Paula y Bobby
Padres de Lillie
Neurofibromatosis, Type I (NF1)
¿Que es Neurofibromatosis, Type I (NF1)?
La neurofibromatosis, tipo 1 es una condición genética que afecta a hombres y mujeres por igual.
Síntomas puede variar ampliamente entre individuos diagnosticados con el síndrome.
El síndrome se caracteriza por anomalías cutáneas y de pigmentación y tumores fibromatosos de la piel.
CORD4 Neurofibromatosis, tipo periférico NF1; Neurofibromatosis periférica Enfermedad de Von Recklinghausen
¿Qué causan los cambios genéticos Neurofibromatosis, Type I (NF1)?
Un gen NF1 dañado es responsable de causar el síndrome. En el 50% de los casos, el gen defectuoso se hereda de uno de los padres con un patrón autosómico dominante. En el otro 50% de los casos, la mutación es nueva.
En el caso de la herencia autosómica dominante, solo uno de los padres es el portador de la mutación genética y tiene un 50% de posibilidades de transmitirla a cada uno de sus hijos. Los síndromes heredados en una herencia autosómica dominante son causados por una sola copia de la mutación genética.
En algunos casos, un síndrome genético puede ser el resultado de una mutación de novo y el primer caso en una familia. En este caso, se trata de una nueva mutación genética que se produce durante el proceso reproductivo.
¿Cuales son los principales síntomas de Neurofibromatosis, Type I (NF1)?
Los cambios en el color de la piel, específicamente su pigmentación, son los principales síntoma de th síndrome.
Esto incluye café con leche o manchas de color café en la piel que son características de la afección.
El síndrome también provoca el crecimiento de tumores no cancerosos a lo largo de los nervios de la piel, el cerebro y otras partes del cuerpo. Estos tumores pueden desencadenar otras afecciones médicas o de salud.
Las dificultades de aprendizaje son otra reconocida síntoma de la condición.
General síntomas puede variar ampliamente entre individuos en su presentación y gravedad.
Posibles rasgos / características clínicas:
Nódulos de Lisch, Neurofibrosarcoma, Discapacidad intelectual, leve, Meningioma, Discapacidad específica del aprendizaje, Astrocitoma, Estenosis acueductal, Pecas axilares, Mancha café con leche, Glaucoma, Genu valgum, Estatura baja, Hipertensión, Hipertelorismo, Hipsarritmia, Hidrocefalia, Inguinal Neurofibromas espinales, pseudoartrosis tibial, estenosis de la arteria renal, espina bífida, escoliosis, rabdomiosarcoma, adenoma paratiroideo, crecimiento excesivo, glioma del nervio óptico, convulsiones, neurofibroma plexiforme, feocromocitoma, herencia autosómica dominante
¿Cómo se hace la prueba a alguien? Neurofibromatosis, Type I (NF1)?
La prueba inicial para el síndrome de neurofibromatosis tipo 1 puede comenzar con la detección del análisis facial, a través de la plataforma de telegenética FDNA Telehealth, que puede identificar los marcadores clave del síndrome y describir la necesidad de más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista.
Con base en esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.
Información médica sobre neurofibromatosis, tipo I
This common autosomal dominant condition occurs in about one in 3000 individuals. The manifestations are protean and well known. The most common presenting features are cafe au lait patches (more than six greater than 1.5 cms in diameter) and peripheral neurofibromata. Fois et al., (1993) investigated the diagnostic significance of cafe au lait spots. Of children ascertained with typical cafe au lait spots of significant number, 57% went on to develop definite NF1 and in the remainder of the patients the diagnosis was highly likely. Goldberg et al., (1996) provide an extensive review of the clinical features. Cnossen et al., (1998) studied the value of minor disease features in making the diagnosis in children under six years. They provided evidence suggesting that macrocephaly, short stature, hypertelorism, and thorax abnormalities (pectus excavatum and pectus carinatum) were significantly more common in children with NF1 in this age group. Growth charts are available for NF1 children (Clementi et al., 1999; Riccardi 2000; Szudek et al., 2000). Lin et al., (2000) reported that cardiac malformations are more common in patients with the NF1 syndrome with a prevalence of about 2.3%. Sudden death might occur due to a coronary artery vasculopathy (Kanter et al., 2006). High-grade CNS tumors occur occasionally (Rosenfeld et al. 2010).
