Cardiac screening in pediatric patients with neurofibromatosis type 1: similarities with Noonan syndrome?

Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. PURPOSE: The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. METHODS: Fifty-eight patients with NF1 (ages 0-18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. RESULTS: Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. CONCLUSIONS: Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored.

Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor.

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life-threatening plexiform neurofibroma in a 9-month-old female infant with NF1. Germline mutations in two RASopathy-associated genes were identified using whole-exome sequencing-a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein-coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild-type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non-NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy.

Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1.

INTRODUCTION: Plexiform neurofibromas (PNF) in neurofibromatosis type 1 (NF1) are usually diagnosed in childhood and can grow rapidly during this period. In 10% of patients, PNF involve the orbital-periorbital area and may cause visual problems including glaucoma, visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression, or keratopathy. Ptosis, proptosis, and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal involves significant risks and mutilation, and regrowth after debulking is not uncommon. Inhibitors of the RAS/MAPK pathway have recently been investigated for their activity in PNF. We administered the oral MEK inhibitor trametinib to five young children with NF1 and PNF of the orbital area, with visual compromise and progressive tumor growth; and followed them clinically and by volumetric MRI. METHODS: Treatment was initiated at a mean age of 26.8 months (SD ± 12.8) and continued for a median 28 months (range 16-51). Doses were 0.025 mg/kg/day for children aged > 6 years and 0.032 mg/kg/day for those aged < 6 years. RESULTS: Volumetric MRI measurements showed a reduction of 2.9-33% at 1 year after treatment initiation, with maximal reductions of 44% and 49% in two patients, at 44 and 36 months, respectively. No change in visual function was recorded during treatment. One child reported decreased orbital pain after 2 weeks; and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails, grades 1-2. CONCLUSIONS: Trametinib can decrease tumor size in some young children with orbital PNF and may prevent progressive disfigurement.

Role, function and challenges of multidisciplinary centres for rare diseases exemplified for neurofibromatosis type 1 syndrome.

PURPOSE: Neurofibromatosis type 1 (NF1) syndrome is a common rare/orphan disease that manifests itself early in the paediatric age. It imposes a considerable burden upon patients as well as on caregivers. Decisions regarding optimal care often rely on several medical instances working together as a team. METHODS: The authors reviewed the literature and supplied a description of their own clinical work at the NF1 centres. RESULTS: The experience of a multidisciplinary teamwork of three NF centres was summarized in order to enhance awareness for possible multidisciplinary ways of delivery of health and health-related aspects of care to NF1 patients. Both population-focused research centres and family-focused centres were reviewed. CONCLUSIONS: Chronic rare diseases that start in the paediatric age mandate long-term follow-up most often by several disciplines. NF1 syndrome is an example of a multidisciplinary centre in order to enhance the quality of care.

Prevalence of Strabismus Among Children With Neurofibromatosis Type 1 Disease With and Without Optic Pathway Glioma.

PURPOSE: To evaluate the prevalence of strabismus in neurofibromatosis type 1 (NF-1) by comparing children with normal neuroimaging to those with optic pathway glioma. METHODS: A retrospective data collection of all children with NF-1 with neuroimaging studies examined at a single medical center between 2000 and 2016. RESULTS: Of the 198 children with NF-1 reviewed, 109 (55%) were male, 121 (61%) had normal neuroimaging, and 77 (39%) had an optic pathway glioma. Mean age at presentation was 6.3 ± 4.7 years and mean follow-up was 4.8 ± 3.1 years. Strabismus was present in 29 (15%) children and was significantly more prevalent in children with NF-1 with optic pathway glioma (21 of 77 [27%]) than in those with normal neuroimaging (8 of 121 [7%], P < .001). Sensory strabismus was only found in children with optic pathway glioma, accounting for most cases (12 of 21 [57%]). A strong association between strabismus and optic pathway glioma is demonstrated by an odds ratio of 5.29 (P < .001). Children with NF-1 with optic pathway glioma have a 4.13 times higher relative risk of developing strabismus than children with NF-1 without it (P = .001). The direction of ocular misalignment in children with NF-1 with optic pathway glioma was not significantly different than that observed in children without optic pathway glioma (P = .197, Fisher's exact test). Only 5 (17%) children with NF-1 with strabismus (3 with optic pathway glioma) underwent corrective surgery to align their eyes. CONCLUSIONS: Optic pathway glioma in children with NF-1 is associated with an increased risk of strabismus that is often sensory. Although exotropia is the most common ocular misalignment associated with optic pathway glioma, the direction of strabismus cannot be used as an accurate predictor for its presence. [J Pediatr Ophthalmol Strabismus. 2019;56(1):19-22.].

