Search

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

Purpose: Plexiform neurofibromas (pNF) are Schwann cell tumors found in a third of individuals with neurofibromatosis type 1 (NF1). pNF can undergo transformation to malignant peripheral nerve sheath tumors (MPNST). There are no identified serum biomarkers of pNF tumor burden or transformation to MPNST. Serum biomarkers would be useful to verify NF1 diagnosis, monitor tumor burden, and/or detect transformation.Experimental Design: We used microarray gene expression analysis to define 92 genes that encode putative secreted proteins in neurofibroma Schwann cells, neurofibromas, and MPNST. We validated differential expression by quantitative reverse transcription-PCR, Western blotting, and ELISA assays in cell conditioned medium and control and NF1 patient sera.Results: Of 13 candidate genes evaluated, only adrenomedullin (ADM) was confirmed as differentially expressed and elevated in serum of NF1 patients. ADM protein concentrati on was further elevated in serum of a small sampling of NF1 patients with MPNST. MPNST cell conditioned medium, containing ADM and hepatocyte growth factor, stimulated MPNST migration and endothelial cell proliferation.Conclusions: Thus, microarray analysis identifies potential serum biomarkers for disease, and ADM is a serum biomarker of NF1. ADM serum levels do not seem to correlate with the presence of pNFs but may be a biomarker of transformation to MPNST. Clin Cancer Res; 16(20); 5048–57. ©2010 AACR.

PDF file - 6K, List of the forward and reverse quantitative real-time PCR primers are shown in Supplement 1.

ObjectiveTo review and recommend patient-reported outcome (PRO) measures assessing multidimensional domains of quality of life (QoL) to use as clinical endpoints in medical and psychosocial trials for children and adults with neurofibromatosis (NF) type 1, NF2, and schwannomatosis.MethodsThe PRO working group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration used systematic methods to review, rate, and recommend existing self-report and parent-report PRO measures of generic and disease-specific QoL for NF clinical trials. Recommendations were based on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility.ResultsThe highest-rated generic measures were (1) the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales for NF clinical trials for children or for children through adults, (2) the Functional Assessment of Cancer Therapy–General for adult medical trials, and (3) the World Health Organization Quality of Life–BREF for adult psychosocial trials. The highest-rated disease-specific measures were (1) the PedsQL NF1 Module for NF1 trials, (2) the NF2 Impact on Quality of Life Scale for NF2 trials, and (3) the Penn Acoustic Neuroma Quality of Life Scale for NF2 trials targeting vestibular schwannomas. To date, there are no disease-specific tools assessing multidimensional domains of QoL for schwannomatosis.ConclusionsThe REiNS Collaboration currently recommends these generic and disease-specific PRO measures to assess multidimensional domains of QoL for NF clinical trials. Additional research is needed to further evaluate the use of these measures in both medical and psychosocial trials.

Rubinstein-Taybi syndrome (RTS) is a rare genetic disorder. Family-centered care (FCC) is a healthcare delivery approach that aims to create an equal partnership between caregivers and providers. FCC has been shown to improve parental wellbeing, their knowledge of the condition and care, and improve their feelings of self-efficacy and personal control. The purpose of this study was to explore the healthcare experiences of family caregivers of children and adults with RTS to understand the issues they encounter when working with medical professionals and to examine their perspectives on how to improve FCC. Primary family caregivers of individuals with RTS took an online mixed-method survey that contained three primary components: a demographic survey, the Measures of Processes of Care-20 (MPOC-20) [a measure of the FCC an individual feels they receive], and a qualitative assessment of negative and positive interactions with medical professionals and priority areas for improvement. Qualitative data were analyzed using thematic analysis. Quantitative data were analyzed with descriptive statistics. An analysis of variance test was used to determine whether values statistically differed between different-age groups of individuals with RTS being cared for. Sixty-three caregivers completed the survey. The average score of the Providing General Information subscale of the MPOC-20 was 3.18, lower than that seen in other studies. The average scores of the other subscales of the MPOC-20 ranged from 4.60 to 5.02, comparable to other studies of caregivers of children with other medical conditions. All aspects of FCC were ranked as important by caregivers. There were no differences in MPOC-20 values between those caring for the individuals with RTS in different-age groups reviewed. In the qualitative responses, parents noted that experiences with medical professionals would be improved if healthcare providers actively provided FCC, collaborated with parents and other providers, respected caregivers' time and breadth of knowledge and lived experience, gave a more balanced description of the condition, showed greater respect toward their loved ones and included them in the conversation, and made an effort to learn about RTS. The changes that parents would like to see in their child's care were not specific to one discipline and could be implemented by all healthcare specialists. While caregivers report that they receive moderate levels of FCC, they indicated that areas of FCC could be improved.