Complications can include plexiform neurofibroma of the eyelid, macrocephaly, short stature, scoliosis, pseudarthrosis of the tibia (Stevenson et al., 1999), hypertension due to renal artery stenosis (Friedman et al., 2002), phaeochromocytoma, neurofibrosarcomas, meningiomas, and acoustic neuromas. The latter may be confined to the so-called central form of the disease (type 2 - see separate entry). Plexiform neurofibromas occur in about 28% of cases but cause severe cosmetic problems in about 1% of cases. They are usually present in the first year of life but can progress to marked overgrowth. Dugoff and Sujansky (1996) found that during pregnancy 50-60% of women reported growth of new neurofibromas or enlargement of existing neurofibromas. De Smet et al., (2002) reported two cases with glomus tumours of the fingers as did Stewart et al., (2010). Listernick et al., (1994) found optic pathway tumours in 20% of affected children, however in only 10% of these was there evidence of tumour growth or deteriorating vision. In contrast, the report by Thiagalingam et al., (2004) showed that progression occurred in about 50% and that severe visual impairment occurred in 31%. Spontaneous regression of optic gliomas occurred in three cases reported by Piccirilli et al., (2006). Singhal et al., (2002) suggest that the life time risk for optic nerve gliomas is 5-10%. Optic nerve gliomas may be associated with glaucoma. Sigorini et al., (2000) suggested that the visual field evaluation is the most sensitive clinical test to evaluate the presence of optic pathway pathology where there is MRI evidence of an optic nerve glioma. However, Listernick et al., (2001) did not agree with the suggestions of Sigorini et al., (2000). King et al., (2003) do not advocate ""baseline"" MRI in children with NF1, but strongly recommend that all children of the age 10 years and younger with NF1 have complete annual ophthalmologic evaluations. Subtle ocular signs of the disorder include Lisch nodules of the iris. Curless et al., (1998) suggest that there are characteristic MRI findings (high signal changes on T2-weighted images, sometimes also seen in T1-weighted images). These authors suggest that these findings may be enough to establish a diagnosis of NF1 in a patient with optic nerve glioma in the absence of cafe au lait spots. Zeid et al., (2007) question the intervention aimed at treating optic nerve gliomas unless there is clear evidence clinically or radiologically of progression.
Griffiths et al., (1999) investigated such Neurofibromatosis Bright Objects (NBOs) in 46 children with NF1 and found them in 93%. They were most prevalent between the ages of four and 10 years. There was a suggestion of proliferative change in 11% of the children, but in most cases the NBOs regressed with age. However the authors suggest that young children with a large number and volume of NBOs should be followed closely with regular MR scans. Raininko et al., (2002) studied 35 patients with NF1 ranging from nine months to 18 years. They found that NBOs appeared at all ages, and could disappear. The differential diagnosis between neoplastic and non-neoplastic lesions was not clear. Drappier et al., (2003), in a large series, compared screening, including extensive imaging and analysis of 24-hour urinary catecholamine levels to regular clinical examination only, and found no difference in the number of complications picked up. Opercular and paracentral lobular polymicrogyria can occur (Ruggieri et al., 2011).
There is an increased tendency to leukaemias, particularly of the myeloproliferative form (Bader et al., 1978, Brodeur et al., 1994, Lichtman et al., 1994, Shannon et al., 1994). Bollag et al., (1996) suggested that neurofibromin negatively regulates granulocyte-macrophage colony stimulating factor (GM-CSF) through Ras. An association between NF1, juvenile chronic myelogenous leukemia and juvenile xanthogranulomas has been noted. Zvulunov et al., (1995) review the literature and conclude that this is a true association. Infants with this combination have a higher incidence of family history of NF1. The authors suggest that the combination of NF1 and juvenile xanthogranuloma carries a 20-32-fold higher risk for juvenile chronic myelogenous leukemia. Saenger (1998) discusses the risk of tumours developing in children given growth hormone for growth deficiency in NF1. Risks seem to be low, but caution is still advised.