Cranial irradiation in childhood mimicking neurofibromatosis type II.

Neurofibromatosis type II (NF2) is a genetic disease characterized by bilateral vestibular schwannomas (VS) and other nerve system tumors. However, such tumors may be associated with environmental, rather than a genetic, etiology. Individuals fulfilling the clinical criteria of NF2 who had been treated by head ionized irradiation at a young age were compared for disease characteristics and molecular analysis with non-irradiated sporadic NF2 cases. In the study cohort, three of 33 sporadic adult cases fulfilling NF2 diagnostic criteria had a history of early age cranial irradiation exposure. None of the irradiated patients had bilateral VS compared with 73.3% of the non-irradiated individuals. One of the irradiated patients had no VS, while none of the non-irradiated NF2 cases had absence of VS. All of the irradiated individuals had brain meningiomas and thyroid tumors compared with 47% and 0%, respectively, of the non-irradiated individuals. Molecular analyses for NF2 mutations in blood of the irradiated individuals failed to detect disease-causing mutations. This study suggest that environmental factors may mimic NF2. Identifying such non-genetic cases fulfilling clinical criteria of the genetic disease may be crucial for the purposes of genetic counseling and patient management.

Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules.

BACKGROUND: Although isolated cafe-au-lait macules (CALMs) are a common skin finding, they are an early feature of neurofibromatosis type 1 (NF1). OBJECTIVE: We sought to develop an algorithm determining the risk of children with CALMs to have constitutional NF1. METHODS: We conducted a retrospective study of patients with isolated CALMs. Diagnosis of NF1 was based on detecting NF1 mutation in blood or fulfilling clinical criteria. RESULTS: In all, 170 of 419 (41%) and 21 of 86 (24%) children with isolated CALMs who underwent molecular testing and clinical follow-up, respectively, were given a diagnosis of NF1. Presence of fewer than 6 CALMs at presentation or atypical CALMs was associated with not having NF1 (P < .001). An algorithm based on age, CALMs number, and presence of atypical macules predicted NF1 in both cohorts. According to the algorithm, children older than 29 months with at least 1 atypical CALM or less than 6 CALMs have a 0.9% (95% confidence interval 0%-2.6%) risk for constitutional NF1 whereas children younger than 29 months with 6 or more CALMs have a high risk (80.4%, 95% confidence interval 74.6%-86.2%). LIMITATIONS: The study was designed to detect constitutional NF1 and not NF1 in mosaic form. CONCLUSIONS: A simple algorithm enables categorization of children with isolated CALMs as being at low or high risk for having NF1.

The effect of parental age on the presence of de novo mutations - Lessons from neurofibromatosis type I.

BACKGROUND: Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous disease with a prevalence of 1:2500. Approximately, 50% of the cases are sporadic. Advanced paternal age is associated with germline mutations and autosomal diseases. We aimed to use NF1 as a paradigm to study the effect of parental age on sporadic mutation rates for both advanced and younger parental ages. METHODS: The medical charts of 118 NF1 pediatric patients followed in a specialized Israeli NF1 clinic were evaluated. Thirty-one cases were diagnosed by genetic tests and 87 by NIH clinical criteria. Sixty-four cases (54%) had a negative family history of NF1 (sporadic cases). Data on parental ages at the time of the children's birth were compared to the national population database. RESULTS: Parental age of children with sporadic NF1 was higher than the general population (32.7 years vs. 30.1 years, respectively, for the mothers and 36.5 years vs. 32.6 years, respectively, for the fathers; P < 0.0001 for both groups). In contrast, the age of the mothers and the fathers in the familial cases (30.3 and 33.9 years, respectively) did not differ from the general population. Significantly, fewer fathers of the sporadic group had been 25-29 years old at their child's birth compared with fathers in the general population (7.8% vs. 21%, respectively, P = 0.009), and significantly more fathers were ≥40 years old (29.7% vs. 13.6%, respectively, P = 0.0002). Differences in maternal age between these two groups were less prominent. CONCLUSION: Parents of sporadic NF1 cases are older. The risk for sporadic NF1 was lower when the fathers were younger at the time of the affected child's birth, and gradually increased with paternal age.

