorder, with a birth incidence of 1 in 2500-3000. Diagnosis is difficult because of the size of gene NF1 that has few hot-spots sites, the absence of a clear genotype-phenotype relation, and a heterogeneous clinical manifestation. A NF1 suspected case from Jujuy province was analyzed by multiplex ligation-dependent probe amplification (MLPA). Mestizo female teenage (Amerindian/European), with a maxilar osteoma, lumbar lordosis, cutaneous neurofibromas and café au lait spots. MLPA detected an alteration in exon 13 of the NF1 gene. By sequencing of exon 13, a missense mutation (NM_000267.3:c.1466A>G) was found which introduces an aberrant splicing site and is registered as pathogenic in the clinical variants database of NCBI. As far as we are aware, this is the first report of a NF1 mutation in mestizo population of Northwest Argentina. 1466A>G has been described before in patients of European origin, suggesting that the affected site could be a hot-spot site of the gene. For countries as Argentina, with limited availability of molecular diagnostic methods, we propose a diagnosis algorithm by starting the mutational analysis of NF1 with MLPA. This methodology is relatively simple and of low cost, avoiding to send samples abroad for genetic analyses.

Neurofibromatosis Type I Associated with Malaria: A Case Report and Review of Literature.

Neurofibromatosis (von Recklinghausen disease) is a genetic disorder which is now not been considered to be most common due to a gradual increase in its number of cases worldwide. Its prevalence found is around 1 in 4000-5000 individuals with the incidence been found equally in all regions and reported in almost all ethnic groups. Two-three million cases are reported all over world so far with this disorder. It is an autosomal dominant trait with varied age range of the cases reported from 6 years to late adulthood. Disease occurs by a genetic mutation in the neurofibromatosis Type 1 (NF1) gene (tumor suppressor gene) which is located on chromosome no. 17 at 17q11.2, responsible for coding of neurofibromin, a cytoplasmic protein. The effect of this mutation is elicited in almost all systems of the body with mild to severe complications. About half of the cases reported are present with new mutations in the NF1 genes. A patient afflicted with NF1 has around 50-60% of chances of transmitting the disease to each of his/her offspring. Presenting here a case of the female patient diagnosed malaria associated with NF1.

Abordaje clínico de variantes fenotípicas en neurofibromatosis de tipo 1 / Clinical approach of phenotype variants in neurofibromatosis type 1

La neurofibromatosis de tipo 1 es una enfermedad genética de herencia autosómica dominante, de afectación multisistémica y gran variabilidad fenotípica, causada por una mutación del gen NF1 localizada en el cromosoma 17 q11.2 que afecta la codificación de la neurofibromina. La prevalencia mundial se estima en 1 de cada 4.000 a 5.000 individuos. En Colombia se desconoce su prevalencia. Los criterios diagnósticos establecidos por los National Institutes of Health incrementaron la sensibilidad diagnóstica para pacientes con neurofibromatosis de tipo 1, quienes presentan manifestaciones clínicas cutáneas y extracutáneas, para las cuales se propone una clasificación en siete grupos, según el sistema u órgano afectado, y en tres tipos de variantes clínicas: tumores, alteraciones esqueléticas y alteraciones oftalmológicas. Se describe la disponibilidad de pruebas diagnósticas y asesoría genética.

Loss of Y Chromosome in the Malignant Peripheral Nerve Sheet Tumor of a Patient with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is one of the most commonly inherited autosomal dominant disorders. In order to determine whether genomic alterations and/or chromosomal aberrations involved in the malignant progression of NF1 were present in a Korean patient with NF1, molecular and cytogenetic analyses were performed on the pathologically normal, benign, and malignant tissues and primary cells cultured from those tissues of the patient. The comparative genomic hybridization (CGH) array revealed a Y chromosome loss in the malignant peripheral nerve sheet tumor (MPNST) tissue. G-banding analysis of 50 metaphase cells showed normal chromosomal patterns in the histopathologically normal and benign cultured cells, but a mosaic Y chromosome loss in the malignant cells. The final karyotype for the malignant cells from MPNST tissue was 45,X,-Y[28]/46,XY[22]. The data suggest that the somatic Y chromosome loss may be involved in the transformation of benign tumors to MPNSTs.

Rare association of Turner syndrome with neurofibromatosis type 1 and tuberous sclerosis complex.

We report a rare association of Turner syndrome with both Neurofibromatosis type I and Tuberous Sclerosis. The patient had XOkaryotype with Turners stigmata and also had features of Neurofibromatosis 1 in the form of significant café-au-lait spots and Plexiform neurofibroma along with typical features of Tuberous Sclerosis complex. Pedigree analysis revealed that the elder brother of the proband in the family also suffered from Tuberous Sclerosis without the manifestation of Neurofibromatosis or any other genetic disorders. We hypothesize that these associations could be due to new independent mutations and also increased maternal and paternal age in a pre-disposition of Turner syndrome.

Neurofibromina: qué hay de nuevo / Neurofibromin: what's new

La neurofibromina es una proteína citoplasmática codificada por el gen NF1, localizado en el cromosoma 17q11.2. Participa en la regulación de diversas vías de señalización molecular: MAPK, P13K, Caveolina y PKA. Cada vía cumple una función particular, con un objetivo final común, el control de genes involucrados en el crecimiento, apoptosis, diferenciación y migración celular. Realizamos una revisión sobre la neurofibromina, las vías de señalización en las que está implicada y su relación con las manifestaciones clínicas de la neurofibromatosis.

