Neurofibromatosis Type 1 Children Research Articles

Thalamo-Striatal T2-Weighted Hyperintensities (Unidentified Bright Objects) Correlate With Cognitive Impairments in Neurofibromatosis Type 1 During Childhood

Learning disabilities represent the main childhood complication in neurofibromatosis type 1 (NF1). Patients frequently exhibit T2-weighted hyperintensities called unidentified bright objects (UBOs) on brain magnetic resonance imaging (MRI), with unclear relationship to such cognitive disabilities. This study aimed to determine whether thalamo-striatal UBOs correlate with cognitive disturbances. Thirty-seven NF1 children were studied: 24 with UBOs (18 of which were thalamo-striatal UBOs), and 13 without UBOs. NF1 subjects carrying thalamo-striatal UBOs had significantly lower IQs and visuospatial performances than those without UBOs in this location. These results suggest that UBOs may contribute to NF1 cognitive impairments through thalamo-cortical dysfunction.

Is “watchful waiting” superior to surgery in children with neurofibromatosis type 1 presenting with extracranial and extramedullary tumor mass at diagnosis?

The aim of this study was to compare aggressive surgery to "watchful waiting" in neurofibromatosis type 1 (NF-1) patients with benign peripheral nerve sheath tumors exceeding 150 cm(3). Observational study based on imaging studies and results of surgery was utilized. Twenty-seven out of 114 NF-1 patients (mean age of 12.8 years) registered throughout the last 10 years were studied. The mean tumor volume was 237 cm(3). Among them, 18 (66%) underwent surgery. In 15 (84%), regrowth of a tumor was observed. Reoperation was necessary in five (27%). Two out of these five children (2/18, 11%) required a third operation. Stable process has been shown in the remaining nine children (34%) since diagnosis and in most operated children (10/18; 56%), besides the regrowth of the tumor. "Watchful waiting" could be superior to aggressive surgery in selected patients without "oncological awareness" confirmed by imaging techniques (mostly magnetic resonance imaging). NF-1 children with gross tumor mass require lifetime imaging monitoring and complex medical evaluation.

Evidence of Increased Bone Resorption in Neurofibromatosis Type 1 Using Urinary Pyridinium Crosslink Analysis

Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5-19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.

T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning

Background:Neurofibromatosis type 1 (NF1) is a single gene disorder associated with a high frequency of cognitive deficits and a complex cognitive phenotype. These cognitive deficits have been associated with focal...

ELEVATED DEOXYPYRIDINOLINE/PYRIDINOLINE RATIOS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 SUGGEST ABNORMALITY OF BONE REMODELING RATHER THAN COLLAGEN BREAKDOWN FROM OTHER TISSUES.

Objective Neurofibromatosis type 1 (NF1), although classically thought of as a neurocutaneous disorder, is associated with localized skeletal abnormalities, including long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and bone cysts. Our preliminary studies have documented decreased bone mineral density in children with NF1. Pyridinium cross-links [pyridinoline (Pyd) and deoxypyridinoline (Dpd)] are hydroxylysine-derived cross-links of mature collagen excreted in urine as a result of collagen degradation. Both Pyd and Dpd are found in bone and cartilage, but Dpd is most abundant in bone and reflects more the status of bone. To draw inferences of bone resorption, studies were designed to assess the Dpd/Pyd ratio in individuals with NF1 compared with individuals without NF1. Methods The total (free plus peptide-bound) pyridinium cross-links from two consecutive first morning urines from 60 NF1 children (ages 5-19) were extracted after acid hydrolysis and analyzed by high-performance liquid chromatography. Data were compared with 99 healthy controls without NF1. Regression analysis controlling for age and skeletal dysplasia status (defined as scoliosis, long-bone dysplasia, and/or sphenoid wing dysplasia) was used. Results Statistically significant increases of Pyd (p = .019) and Dpd (p Conclusions The elevated urinary excretion of pyridinium cross-links, both Dpd and Pyd, reflects increased collagen degradation in children with NF1. In addition, the elevated Dpd/Pyd ratio shows that the increased collagen breakdown products are predominantly due to abnormal resorption of bone and not from collagen breakdown of other tissues. The linear regression analysis adjusting for skeletal dysplasia status suggests that NF1 haploinsufficiency contributes to increased bone resorption and a generalized abnormality of bone remodeling predisposing individuals with NF1 to localized skeletal defects.