Sutphen et al., (1995) reported four cases with clitoral hypertrophy, but with normal endocrinological studies. They found 26 cases with this association in the literature. Habiby et al., (1995) found seven cases with precocious puberty out of 219 children with NF1. All had optic pathway tumours and the incidence of precocious puberty amongst cases with this complication was 39%. However, Zacharin (1997) reported two children with precocious puberty without optic chiasmal gliomas. Cnossen et al., (1997) also stress that this was not a necessary association.
About 5% of gene carriers may have mild mental retardation (Legius et al., 1994), and a third have serious complications at some stage during their life. A figure 81% for moderate to severe impairment in one or more areas of cognitive functioning, was found by Hyman et al., (2005). Sustained attention difficulties were present in 63%. Friedman and Birch (1997) provide a good review of 1,728 registered cases, with a useful estimate of the incidence of different complications in the condition. Another good population review is provided by McGaughran et al., (1999). Cerebrovascular dysplasia occurs in 2-5% of cases (Cairns and North 2008). A moyamoya-like picture can occur and also scalp defects (Smith et al., 2011). A Foix-Chavany-Marie like syndrome can also occur (Mastrangelo et al., 2009).
Clausen et al., (1989) reported a family where a mother had ganglioneuromas, two daughters had neuroblastomas and a son had neurofibromatosis, as did one of the mother's brothers. Other family members had Hirschsprung disease.
Schotland et al., (1992) reported a family where four members had both features of NF-1 and osseous fibrous dysplasia - they reviewed other cases from the literature with this combination.
Lampe et al., (2002) reported a 21-month-old boy who had a prostatic embryonal rhabdomyosarcoma and review the literature suggesting that these tumours are over represented in NF1 patients. Four patients with non-neurogenic sarcomas were reported by Coffin et al., (2004). A giant cell granuloma, reported by Martinez-Tello et al., (2005), gave the impression of cherubism. There were in addition, lytic bone lesions in the long bones.
Chang et al., (1993) reported two cases where neurofibromatosis type 1 was associated with piebaldism and Zein et al., (2004) reported a case with a CNS lymphoma. Multiple subcutaneous lipomata, a juvenile polyp of the ascending colon, anomalous venous connections in the liver and a horse-shoe kidney were all features in the case (without a PTEN mutation) reported by Oktenli et al., (2004).
Poyhonen et al., (1997) reported a family where seven individuals in three generations had spinal neurofibromatosis. All patients had cafe au lait spots but none had Lisch nodules. Linkage studies showed that the disorder was likely to be allelic with NF1. Ars et al., (1998) reported a family with spinal neurofibromatosis where a frameshift mutation in the NF1 gene was found. Lee et al., (1996) reported other cases with intramedullary spinal cord tumours in neurofibromatosis. In NF1 these appeared to be astrocytomas, whereas in NF2 they were ependymomas or intramedullary schwannomas. King et al., (2000) investigated the incidence of malignant peripheral nerve sheath tumours in NF1. These are rare, aggressive, malignant tumours of peripheral nerves. They appear to occur in 2% of patients between the 2nd and 5th decade of life. De Raedt et al., (2003) reported that NF1 microdeletion individuals have a substantially higher lifetime risk for the development of malignant peripheral nerve sheath tumors. Distemaier et al., (2007) reported a patient with a glioblastoma multiforme.
Faravelli et al., (1999) reported a family where several individuals had CNS tumours (brain stem glioma). Two individuals did not have cutaneous features of NF1. A splice-site mutation in exon 29 of the NF1 gene was detected. Wimmer et al., (2002) reported a patient with spinal neurofibromas who had a IVS19b-3C
Perini and Gallo, (2001) report three patients with NF1 and multiple sclerosis. They reviewed the literature and concluded that the chances of having both disorders is higher than would be expected by chance.