Congenital tibial pseudarthrosis is a rare condition seen in neurofibromatosis type 1 (NF1), and treatment is complex. A randomized, placebo-controlled trial of bone morphogenetic protein (rhBMP-2; INFUSE bone graft) at time of tibial surgery was developed by the Neurofibromatosis Clinical Trials Consortium. Patients were randomized to receive rhBMP-2 that would, or would not, be added to the standard surgical procedure consisting of resection of pseudarthrosis tissue, insertion of a rigid intramedullary rod, and placement of autogenous iliac crest bone graft. Despite involvement of 16 centers with wide experience with NF1 orthopaedic management, only 5 patients (of 54 required) were able to be enrolled in the study during a 3-year time period. Because of the inability to recruit sufficient patients, this study was closed in June 2019, with plans to terminate. The obstacles that were encountered during the study are summarized. The authors question whether a randomized, placebo-controlled trial of a rare pediatric orthopaedic condition is possible to accomplish. Recommendations are provided to guide future studies of orthopaedic manifestations of NF1.Level of Evidence: Level V.

Early‐phase clinical trials using oral inhibitors of MEK, the mitogen‐activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)‐associated tumors, particularly progressive low‐grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side‐effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. Implications for Practice Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low‐grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1‐related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects., As treatment for neurofibromatosis type 1 (NF1)‐associated complex and inoperable tumors, MEK inhibitor therapy is likely to become more widely used. To aid clinicians who may not have experience with the use of this class of agents, the Clinical Care Advisory Board of the Children's Tumor Foundation presents an overview of the use of MEK inhibitors in the NF1 population, covering relevant clinical trial results, common side effects, basic symptom management, recommended screening guidelines, and patient counseling approaches.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

Objective Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism‐based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test‐retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods Data were analyzed from the STARS clinical trial (n = 146), a multi‐center double‐blind placebo‐controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra‐class correlation coefficients were generated between pre‐ and post‐performances (16‐week interval) on neuropsychological endpoints in the placebo group to determine test‐retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results Test‐retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test‐retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test‐retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. ispartof: GENETICS IN MEDICINE vol:23 issue:8 pages:1506-1513 ispartof: location:United States status: published

¼: Early-onset scoliosis (EOS) or kyphosis is common in patients with neurofibromatosis (NF) and is characterized by rapid progression of deformity. ¼: Traditional growing rods provide good functional and deformity outcomes in patients with NF and EOS; magnetically controlled growing rods (MCGRs) also provide good deformity correction, although high rates of revision have been reported after their use. ¼: Among patients with NF type 1 (NF1), morphologic characteristics of the spinal deformity are different in those with paraspinal neurofibromas than in those without paraspinal tumors. ¼: Patients with NF1 are at low risk for developing malignant peripheral nerve sheath tumors during childhood (

PURPOSE Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. METHODS Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m2/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. RESULTS Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. CONCLUSION To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

BACKGROUND Plexiform neurofibromas (PNs) can cause significant morbidity. In this phase 2 study, we assessed imaging and functional outcomes to the MEK-inhibitor Binimetinib in pediatric patients with PNs. METHODS Children (age 1–17 years) with PN that were progressive or causing significant morbidity were eligible. Binimetinib is dosed twice-daily (starting dose of 32mg/m2) for maximum of 24 four-week courses. Participants with partial response (PR; >20% decrease in PN volume on central MRI review) at cycle 12 may stay on therapy. Participants undergo MRI and functional assessments at baseline and after courses 4, 8, 12, 18 and 24. Functional assessments are based on PN location. RESULTS Here we present 1-year response data. Twenty participants (55% male) with median age 12 years (range 2–16 years) enrolled; 19 are evaluable for response. Median baseline tumor volume was 326 ml (range, 8-6661 ml). Fourteen participants (74%) met criteria for PR, with 11 achieving PR by course 5. Median maximal PN volume reduction was 25.5% (range, 9–54%). As of August 2020, 14 participants received at least 12 cycles of Binimetinib; 10 remain on therapy. Off study reasons include treatment associated toxicities (n=2), subject withdrawal (n=2), non-compliance (n=2), prolonged treatment delay (n=1), and lack of response (n=3). Thirteen participants underwent dose reduction. Institution-reported related grade 3 toxicities included dry skin, weight gain, muscle weakness, rash, paronychia, cellulitis, diarrhea, gastric hemorrhage and CPK increase. CONCLUSIONS Binimetinib appears reasonably well-tolerated and shows promising activity in children with NF1-associated PNs. Outcomes on functional improvement will be reported at the meeting.

Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2). To study the role of Copb2 in neural development, we utilized genome editing technology to generate an allelic series in the mouse. Two independent null alleles revealed that Copb2 is essential for early stages of embryogenesis. Mice homozygous for the patient variant (Copb2R254C/R254C) appear to have a grossly normal phenotype, likely due to differences in corticogenesis between the two species. Strikingly, mice heterozygous for the patient mutation and a null allele (Copb2R254C/Znf) show a severe perinatal phenotype including low neonatal weight, significantly increased apoptosis in the brain, and death within the first week of life. Immunostaining of the Copb2R254C/Znf brain revealed a reduction in layer V (CTIP2+) neurons, while the overall cell density of the cortex is unchanged. Moreover, disruption of Copb2 in mouse neurospheres resulted in reduced proliferation. These results identify a general requirement for COPB2 in embryogenesis and a specific role in corticogenesis. We further demonstrate the utility of CRISPR-Cas9 generated mouse models in the study of potential pathogenicity of variants of potential clinical interest.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care. ispartof: GENETICS IN MEDICINE vol:21 issue:4 pages:867-876 ispartof: location:United States status: published

Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.

Tumor growths, migraine headaches, and other health-related complications reported in patients with neurofibromatosis type 1 (NF1) are often associated with pain. Thus, this study sought to describe and quantify the pain experience in children and young adults with NF1. Surveys were administered to 49 participants (28 children and 21 adults), ages 8 through 40 years. The survey included the Numeric Rating Scale 11 (NRS11) to assess pain intensity and the Patient Reported Outcomes Measurement Information System (PROMIS) to assess pain interference. A supplemental survey was created to measure pain frequency, chronicity, quality, and location. Results suggest pain is not only present in 55% of the cohort, but that it can begin at early ages. Pain was chronic in 35% of participants, with 41% reporting the use of medication to manage pain symptoms. Common sources of pain included migraine headaches and NF-related tumors. Pain was described as having neuropathic features (i.e., burning, tingling, numbness, or itching), and was localized to the head, back, and extremities. Further, subsets of participants reported moderate-to-severe pain intensity, high frequency of pain, and interference of pain in daily activities. Continued investigation of the pain experience in a multisystem disorder, such as NF1, remains essential to providing guidance in the setting of complex pain management.

A correction has been published to this Article. The PDF and HTML have been updated accordingly.

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia, and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies.

Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling.We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma.A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Background Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamcyin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity. Procedure We conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry. Results No subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus. Conclusions This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes. Pediatr Blood Cancer 2014;61:982–986. © 2013 Wiley Periodicals, Inc.

Objectives: Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity. Methods: The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process. Results: Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages $8 years. Conclusions: The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials. Neurology® 2013;81 (Suppl 1):S6–S14

STUDY DESIGN Retrospective chart and radiographical review. OBJECTIVE To present the demographics of patients with scoliosis and neurofibromatosis type 1 (NF-1), to record the incidence of dystrophic features, and to determine whether the presence of dystrophic features increase the risk of surgery in patients with NF-1 and associated spinal pathology. SUMMARY OF BACKGROUND DATA The most common of the osseous complications of NF-1 is spinal deformity, occurring in 10% to 30% of individuals with NF-1. Many of these patients will eventually require surgery for curve progression, which makes study of demographics and identification of features predicting the need for surgery essential in this patient population. METHODS A retrospective review was performed in patients with NF-1 and spinal deformities, followed in a multidisciplinary neurofibromatosis center. A subset of 56 patients with complete radiographical evaluation was reviewed for identification of risk factors for spine surgery. RESULTS One hundred thirty-one patients from a population of 694 patients with NF-1 (19%) had scoliosis. Mean age at diagnosis of scoliosis was 9 years (range; 1-17 yr). Scoliosis and need for surgery were equally distributed between males and females. In the group of 56 patients, 63% had 3 or more dystrophic features. The presence of 3 or more dystrophic features was the strongest predictor of the need for surgery (odds ratio = 14.34; P < 0.001). Individual features most predictive of need for surgery were the presence of vertebral scalloping (odds ratio = 13.19; P < 0.001) followed by the presence of dural ectasia (odds ratio = 6.38; P = 0.005). Patients with no dystrophic features were unlikely to progress to need for surgery. CONCLUSION Scoliosis and need for surgery were equally distributed between males and females. The presence of 3 or more dystrophic features was highly predictive of the need for surgery, with the most significant individual predictors being vertebral scalloping and dural ectasia. A combination of radiographical and MRI features can be used to predict need for spinal surgery. LEVEL OF EVIDENCE 3.