Quality of life and psychological adjustment in children and adolescents with neurofibromatosis type 1

To assess quality of life (QoL) and psychological adjustment in children and adolescents with neurofibromatosis type 1 (NF1). Forty-six patients with NF1 were investigated between the ages of 7 and 16 years (mean, 11.6 years), with children and parents used as informants. TNO-AZL Questionnaire for Children's Health-Related Quality of Life and Child Behavior Checklist scores were compared with healthy reference groups. Predictive values of sociodemographic variables, illness-related variables, and family-related variables for quality of life and psychological adjustment were assessed. Most dimensions of QoL in NF1 children and adolescents were different from reference values. Deviations in the NF1 group were an impairment of motor, cognitive, and social functioning and a reduction of positive and negative emotions. Also, psychological adjustment in patients with NF1 was significantly impaired compared with normal subjects. Illness-related variables had a negative impact on the emotional domain of QoL. Good family relationships positively affected both QoL and psychological adjustment. QoL and psychological adjustment are impaired in children and adolescents with NF1. Illness-related variables and the quality of family relationships are important predictors.

The nature and frequency of cognitive deficits in children with neurofibromatosis type 1

To assess the frequency and severity of specific cognitive deficits in children with neurofibromatosis type 1 (NF1) in a large unbiased cohort. Extensive cognitive assessments were performed in 81 children with NF1 ages 8 to 16 years and their performance was compared with that of 49 unaffected sibling controls. Eighty-one percent of the children with NF1 had moderate to severe impairment in one or more areas of cognitive functioning. Although 51% of children with NF1 performed poorly on tasks of reading, spelling, and mathematics, specific learning disabilities (as defined by IQ-achievement discrepancies) were present in only 20% of the children. Sustained attention difficulties were present in 63% of children with NF1, with 38% of children with NF1 fulfilling the diagnostic criteria for attention deficit-hyperactivity disorder. The NF1 neuropsychological profile is characterized by deficits in perceptual skills (visuospatial and visuoperceptual), executive functioning (planning and abstract concept formation), and attention (sustained and switching). Interestingly, both verbal and visual memory was unaffected in NF1 children, and their memory skills were in general stronger than their level of general intellectual function. Although both expressive and receptive language skills were significantly impaired in NF1 children, they appeared to be relatively better preserved than visuospatial abilities once IQ is taken into account. There is an extremely high frequency of cognitive problems in children with neurofibromatosis type 1, making cognitive dysfunction the most common complication to affect quality of life in these children.

Resection of small plexiform neurofibromas in neurofibromatosis type 1 children

BackgroundPlexiform neurofibromas (PNF) are benign tumors of the peripheral nerve which mostly develop in patients with neurofibromatosis type 1 (NF1). Surgical interventions are usually not applied to children with small tumors. These are rather restricted to debulking of larger tumors in adults that cause clinical complications or aesthetic disfigurement. In most cases, a total resection of PNF is not possible due to the network-like growth of the tumors.Patients and methodsEarly surgical intervention was carried out for 9 small PNFs in 7 NF1 children. Tumor resection was performed following the graphical delineation of the affected skin and according the MRI findings.ResultsTotal resection was achieved for all 9 PNF without causing any neurological or organic deficit. Annual magnetic resonance tomography over a period of four years did not reveal any relapse of the tumors.ConclusionsEarly surgical intervention for small superficial PNFs in NF1 children have various advantages and may especially be considered a strategy to prevent progression.

Behavioural, academic and neuropsychological profile of normally gifted Neurofibromatosis type 1 children

In the present study the neuropsychological, academic and social-emotional profiles were examined in Neurofibromatosis type 1 (NF1) children. 17 NF1 children (ages 7-11) with NF1 without serious medical problems and with a full scale IQ (FSIQ) above 70. Wechsler Intelligence Scale for Children-Revised (WISC-R), academic tests and an exhaustive neuropsychological test battery were administered in all children. Parents and teachers filled out the Child Behavioural Checklist (CBCL) and Teacher Report Form (TRF), respectively, the NF1 children the Experienced Competence Scale for Children (ECSC). Nearly 50% (8/17) of the children showed learning disabilities, when corrected for IQ in the academic evaluations. Isolated impaired literacy skills, particularly spelling problems, were most frequent (4/8), whereas a pure arithmetic learning disability was rare (1/8). Three children presented both learning disabilities. Results on academic and neuropsychological tests did not fit the well-known types of learning disabilities -- nonverbal learning disability (NLD) and dyslexia. Nearly all NF1 children showed visual perceptual and executive dysfunctions. In this study, teachers more frequently reported behavioural problems in NF1 children than parents, as opposed to literature data in a general population. The correspondence of the perception of internalizing problems between the children and teachers was greater than between children and their parents. No correlation was found between the performances on the WISC-R, specific neuropsychological results, academic performances and behavioural problems. The Deficiency in Attention, Motor and Perception (DAMP) concept seems most appropriate in order to describe the neuropsychological deficits and their repercussions on behavioural and academic performances seen in NF1 children.