The gene has been localised to 17q22. It is 350kb in length with an 11-13kb transcript. The protein, neurofibromin, appears to be a GTPase activating protein (GAP) (Wallace et al., 1990; Cawthon et al., 1990; Davis 2000; Guo et al., 2000). North et al., (2000) presents a good review of the developmental biology. Lazaro et al., (1994) demonstrated germline mosaicism in a clinically normal father. Kayes et al., (1994), Wu et al., (1995), Wu et al., (1997), Upadhyaya et al., (1998) and Oktenli et al., (2003) report deletions giving a more severe phenotype including significant retardation and some facial features of Noonan syndrome. One case had iris colobomas and another retinal detachment. Korf et al., (1999) reported five cases with deletions and demonstrated structural abnormalities of the brain including agenesis of the corpus callosum, megacisterna magna, cava septum pellucidum, Chiari 1 malformation and enlarged ventricles. Lazaro et al., (1995) demonstrated germline mosaicism for a 12-kb deletion in the NF1 gene in an unaffected father who had two affected children. Riva et al., (1996) reported a case with a 17q11.2 deletion who had NF1 as well as skeletal anomalies consisting of scoliosis, pectus excavatum, bilateral dislocation of the hip. However Tongard et al., (1997) presented evidence suggesting that the presence of deletions could not be predicted with certainty on the basis of the clinical phenotype. Venturin et al., (2004) report that the presence of dysmorphism, MR and cardiac malformations are signs indicating a microdeletion.
Upadhyaya et al., (1994) and Shen et al., (1995) review the range of mutations in this condition. Ars et al., (2000) found mutations in 87% of familial cases but 51% of sporadic cases. 50% of the mutations resulted in splicing alterations. Colman et al., (1996) reported a case shown to be mosaic for a deletion of most of the coding region of the gene. The phenotype, however, was not 'segmental'. The patient reported by Vandenbroucke et al., (2004) was clinically (and genetically) mosaic, but only if you looked carefully.
Heim et al., (1995) studied 21 NF1 cases using a protein truncation assay and found truncating deletions in 14 individuals. Rasmussen et al., (1998) studied 67 probands and found large deletions in 5 (7.5%). They did not find an increased severity of disease manifestations in these cases. Dorschner et al., (2000) showed that microdeletion breakpoints are clustered around flanking repetitive sequences. Lopez Correa et al., (2000) showed that unequal meiotic crossing-over was a frequent cause of NF1 microdeletions. Lopez-Correa et al., (2001) demonstrated recombination hotspots in patients with microdeletions of the NF1 gene. There is a high frequency of mosaicism in patients with microdeletions. Kehrer-Sawatzki et al., (2004) found that in 20 patients with sporadic NF1 who had microdeletions, 40% were mosaics. These are largely of maternal origin. Three out of 13 patients reported by Descheemaeker et al., (2004), with microdeletions, were retarded. Park and Pivnick (1998) used a protein truncation test to screen 15 patients and found mutations in 11 (73%). Individuals with an NF1 microdeletion have, as a group, more neurofibromas at a younger age than the group of all individuals with NF1. Viskochil (1999) provides a good review of genotype-phenotype correlation. Gutmann (2001) reviews the mechanism of tumour initiation and progression in the neurofibromatoses. Ferner et al., (2007) have an excellent review on diagnosis and management.
Santoro et al. (2015) investigated the genotypeþphenotype association in 219 genetically confirmed neurofibromatosis type 1 patients. The c.5425C>T substitution was identified in three unrelated probands, who showed a mild phenotype. The results replicated data by Pinna et al. (2015), who reported six unrelated patients with the heterozygous c.5425C>T p.(Arg1809Cys) missense variant that causes a mild form of NF1, characterized by cafe-au-lait spots and skinfold freckling without other typical features such as Lisch nodules and neurofibromas but with Noonan syndrome features. NF1-related tumors and congenital heart defects were not observed.
Cassiman et al. (2016) compared the presence of choroidal nodules between patients with NF1 and patients with Legius syndrome. Choroidal nodules were diagnosed in 65% of the NF1 group (71% of patients with a truncating mutation and 50% of patients with a non-truncating mutation). Choroidal nodules were seen in 18% of Legius syndrome patients, never more than one nodule per eye was detected in this group. The authors concluded that the number of choroidal nodules in Legius syndrome is comparable with their presence in healthy individuals.
Tripolszki et al. (2017) described a female patient with congenital hypertrophy of the left leg mimicking overgrowth syndrome.
* This information is courtesy of the L M D.
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