Background Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with various skeletal abnormalities occurring as part of a complex phenotype. Tibial dysplasia, which typically presents as anterolateral bowing of the leg with subsequent fracture and nonunion (pseudarthrosis), is a serious but infrequent osseous manifestation of NF1. Over the past several years, results from clinical and experimental studies have advanced our knowledge of the role of NF1 in bone. On the basis of current knowledge, we propose a number of concepts to consider as a theoretical approach to the optimal management of tibial pseudarthrosis. Methods A literature review for both clinical treatment and preclinical models for tibial dysplasia in NF1 was performed. Concepts were discussed and developed by experts who participated in the Children's Tumor Foundation sponsored International Bone Abnormalities Consortium meeting in 2011. Results Concepts for a theoretical approach to treating tibial pseudarthrosis include: bone fixation appropriate to achieve stability in any given case; debridement of the "fibrous pseudarthrosis tissue" between the bone segments associated with the pseudarthrosis; creating a healthy vascular bed for bone repair; promoting osteogenesis; controlling overactive bone resorption (catabolism); prevention of recurrence of the "fibrous pseudarthrosis tissue"; and achievement of long-term bone health to prevent recurrence. Conclusions Clinical trials are needed to assess effectiveness of the wide variation of surgical and pharmacologic approaches currently in practice for the treatment of tibial pseudarthrosis in NF1. Level of evidence Level V, expert opinion.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with osseous abnormalities occurring in up to one-third of patients. Several studies have documented osteopenia in both children and adults with NF1; however, the significance of lower bone mineral density (BMD) in relationship to fracture incidence is not well elucidated in NF1, particularly in children. We undertook a retrospective study to determine prevalence and location of fractures in children and adolescents with NF1, ages 5-20 years, using a standardized questionnaire. We surveyed 256 individuals with NF1 from two multidisciplinary NF centers and 178 controls without NF1 of similar ages and sex. Participants with known long bone dysplasia (LBD) were analyzed separately. Data collected included numbers and location of fractures, dietary calcium intake, and physical activity levels. There was no difference in prevalence of ever having a fracture between the NF1 group without LBD (22%) and the control group (25%); median number of fractures also did not differ. There were significant differences in fracture location with a higher frequency of fractures of the lower extremities in NF1 individuals without LBD compared to controls. Both NF1 cohorts had lower rates of physical activity than controls (P < 0.0001). Our data demonstrate that the likelihood of having had a fracture is not higher in young NF1 individuals without LBD in comparison to healthy controls. The lower physical activity level may have a "protective effect" for those with NF1, thus keeping their fracture incidence lower than expected for their relative degree of osteopenia.

Phenotypic variability among individuals with neurofibromatosis type 1 (NF1) has long been a challenge for clinicians and an enigma for researchers. Members of the same family and even identical twins with NF1 often demonstrate variable disease expression. Many mechanisms for this variability have been proposed. We have performed an exploratory study of copy number variants (CNVs) as a possible source of phenotypic variability in NF1. We enrolled 11 pairs of monozygotic (MZ) twins with NF1 and their parents, catalogued their clinical characteristics, and utilized a single nucleotide polymorphism (SNP) microarray to identify CNVs in blood and saliva. The 11 twin pairs showed high concordance for presence and number of cafe-au-lait spots, cutaneous neurofibromas, IQ, and ADHD. They were more likely to be discordant for optic pathway glioma, plexiform neurofibromas, skeletal manifestations, and malignancy. Microarray analysis identified a total of 81 CNVs meeting our conservative criteria, 37 of which overlap known genes. Of interest, three CNVs were previously unreported. Microarray analysis failed to ascertain any CNV differences within twin pairs, between twins and parents, or between tissues in any one individual. Results of this small pilot study did not demonstrate any de novo CNV events in our MZ twin pairs, nor were de novo CNVs overrepresented in these individuals with NF1. A much larger sample size would be needed to form any conclusions about the role of CNVs in NF1 variable expressivity. Alternative explanations for discordant phenotypes include epigenetic changes, smaller genetic alterations, or environmental factors. © 2016 Wiley Periodicals, Inc.

Neurofibromatosis 1 (NF-1) is a multisystemic, autosomal dominant genetic disorder. Skeletal complications usually present early in life and can be attributed to abnormalities of bone growth, remodeling, and repair, or can be secondary to nearby soft-tissue abnormalities complicating NF-1. Skeletal complications can be categorized as generalized or focal manifestations. The incidence of spinal deformities in association with NF-1 varies from 2% to 36%, with scoliosis being the most common. Both heritable and nonheritable factors contribute to the pathogenesis of spinal deformities in NF-1 patients. Traditionally, the spinal deformities are classified into dystrophic or nondystrophic. The pathophysiology of dystrophic curves is still uncertain, but may require a nonhereditary event, such as an adjacent tumor or a second hit event in local bone cells, leading to the underlying dysplasia. Dystrophic curves may result in scoliosis, kyphosis, or frequently, kyphoscoliosis. The goal of surgical management is to arrest the progression of deformity instead of achieving complete correction. The current state-of-the-art treatment for significant deformity is combined anterior and posterior spinal arthrodesis. Postoperative orthotic immobilization is almost always recommended in an effort to prevent pseudoarthrosis. The orthosis should be maintained until a fusion mass is obtained. Assessment of the fusion mass by computed tomography (CT) or magnetic resonance imaging (MRI) should be performed. Major complications, such as paraplegia, pseudoarthrosis, intraoperative hemorrhage, and postoperative progression of the deformity may occur. In an attempt to eliminate complications and achieve the best results, a multidisciplinary treatment strategy is needed. The intent of this article is to present the spinal deformities that are most commonly associated with NF-1, to identify the underlying biology of spinal deformities based on the most recent literature, and to address the common complications and pitfalls of their surgical management.