High prevalence of elevated blood pressure among children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common neurocutaneous disease characterized by café-au-lait spots, axillary and inguinal freckling, neurofibromas, and optic gliomas. Increased rates of hypertension (HTN) were reported among NF1 patients, however, the prevalence of HTN and pre-HTN in pediatric NF1 patients has not been clarified. METHODS: Blood pressure (BP) measurements, weight, and renal ultrasound were assessed in 224 NF1 pediatric patients followed in a specialized NF1 clinic. RESULTS: The cohort's mean age was 9.1 ± 4.1 years. Overweight and obesity were found in 12.9 and 10.3 % of them, respectively. BP was measured averagely 2.9 times per patient on different occasions. Blood pressure was in the pre-HTN and HTN ranges in 14.9 and 16.9 % of measurements, respectively. BP >95th was detected in 20.5 % at the first measurement. Of 114 children with at least three BP measurements, 18.4 % had two values in the HTN range and 6.14 % had at least three. Overweight was not associated with HTN among children with NF1. Urinary tract ultrasonographic abnormalities were detected in 6.8 % (11/161) of cases. CONCLUSIONS: The prevalence of increased BP in pediatric NF1 is much higher than in the general pediatric population. BP has to be regularly assessed and managed in this high-risk population.

Increased prevalence of ametropia in children with neurofibromatosis type 1 disease.

Neurofibromatosis type 1 disease is an autosomal dominant disorder associated with numerous ophthalmic and systemic manifestations. Organic causes of visual loss include optic pathway gliomas, orbital plexiform neurofibroma, and glaucoma. In this study, the authors analyzed the prevalence of ametropia as a cause for visual loss in children with neurofibromatosis type 1 disease younger than age 12 years compared to matched controls. Only children with normal neuroimaging were evaluated. Myopia, hyperopia, astigmatism, and anisometropia were all more common in children with neurofibromatosis type 1 disease; however, statistically significant differences were observed in mild myopia and astigmatism alone. A higher need for optical correction was found in children with neurofibromatosis type 1 disease (33.3% vs 17.1% of controls, P = .049). In conclusion, children with neurofibromatosis type 1 disease have a higher prevalence of ametropia, especially mild myopia and astigmatism, often requiring optical correction. Routine refraction screening is recommended for limiting preventable visual loss.

Anisometropia in children with neurofibromatosis type 1 and unilateral optic nerve glioma.

BACKGROUND: Optic nerve glioma (ONG) occurs in 5% to 25% of individuals with neurofibromatosis type 1 (NF1). Recently an association between this lesion and unilateral myopia was reported in a series of 4 pediatric patients. The purpose of this study was to determine whether unilateral ONG is associated with an increased prevalence of anisometropia. METHODS: The medical records of children <16 years of age with NF1 disease and unilateral ONG or normal neuroimaging examined at Tel-Aviv Medical Center between April 2008 and July 2013 were retrospectively reviewed to determine the prevalence of anisometropia and anisoastigmatism. RESULTS: A total of 75 children with NF1 disease were included. Of these, 25 (11 boys) had a unilateral ONG (mean age, 7.2 years; range, 2-16 years) and 50 (29 boys) had normal neuroimaging (mean age, 8.3 years; range, 1-15 years). The mean refraction (spherical equivalent) of eyes with ONG did not differ significantly from that of the contralateral eyes (0.74 ± 1.41 D vs 0.71 ± 1.19 D; P = 0.935; 95% CI, -0.710 to 0.770); moreover, there was a high correlation between the refraction of eyes with ONG and contralateral eyes (r = 0.946, P < 0.001). The prevalence of anisometropia in children with ONG and in NF1 children with no orbital pathology did not differ significantly (8% vs 16%; P = 0.480), and the prevalence of anisoastigmatism was also similar in both groups (4% vs 14%, P = 0.255). CONCLUSIONS: ONG in children with NF1 is not associated with increased prevalence of anisometropia.

Is there a relationship between executive functions and academic success in children with neurofibromatosis type 1?

