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The available clinical, epidemiological, radiological and genetic data from children with NF1, who attended at a specialist NF1 clinic between January and December were recorded.. The mean age at diagnosis was 2. In our series The NF1 genetic study was performed in 86 patients, and a description of the gene mutations found in 72 of them is presented. Furthermore, other clinical data previously associated with NF1, either because of their frequency or their severity, are detailed..

Common Neurocutaneous Syndromes

The difficulty for clinical diagnosis of NF1 early ages is still evident. Although, the need for further studies in asymptomatic patients is discussed, cranial MRI in children with NF1 may be helpful in the clinical diagnosis, given the high frequency of optic glioma observed in this cohort.. Se describen las mutaciones encontradas en 72 pacientes. Its clinical expression is heterogeneous, even within a single family, and its morbidity and mortality are associated with multisystemic complications. Most reviews retrieve the data from the same studies, mainly from those conducted by Huson in south-east Wales in and , but the proportion of children in these studies was low.

There have been significant advances in the understanding of its genetic basis. However, genetic studies include few clinical data, and phenotypic studies, most of which were conducted long ago, do not include genetic data. Our aim was to provide an exhaustive phenotypical description in a broad sample of paediatric patients with NF1 along with all the available molecular data.. We conducted a descriptive, cross-sectional, observational retrospective study.

We collected the clinical, epidemiological, radiological and genetic data available for every patient 0—18 years of age that received care at a specialist neurofibromatosis clinic between January and December and met the clinical diagnostic criteria for NF1 established by the National Institute of Health of the United States 7 Table 1 or with a genetic diagnosis of NF1.

The diagnosis of neurofibromatosis-Noonan syndrome NFNS required that the patient also met the clinical criteria for Noonan syndrome proposed by van der Burgt 8 Table Clinical diagnostic criteria for NF Diagnosis of Noonan syndrome. Criteria proposed by van der Burgt : typical facies and one major criterion or 2 minor criteria, or suggestive facies with 2 major or 3 minor criteria.. We analysed the data of patients, of which children from families met the inclusion criteria; 14 children had either siblings or cousins that were included in the sample.

Sixty-seven patients had a father or mother diagnosed with NF1. The mean age of the patients was 8. Children were diagnosed before age 8 years in The mean age of each subgroup increased with the number of criteria. Table 3 presents data for additional clinical features previously associated with NF1 due to their frequency or severity, along with their frequency in our series.

The age at diagnosis of optic nerve glioma ONG was documented in 70 patients, with a mean age of 3. There were a total of 72 plexiform neurofibromas PNFs , 23 of which were internal and 49 external, in 55 patients as many had more than one PNF. Thirty percent of the PNFs were symptomatic: 2 were located in the mediastinum and were accompanied by respiratory symptoms and scoliosis, 4 were paraspinal or at the nerve roots and were associated with pain and scoliosis, 7 were facial with ptosis, exophthalmos or facial deformity, and 9 were located in the torso or limbs and caused deformities, with 5 of the latter manifesting with pain and functional impotence.

A psychometric test was performed in 87 patients, the mean IQ of whom was Three patients experienced secondary headache, which was due to moyamoya disease in one, and to hydrocephalus in the other two. Four patients had orbitotemporal involvement with unilateral bone, soft-tissue and vision abnormalities. In addition, two of them had ONG, two had sphenoid dysplasia, three had plexiform neurofibroma and three had exophthalmos and ptosis.

Cranial magnetic resonance imaging MRI was performed in patients, and hyperintensities were observed in Hyperintensities were most frequently located at the cerebellum, brainstem, basal ganglia, thalamus and hippocampus.. Left, distribution of clinical criteria of the patients. Clinical signs and symptoms of the children with NF Genetic analysis of the NF1 gene was performed in 86 patients.

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Indirect haplotyping was performed in 11 patients. Five patients had microdeletion syndrome, of which four had general learning disabilities and attention deficit hyperactivity disorder ADHD. Also, one patient had moderate intellectual disability and another 3 borderline intellectual functioning.

Three patients had subcutaneous neurofibromas and one also had internal plexiform neurofibromas. Confirmation was done by indirect testing in one, and the others correspond to patients 8, 20, 28, 33, 36, 38, 55 and 64 in Table Analysis of the mutations found in the NF1 gene..

The results of our study were consistent with those of other authors 3,6,10,11 when it came to the frequency of each of the clinical criteria Table 5.

Our study did diverge in that we found a much higher prevalence of the ONG criterion, which was probably due to the greater number of cranial MRI scans performed in our hospital, where this test is usually done in asymptomatic patients older than 2 years that meet cutaneous criteria for NF. At present, there is no consensus on the diagnostic tests that should be performed in the diagnosis and followup of asymptomatic children with NF1, especially in relation to the indication of cranial MRI. But given the importance of diagnosing NF1 complications early and that adequate neurological and ophthalmological examinations depend on the cooperation of the patient, which in turn is determined by patient age and presence or absence of intellectual disability, some authors propose that MRI scans should be done even in asymptomatic patients, 12—14 while others consider that it is only indicated when eye exams cannot be carried out appropriately.

On the other hand, although hyperintensities in T2-weighted images, so frequent in cranial MRI, are neither diagnostic nor pathognomonic, they can support the clinical suspicion of NF1 in young children if they are well defined and appear in typical regions such as the cerebellum, the brainstem and the basal ganglia.

It is mostly useful to diagnose and monitor gliomas in the optic nerve or other locations, but also other complications that are less frequent, such as hydrocephalus or vascular diseases. It is precisely in studies that review the records of patients with NF1 with a focus on a specific neurologic pathology such as cerebrovascular disease or epilepsy that some authors have directly or indirectly proposed testing to detect cases of still-asymptomatic neurologic pathology.