To characterize morbidity, mortality, and surgical outcomes in pediatric patients with symptomatic plexiform neurofibromas (PNFs).We conducted retrospective analysis of data from clinical records of surgical history and other neurofibromatosis type 1 (NF1)-related complications in children with PNFs seen at Cincinnati Children's Hospital Medical Center between 1997 and 2007.A total of 154 children with NF1 and PNFs were identified. Children with symptomatic PNFs had increased incidence of other NF1-related tumors (P.05). Patients with NF1 and PNFs had a higher mortality rate (5/154, 3.2%) when compared with patients without or with asymptomatic PNFs (2/366, 0.5%; P = .024). The most common morbidities leading to surgeries were neurologic, disfigurement, orthopedic, and airway complaints. Less extensive resection predicted a shorter interval to second surgery (P.0019). The highest recurrence was seen in tumors located in the head, neck, and thorax (P.001).These findings quantify the increased risk for additional tumors and mortality associated with symptomatic PNFs. Surgical interventions were required in many cases and resulted in added morbidity in some cases. Patients with PNFs were more likely to benefit from surgery when the indications were airway compression or disfigurement.

The neurofibromatoses (NF) encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect 100,000 Americans; over 2 million persons worldwide; and are caused by mutation of tumor suppressor genes. Individuals with NF1 in particular may develop tumors anywhere in the nervous system; additional manifestations can include learning disabilities, bone dysplasia, cardiovascular defects, unmanageable pain, and physical disfigurement. Ultimately, the NFs can cause blindness, deafness, severe morbidity, and increased mortality and NF1 includes a risk of malignant cancer. Today there is no treatment for the NFs (other than symptomatic); however, research efforts to understand these genetic conditions have made tremendous strides in the past few years. Progress is being made on all fronts, from discovery studies-understanding the molecular signaling deficits that cause the manifestations of NF-to the growth of preclinical drug screening initiatives and the emergence of a number of clinical trials. An important element in fuelling this progress is the sharing of knowledge, and to this end, for over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share ideas and build collaborations. The 2010 NF Conference held in Baltimore, MD June 5-8, 2010 hosted over 300 NF researchers and clinicians. This paper provides a synthesis of the highlights presented at the Conference and as such, is a "state-of-the-field" for NF research in 2010.

Plexiform neurofibromas (PNs) can cause significant disfigurement, compression of vital structures, neurologic dysfunction, and pain. MEK pathway inhibition results in significant PN shrinkage in neurofibromatosis type 1 (NF1) mouse models of PN. We evaluated the efficacy of the MEK inhibitor, PD0325901, in adolescents (≥ 16 years of age) and adults with symptomatic or growing NF1-PN in a phase II open label study. The primary aim was to assess tumor response by cycle 12 using centrally read MRI, defined as at least 20% decrease in tumor volume from baseline. Subjects received PD-0325901 by mouth twice daily at 2 mg/m2/dose (maximum dose 4 mg bid). Each course was 4 weeks, and subjects received drug on a 3 week on / 1 week off schedule. NF106 enrolled 19 subjects (7M;12F) in two stages with a median age of 24 years (range 16-39 years). The mean PN volume was 797.8 mL. Eight subjects (42.1%; 95% CI: 20%, 67%) had a response. PD0325901 was well tolerated, with the most common dose limiting toxicity being acneiform rash in 3/19 patients (16%). Five subjects (26.3%) developed Grade 3 toxicities, mostly pain (4/19; 21%). No subjects developed Grade 4 or higher toxicities. Five subjects (26.3%) had a dose reduction for toxicity: one for Grade 3 abdominal and back pain, the others for intolerable Grade 1-2 nausea, rash, or fatigue. This study demonstrated that PD0325901 is well tolerated and results in PN shrinkage in 42% of adolescent and adult subjects with NF1-PN. Supported by DOD Award W81XWH-12-1-0155.