The present study aimed to compare the executive function (EF) of children with neurofibromatosis type 1 (NF1) to those of typically developing children and to investigate whether those abilities could predict the child's academic success in terms of academic skills and enablers. Twenty-nine children with NF1 and 27 age-and-gender-matched controls (aged 8-16 years) were examined with two tests to measure EF in an ecologically valid manner: the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C) and the parent questionnaire for the Behavior Rating Inventory of Executive Function (BRIEF). In order to evaluate academic success we used the Academic Competence Evaluation Scales (ACES). The performance of the NF1 group was significantly lower on the Water and Key search subtest of the BADS-C and on four scales of the BRIEF: initiate; working memory; plan/organise and organisation of materials. Significant correlations and predictive models via regression analysis were generated for: BADS-C, BRIEF and ACES scores. Based on these findings, children with NF1 have executive dysfunction that partially accounts for their difficulties in academic achievements.

Underlying mechanisms of writing difficulties among children with neurofibromatosis type 1.

Writing is a complex activity in which lower-level perceptual-motor processes and higher-level cognitive processes continuously interact. Preliminary evidence suggests that writing difficulties are common to children with Neurofibromatosis type 1 (NF1). The aim of this study was to compare the performance of children with and without NF1 in lower (visual perception, motor coordination and visual-motor integration) and higher processes (verbal and performance intelligence, visual spatial organization and visual memory) required for intact writing; and to identify the components that predict the written product's spatial arrangement and content among children with NF1. Thirty children with NF1 (ages 8-16) and 30 typically developing children matched by gender and age were tested, using standardized assessments. Children with NF1 had a significantly inferior performance in comparison to control children, on all tests that measured lower and higher level processes. The cognitive planning skill was found as a predictor of the written product's spatial arrangement. The verbal intelligence predicted the written content level. Results suggest that high level processes underlie the poor quality of writing product in children with NF1. Treatment approaches for children with NF1 must include detailed assessments of cognitive planning and language skills.

Using a Virtual Classroom environment to describe the attention deficits profile of children with Neurofibromatosis type 1.

The objectives of this study were to describe the nature of the attention deficits in children with Neurofibromatosis type 1 (NF1) in comparison with typically developing (TD) children, using the Virtual Classroom (VC), and to assess the utility of this instrument for detecting attention deficits. Twenty-nine NF1 children and 25 age-and gender-matched controls, aged 8-16, were assessed in a VC. Parents' ratings on the Conners' Parent Rating Scales-Revised: Long (CPRS-R:L) questionnaire were used to screen for Attention Deficit-Hyperactivity Disorder (ADHD). Significant differences were found between the NF1 and the control groups on the number of targets correctly identified (omission errors) and the number of commissions (commission errors) in the VC, with poorer performance by the NF1 children (p < 0.005). Significant correlations were obtained between the number of targets correctly identified, the number of commission errors, and the reaction time. Significant correlations were also found between the total correct hits and the cognitive problems/inattention scale, as well as two other indexes of the CPRS-R:L: the DSM-IV Symptoms Subscale and the ADHD Index. The VC results support the hypothesis that NF1 is marked by inattention and impulsivity and that participants with NF1 are more inattentive (omission errors) and impulsive (commission errors) than normal controls. The VC appears to be a sensitive and ecologically valid assessment tool for use in the diagnosis of attention deficits among children with NF1.

The handwriting performance of children with NF1.

The objective of this study was to analyze the process and product of handwriting among children with Neurofibromatosis Type 1 (NF1) in comparison to those of Typically Developing (TD) children. Children with NF1 are at risk for some cognitive deficits, a wide range of deficits in perceptual skills and, motor and visual-motor integration skills which may interfere with handwriting competency, which is an essential ingredient for success at school. Participants were 30 NF1 children and 30 age and gender matched TD children, between the ages 8 and 16.08. The handwriting performance of children with NF1 was evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI), for copying text and free style writing tasks, using: (1) Computerized Penmanship Evaluation Tool (ComPET) to assess mechanical aspects of the writing process. (2) The Hebrew Handwriting Evaluation (HHE) to examine product legibility. (3) The Six-Trait Writing Model to judge the quality of the written product. Significant differences between the NF1 children and the control group were found in the process and product measures. Significant correlations were found between the VMI, the ComPET, the HHE and the Six-Trait Writing Model variables for both groups. We suggest a possible relationship between executive dysfunction and poor performance in handwriting.