Neurofibromatose tipo 1 na infância: revisão dos aspectos clínicos / Neurofibromatosis type 1 in childhood: review of clinical aspects

OBJETIVO: Realizar uma revisão da literatura sobre neurofibromatose tipo 1 (NF1) em crianças e adolescentes, enfatizando as manifestações clínicas. FONTES DE DADOS: Artigos publicados, indexados na base de dados Medline e publicados entre 1998 a 2007, buscados pelos seguintes termos: "neurofibromatosis type 1", "neurofibroma", "von Recklinghausen" e "optic pathway gliomas". SÍNTESE DOS DADOS: A NF1 é uma doença genética autossômica dominante, crônica e progressiva, com incidência de 1/2.000 a 1/7.800 nascidos vivos. Tem sido observada em diferentes partes do mundo, em todas as raças e nos dois sexos. Metade dos casos representa mutações novas. A taxa de mutação para o gene NF1 é de 1/10.000, a qual se deve ao fato do gene ser grande e possuir estrutura interna atípica, que predispõe a deleções e mutações. O diagnóstico presuntivo da NF1 é feito por critérios clínicos. As três principais manifestações - neurofibromas, manchas café-com-leite e nódulos de Lisch - ocorrem em mais de 90 por cento dos pacientes até a puberdade. CONCLUSÕES: Os cuidados com os pacientes com NF1 devem antecipar as principais complicações e oferecer um tratamento precoce. No aconselhamento genético, é importante informar pais e familiares a respeito do panorama geral da doença e suas possíveis complicações, enfatizando que a maioria dos pacientes apresenta vida saudável e produtiva.

OBJECTIVE: To review clinical and diagnostic features of neurofibromatosis type 1 (NF1) in children and adolescents. DATA SOURCES: Articles published from 1998 to 2007 and retrieved by the words "neurofibromatosis type 1"; "neurofibroma", "von Recklinghausen" and "optic pathway gliomas" in Medline database. DATA SYNTHESIS: NF1 is a chronic and progressive autosomal dominant disorder with an incidence of 1/2,000 to 1/7,800 live births. There is no racial, geographic or gender preference. Half of the cases represent new mutations, and the mutation rate for NF1 gene is 1/10.000. The high mutation rate of NF1 may reflect the fact that the gene is large and/or that it has an unusual internal structure, predisposing it to deletions and other mutations. The presuntive diagnosis of NF1 is made on clinical basis. The three main features - neurofibromas, café-au-lait spots and Lisch nodules - are present in more than 90 percent of all affected patients until puberty. CONCLUSIONS: The mainstay of care for patients with NF1 is anticipatory guidance and early detection and treatment of disease complications. Counseling of patients and their families should provide a realistic overview of possible clinical complications, while emphasizing that most individuals with NF1 have healthy and productive lives.

Manifestação clínica familiar em pacientes com defeito neuromesoectodérmico / Familial clinical manifestation in patients with neuromesoectodermic defect

Relatamos a associação de dois casos distintos de neuromesoectodermose ocorridos em uma mesma família, um manifestado através da neurofibromatose tipo 1 e outro através da esclerose tuberosa. O encontro de dois distúrbios entre primos de primeiro grau, ocasionados por diferentes mutações genéticas e transmitidos por herança autossômica dominante, sugere uma possível correlação entre eles. Também são descritas as manifestações clínicas, suas conseqüências e os critérios diagnósticos das duas doenças, visando ressaltar a importância do diagnóstico precoce.

We relate the association of two distinct cases of neuromesoectodermosis occurred in a family, one manifested as neurofibromatosis type 1 and the other as tuberous sclerosis. The two anomalies at cousins, caused by different genetic mutations and transmitted by autosomal dominant inheritance, suggest a possible relation between them. Also, clinical manifestations are described, their consequences and the diagnostic criteria of both illnesses, emphatizing the importance of the precocious diagnosis.

Neurofibromatosis: reporte de un caso / Neurofribromatosis: report of one case

Informamos del caso de un paciente de 8 años de edad, con historia de masas en tórax anterior y posterior de dos años de evolución. Se presentó a la Consulta Externa de Pediatria del Hospital ôDr. Leonardo Martinez Valenzuelaõ, donde se diagnosticó Neurofibromatosis Tipo 1. Se programó para resección de masa torácica y biopsia, ésta última confirmó el diagnóstico clínico. Se remitió a Oftalmología y Otorrinolaringología para evaluación, la cual fue normal. Se remite al Hospital Nacional ôDr. Mario Catarino Rivasõ para realización de tomografia axial computarizada cerebral...

The Spectrum of NF1 Mutations in Korean Patients with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations in the NF1 gene which consists of 57 exons and encodes a GTPase activating protein (GAP), neurofibromin. To date, more than 640 different NF1 mutations have been identified and registered in the Human Gene Mutation Database (HGMD). In order to assess the NF1 mutational spectrum in Korean NF1 patients, we screened 23 unrelated Korean NF1 patients for mutations in the coding region and splice sites of the NF1 gene. We have identified 21 distinct NF1 mutations in 22 patients. The mutations included 10 single base substitutions (3 missense and 7 nonsense), 10 splice site mutations, and 1 single base deletion. Eight mutations have been previously identified and thirteen mutations were novel. The mutations are evenly distributed across exon 3 through intron 47 of the NF1 gene and no mutational hot spots were found. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. A genotype- phenotype correlation analysis suggests that there is no clear relationship between specific NF1 mutations and clinical features of the disease.