The skeleton is frequently affected in individuals with neurofibromatosis type 1, and some of these bone manifestations can result in significant morbidity. The natural history and pathogenesis of the skeletal abnormalities of this disorder are poorly understood and consequently therapeutic options for these manifestations are currently limited. The Children's Tumor Foundation convened an International Neurofibromatosis Type 1 Bone Abnormalities Consortium to address future directions for clinical trials in skeletal abnormalities associated with this disorder. This report reviews the clinical skeletal manifestations and available preclinical mouse models and summarizes key issues that present barriers to optimal clinical management of skeletal abnormalities in neurofibromatosis type 1. These concepts should help advance optimal clinical management of the skeletal abnormalities in this disease and address major difficulties encountered for the design of clinical trials.

We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.6 Mb microduplication involving a portion of the minimal deletion critical region in a 15-year-old male with short stature, mild mental retardation, attention deficit hyperactivity disorder, Asperger syndrome, decreased joint mobility, digital abnormalities, and characteristic facial features. Some of these features are shared with a recently reported case with a 15q24 microduplication involving the minimal deletion critical region. We also report two siblings and their mother with duplication adjacent and distal to this region exhibiting mild developmental delay, hypotonia, tapering fingers, characteristic facial features, and prominent ears. The deletion and duplication breakpoints were mapped by array comparative genomic hybridization and the genomic structure in 15q24 was analyzed further. Surprisingly, in addition to the previously recognized three low-copy repeat clusters (BP1, BP2, and BP3), we identified two other paralogous low-copy repeat clusters that likely mediated the formation of alternative sized 15q24 genomic rearrangements via non-allelic homologous recombination.

Lower leg bowing with tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1). The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1.Peripheral quantitative computed tomography (pQCT) of the lower limb was performed (90 individuals with NF1 without tibial and/or fibular dysplasia: 474 healthy individuals without NF1). Subjects were 4-18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and gender).Using pQCT, NF1 individuals without bowing of the lower leg have smaller periosteal circumferences (p0.0001), smaller cortical area (p0.0001), and decreased tibial cortical and trabecular bone mineral content (BMC) (p0.0001) compared to controls.Individuals with NF1 have a different geometry of the lower leg compared to healthy controls suggesting that NF1 haploinsufficiency impacts bone homeostasis although not resulting in overt anterolateral bowing of the lower leg.

Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly/intellectual impairment syndrome. Loss of function in CREBBP or EP300 genes has been found in about 50% of patients with RTS. Genotype-phenotype correlations were investigated in 93 patients meeting diagnostic criteria for RTS during 2 international RTS family conferences. Mutation analysis of CREBBP was performed on all 31 coding exons and exon-intron junctions; a subset of patients had FISH analysis for large deletions. A total of 64 different variations were observed in the DNA sequence, and determined to be definitive mutations in 52 patients (56%). Mutations detected included: 10 missense mutations; 36 truncating or splice-site mutations; and 6 large deletions detectable by FISH. Fourteen patients had synonymous changes of unknown significance. The majority of mutations affected the HAT domain of CREBBP or predicted termination of the protein before the HAT region. Extensive phenotypic data were collected on each patient and analyzed to determine correlations with mutation types, that is, truncating, large deletions, single amino acid substitutions, or no CREBBP mutation. All four groups displayed the characteristic facial and thumb dysmorphology. Growth retardation in height and weight was seen more frequently in patients with no CREBBP mutation; seizure disorder was more frequent in those with CREBBP mutations. Degree of mental retardation was similar in all groups, although there was a trend toward lower IQ and autistic features in patients with large deletions. Similarity in phenotype between the groups implies that the several genes involved in causing RTS likely have effects through the same pathway.

Objective To compare parental adjustment, social support, and family functioning between families of children with neurofibromatosis 1 (NF1) and a group of demographically similar comparison families, and to examine the impact of disease severity. Methods Questionnaires were completed at home by parents of 54 children with NF1 (54 mothers and 42 fathers) and 51 comparison children (49 mothers and 32 fathers). Results Few differences between groups were identified for parental distress, social support, or family environment. Greater neurological impairment in children with NF1 was associated with greater distress, more family conflict, less positive mealtime interactions, and less social support from the perspectives of mothers. Conclusions Overall, parents of children with NF1 appear similar to parents of comparison children. Mothers who have children with NF1 characterized by greater neurological impairment may be at risk for more difficulties. Future work exploring long-term adjustment for these mothers as well as interventions to ameliorate any potential difficulties may be appropriate.