This notion is supported by cases such as those of the two patients included in the study after the disease was confirmed by genetic testing that did not meet enough criteria for the diagnosis of NF1, demonstrating that it is not always easy to make the diagnosis based solely on clinical criteria in the early years of life.. Table comparing different cohorts of children with neurofibromatosis type We observed a greater frequency of plexiform neurofibromas compared to the other types.

This was probably due to our study being conducted on the paediatric population, which is consistent with the findings of other studies on this age group. The mean age at which ONG was detected was 3. However, the frequency of ONG with severe symptoms did not differ significantly from that described by other authors.

However, we found a lower prevalence of sphenoid dysplasia and no patient had vertebral dysplasia. The four patients with orbitotemporal involvement set apart in the literature as a specific subgroup, orbitotemporal NF 20 had a clinical presentation that appeared as a separate entity, aggressive and with a multifactorial aetiology.. Recently, the clinical relevance of nevus anemicus and juvenile xanthogranuloma has been growing due to their presence in children younger than 2 years, as at these ages patients with de novo NF usually meet a single clinical criterion, and this results in diagnostic delays.

Since this is a retrospective study, we suppose that their prevalence must be greater than the one we are reporting, as nevus anemicus must be purposefully sought by the clinician during the examination by rubbing the affected area, and juvenile xanthogranuloma tends to resolve spontaneously. All patients had been assessed for arterial blood pressure. However, hypertension was not found as frequently as it was by other authors that were probably studying older patients.

As for cognitive disorders, it is known that only a minority of patients with NF present with intellectual disability. Unlike what has been reported by several authors 25 that found a high prevalence of autism spectrum disorders in children with NF1, we only found one child with such a diagnosis. At present, it is known that the literature on this subject is contradictory, and is probably related to the cognitive phenotype features like deficits in executive function and nonverbal analysis than with social features.

Minor neurological signs and motor disability are usually observed in childhood, and patients perform more poorly in tasks used to evaluate fine motor skills, manual dexterity and balance. On the other hand, hypotonia may contribute to motor abnormalities, causing delays in walking. We did not find any studies in the literature with a large sample of children with NF1 that reported the age the children learned to walk..

While malformations of the central nervous system rarely occur in this disease, they are not considered coincidental. Even though cranial MRI was performed in most of our patients, we did not observe a higher incidence of these malformations than that previously reported, unlike what occurred with ONG.

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Furthermore, all the documented malformations had been previously described in association with NF1. We ought to underscore the presence of headache secondary to intracranial pathology in children with NF1 given the frequency and severity of these cases and their prognostic and therapeutic implications. We observed a 3. However, this prevalence is still small compared to that in other neurocutaneous disorders. No identifiable aetiology had been documented for any of the patients, which supports that this is probably a primary characteristic.

We observed the types most frequently reported in children. This association has already been questioned by other authors.

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In addition, the recently described Legius syndrome, which has a clinical phenotype similar to that of NF1, presents the need to once more update the diagnostic criteria for NF1, as at present NF1 can be diagnosed if the patient meets the CALM and the axillary or inguinal freckling criteria, and both manifestations can be found in Legius syndrome.

Facial dysmorphism is one of the variable clinical characteristics shared by all RASopathies. In 9 of the 12 patients genetic testing of the de NF1 gene was performed, confirming the diagnosis.

Overall, these results suggest the presence of a characteristic phenotype in some children with NF1 that overlaps with other RASopathies, and as de Luca et al. In fact, it has been proposed that testing for mutations in the NF1 gene is performed in patients that have both a Noonan phenotype and CALMs. In 83 patients, the disease was confirmed by means of genetic testing.

In three patients, the results of direct testing for mutations were negative. These patients met two, three, and four criteria, respectively. We decided not to exclude them from the sample because they met the clinical criteria for NF1 and they did not exceed the percentage of false negatives reported for genetic testing.

The mutations are distributed along the entire NF1 gene and most of them are frameshift and nonsense mutations, which were also the most frequent types found in other studies.

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The data available on the phenotypical, radiological and genetic characteristics of paediatric patients with NF1 that we present here provide an overview of the main findings and complications that characterise these patients in one of the largest cohorts to be found in the international literature. They evince that it continues to be difficult to make a clinical diagnosis at early ages. While the need of performing diagnostic tests in asymptomatic patients remains subject to debate, cranial MRI can be very helpful in the clinical diagnosis of children with NF1 considering the high prevalence of ONG found in our series..

The authors have no conflicts of interest to declare.. An Pediatr Barc. ISSN: Previous article Next article. Issue 3. Pages 01 September Phenotypic and genetic features in neurofibromatosis type 1 in children. Download PDF. Corresponding author. This item has received. Article information. Table 1.


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Table 2. Table 5. Show more Show less. Introduction Neurofibromatosis type 1 NF1 is the most common neurocutaneous disease, nevertheless the number of publications providing clinical and genetic data from a significant number of children is limited. Material and methods The available clinical, epidemiological, radiological and genetic data from children with NF1, who attended at a specialist NF1 clinic between January and December were recorded. Furthermore, other clinical data previously associated with NF1, either because of their frequency or their severity, are detailed.

Conclusions The difficulty for clinical diagnosis of NF1 early ages is still evident.

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Although, the need for further studies in asymptomatic patients is discussed, cranial MRI in children with NF1 may be helpful in the clinical diagnosis, given the high frequency of optic glioma observed in this cohort. Neurofibromatosis type 1.