Growth hormone deficiency in children with neurofibromatosis type 1 without suprasellar lesions

Risk factors for shortness of stature in children with neurofibromatosis type 1 (NF-1) include suprasellar lesions, which can lead to growth hormone deficiency (GHD), skeletal deformities, nutritional insufficiency, and methylphenidate use. At our Neurofibromatosis Clinic, we have observed short children growing poorly without these risk factors. This study investigated whether GHD occurs in children with NF-1 in the absence of suprasellar lesions. Of 251 children with NF-1, 112 were at or below the 25th percentile for height (68 were at or below the 10th). Of these, 51 children, 5-16 years of age were short, growing poorly, and without medical or radiologic findings to explain the poor growth. In 19 of 51, we evaluated GH secretion; 15 of 19 had GHD (peak GH level less than 5 ng/mL in most cases). These findings suggest that GHD may be relatively common in short children with NF-1 without suprasellar abnormalities, suggesting an association with NF-1 independent of organic, pituitary damage. Larger cohorts of NF-1 children should be evaluated to clarify whether NF-1 represents a novel etiology of GHD. Also, a careful assessment of GH secretion in children with NF-1 who are growing poorly in the absence of another clinical explanation is warranted.

MRI Diagnosis of NF-1 in Children Without Café-Au-Lait Skin Lesions

Three of ten children with optic gliomas satisfy the 1987 National Institutes of Health consensus criteria for neurofibromatosis type 1 (NF-1). The diagnosis in these cases is based on the presence of café-au-lait skin lesions in addition to the optic glioma. Two children without skin lesions have typical findings on magnetic resonance imaging (MRI) that also suggest a diagnosis of NF-1. A review of 281 NF-1 children with brain MRI results demonstrates the presence of these abnormalities in 57% of the cases. It is suggested that this MRI abnormality is sufficiently specific to add this feature to the list of diagnostic criteria. When MRI findings are present in a child with optic glioma and without skin lesions, counseling should be given for NF-1. It is noteworthy that these typical MRI findings in NF-1 are less common in adulthood, apparently because of spontaneous resolution.

MRI morphometric analysis and neuropsychological function in patients with neurofibromatosis.

Volumes of cerebral gray and white matter were measured in 22 children with neurofibromatosis type 1 (NF1) and in 20 controls. Judgment of Line Orientation (JLO) and the Developmental Test of Visual-Motor Integration (DTVMI) were administered to 16 of the NF1 patients. General linear models analysis of covariance revealed significantly larger brain volumes in NF1 children than in controls, particularly in white matter, and particularly in girls. JLO and DTVMI performance were positively related to right-hemisphere gray-matter volume. The results implicate a failure of growth control in NF1, leading to aberrant neurodevelopment. Our findings also suggest a basis for refined understanding of learning disabilities, which are a prominent feature of NF1.

Optic gliomas in children with neurofibromatosis type 1

Over a 24-year period, optic gliomas were found in 29 children, 16 of whom had neurofibromatosis type 1 (NF-1). These 16 children comprised 21% of all children referred for management of NF-1 and its complications. The finding of optic glioma led to the diagnosis of NF-1 in 4 children. The mean age at diagnosis of optic glioma in NF-1 children was 6.4 years, and the average estimated duration of visual symptoms prior to diagnosis was 2.1 years. Most optic gliomas in NF-1 children were ascertained because of a visual complaint (69%), and an even greater number of children (88%) had an abnormal ophthalmological examination. The optic chiasm was involved in 75% of the patients. All of the seven children with optic glioma examined by visual evoked potential had an abnormal response ipsilateral to the tumour. The majority of the children received radiation therapy. After a mean follow up period of 5.8 years no deaths had occurred due to optic glioma, but in 35% of the children vision was worse. We conclude that optic glioma is a common, serious complication in NF-1 children. Routine care of such patients should include regular noninvasive investigations aimed at detecting lesions of the optic pathway.