Neurofibromatosis type 1 is diagnosed clinically based on the presence of two of seven criteria developed by a panel of experts in 1987. The sixth criterion focuses on skeletal findings and is as follows: "A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis." The wording for this criterion is misleading. In particular, "thinning of long bone cortex" is not the characteristic radiographic presentation, and no mention of long bone bowing is included. The distinctive clinical feature of long bone dysplasia in neurofibromatosis type 1 is anterolateral bowing of the lower leg (portion of the body delimited by the knee and ankle). The usual radiographic findings of long bone dysplasia in neurofibromatosis type 1 at first presentation, prior to fracture, are anterolateral bowing with medullary canal narrowing and cortical thickening at the apex of the bowing. We suggest that anterolateral bowing of the lower leg, with or without fracture or pseudarthrosis, is a more appropriate description of the primary finding that a clinician will use to fulfill the sixth diagnostic criterion for neurofibromatosis type 1. Clarification of this diagnostic criterion is important for the clinician and for research protocols. Appropriate interpretation will improve understanding of the natural history and pathophysiology of neurofibromatosis type 1.

Neurofibromatosis is a multisystem disease that primarily affects cell growth of neural tissue. The intent of this article is to identify the spinal complications in skeletally immature patients that are most commonly associated with neurofibromatosis and to present strategies for management. The neurofibromatoses are a spectrum of multifaceted diseases involving not only neuroectoderm and mesoderm but also endoderm. These disorders present with a wide range of clinical manifestations that have in common the presence of schwannomas, neurofibromas, and/or cafe au lait spots. Clinically, this multisystemic, hereditary disease may manifest as abnormalities of the skin, nervous tissue, bones, and soft tissues. The primary pathology is believed to be a tumor-suppressor disorder. Previous reports have dealt primarily with specific entities, such as spinal deformity, paraplegia, hemihypertrophy with overgrowth phenomena of the extremities, soft-tissue tumors, neoplasia, and congenital tibial dysplasia and pseudarthrosis following extremity fractures. Scoliosis is the most common musculoskeletal complication of peripheral neurofibromatosis1,2. Most investigators now accept three clinical forms of neurofibromatosis: peripheral or type-1 neurofibromatosis (NF1), central or type-2 neurofibromatosis (NF2), and segmental neurofibromatosis (a mosaic form of NF1)1. A recently described fourth form, schwannomatosis, consists of multiple deep, painful schwannomas and is thought to represent a mosaic form of NF23. A variety of eponyms have been used in the past to describe all forms, although subsequent information has made these names technically inaccurate or incomplete. The most common type (NF1) was previously known as von Recklinghausen disease and is an autosomal dominant disorder that affects approximately one in 4000 persons; multiple hyperpigmented areas ( cafe au lait macules) and neurofibromas are characteristic. In their statement on neur ofibromatosis, the 1987 Consensus Development Conference of the National Institutes of Health concluded that the diagnosis of von Recklinghausen disease or NF1 can be considered …

A new case of 11q interstitial duplication is reported in a patient with mild dysmorphic features but normal development. Chromosome analysis revealed a de novo 11q dup(11)(q14.1q21) on G banding and FISH studies. Additional molecular genetic studies revealed a similar but more distal duplication at the level of 11q21q23.1. Previous cases of isolated 11q duplication that overlapped with this case were associated with a wide variety of clinical findings and variable developmental disability. These cases all included additional material not duplicated in this patient. The current case represents the first de novo case of 11q duplication with normal development suggesting that the segment between 11q14.1 and 11q21 contains few genes that are dose sensitive. Review of other cases that have used conventional cytogenetic resolution studies suggests that the band 11q13.5 may contain genes contributing to the developmental disabilities in the cases previously reported with proximal 11q duplication. Differences between conventional cytogenetic techniques and newer molecular genetic studies are expected. These newer techniques will help refine prognosis and counseling for families in the future.

Parents who decide to continue a pregnancy diagnosed with a sex chromosome abnormality (SCA) experience a variety of emotions as they deal with complex medical and genetic information. To better understand these individuals' psychosocial, educational, and support needs, 26 parents who received prenatal diagnosis of an SCA after 1989 and who had decided to continue their pregnancy were interviewed by telephone. Twenty (77%) reported they initially had a “poor” understanding of the predicted syndrome. All parents later met with a genetics professional. Twenty-two (92%) parents considered sterility and underdevelopment of secondary sexual characteristics to be the most negative aspects of SCAs. Contact with other parents of children with SCAs and with support organizations were generally viewed as helpful experiences. Insight gained from this study should be useful for genetic counselors and other health care providers involved with patients who have received abnormal prenatal diagnosis results.

Background There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES. Objective We demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered. Moreover, we examined the potential cost-effectiveness of WES by examining the cost burden of diagnostic workups. Methods To determine the clinical utility of our hospital’s clinical WES, we performed a retrospective review of the first 40 cases. We utilized dual bioinformatics analyses pipelines based on commercially available software and in-house tools. Results Of the first 40 clinical cases, we identified genetic defects in 12 (30%) patients, of which 47% of the mutations were previously unreported in the literature. Among the 12 patients with positive findings, seven have autosomal dominant disease and five have autosomal recessive disease. Ninety percent of the cohort opted to receive secondary findings and of those, secondary medical actionable results were returned in three cases. Among these positive cases, there are a number of novel mutations that are being reported here. The diagnostic workup included a significant number of genetic tests with microarray and single-gene sequencing being the most popular tests. Significantly, genetic diagnosis from WES led to altered patient medical management in positive cases. Conclusion We demonstrate the clinical utility of WES by establishing the clinical diagnostic rate and its impact on medical management in a large pediatric center. The cost-effectiveness of WES was demonstrated by ending the diagnostic odyssey in positive cases. Also, in some cases it may be most cost-effective to directly perform WES. WES provides a unique glimpse into the complexity of genetic disorders.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P, We thank the patients, their family and their referral physicians for the information. We thank the genetics counselor students who helped to re-contact all referral physicians for confirming information. This work was supported though the Children's Tumor Foundation by the Isaac and Sadie Fuchs Genotype-Phenotype Study (to L.M.) and by internal funds from the Medical Genomics Laboratory at UAB.

To evaluate the utility of screening brain/orbital magnetic resonance imaging (MRI) in a large population of children with neurofibromatosis type 1 (NF1) over a 20-year period.A retrospective analysis of clinical and imaging data from children with NF1 seen at a single center between 1990 and 2010 was performed.During the 20-year study period, 826 individuals with NF1 (402 females, 424 males) ages 1-9 years were screened for optic pathway gliomas (OPGs) using brain/orbital MRI; 18% were identified with OPGs with a median age at detection of 3 years. Fifteen percent of patients with OPGs had radiologic or clinical progression requiring therapy. Children with chiasmatic and postchiasmatic tumors were more likely to require therapy compared with patients with prechiasmatic OPGs (P.0001). Patients with visual deficits at the time of diagnosis were more likely to experience visual decline despite therapy when compared with patients treated based on radiologic progression (P.012).Our findings confirm that chiasmatic and postchiasmatic OPG in children with NF1 have the highest risk for progression and vision loss. Early identification of OPG by screening MRI prior to the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs.

Application of gene expression profiling to human diseases will be limited by availability of tissue samples. It was postulated that germline genetic defects affect blood cells to produce unique expression patterns. This hypothesis was addressed by using a test neurological disease-neurofibromatosis type 1 (NF1), an autosomal dominant genetic disease caused by mutations of the NF1 gene at chromosome 17q11.2. Oligonucleotide arrays were used to survey the blood gene expression pattern of 12 NF1 patients compared to 96 controls. A group of genes related to tissue remodeling, bone development and tumor suppression were down-regulated in NF1 blood samples. In addition, there were blood genomic patterns for gender and age: Y chromosome genes showing higher expression in males, indicating a gene-dosage effect; and genes related to lymphocyte functions showing higher expression in children. The results suggest that genetic mutations can be manifested at the transcriptional level in peripheral blood cells and blood gene expression profiling may be useful for studying phenotypic differences of human genetic diseases and possibly providing diagnostic and prognostic markers.

Blood gene expression profiling has been applied to a variety of hematological malignancies, autoimmune disorders, and infectious diseases. This study applies this approach to genetic diseases without obvious blood phenotypes. Three genetic diseases including tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome were compared with a group of healthy controls. RNA from whole blood was surveyed using Affymetrix U133A arrays. Each disease was associated with a unique gene expression pattern in blood that can be accurately distinguished by a classifier. Genes on chromosome 21 were overexpressed in Down's syndrome, and genes controlling cell cycle and proliferation were associated with tuberous sclerosis complex type 2 or neurofibromatosis type 1. A subset of genes involved in cardiac development or remodeling were overexpressed in patients with Down's syndrome and congenital heart defects. These findings suggest that blood gene expression profiling on a broader basis might be useful for genetic disease screening/diagnosis and might help elucidate mechanisms and pathways that lead to genotype-phenotype differences.

The 18q- syndrome is relatively common among cytogenetic abnormalities occurring in approximately 1 in 40,000 live births. However, interstitial deletions involving 18q12.2 to q21.1 are much less common. Only 15 cases have been reported in the literature. A phenotypic pattern is emerging of mild dysmorphic features, mental retardation, behavior abnormalities, and the lack of serious malformations. We present a 67-year-old woman with minor dysmorphic features, moderate mental retardation, hyperphagia, and del(18)(q12.2q21.1). This patient is presented for the natural history of this deletion syndrome as well as the behavioral phenotype.