Patient-reported measures of tinnitus for individuals with neurofibromatosis type 2-related schwannomatosis: Recommendations for clinical trials.

BACKGROUND: Neurofibromatosis type 2-related schwannomatosis is a genetic disease characterized by the development of bilateral vestibular schwannomas, ependymomas, meningiomas, and cataracts. Mild to profound hearing loss and tinnitus are common symptoms reported by individuals with neurofibromatosis type 2. While tinnitus is known to have a significant and negative impact on the quality of life of individuals from the general population, the impact on individuals with neurofibromatosis type 2 is unknown. Consensus regarding the selection of suitable patient-reported outcome measures for assessment could advance further research into tinnitus in neurofibromatosis type 2 patients. The purpose of this work is to achieve a consensus recommendation by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration for patient-reported outcome measures used to evaluate quality of life in the domain of tinnitus for neurofibromatosis type 2 clinical trials. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis Patient-Reported Outcomes Communication Subgroup systematically evaluated patient-reported outcome measures of quality of life in the domain of tinnitus for individuals with neurofibromatosis type 2 using previously published Response Evaluation in Neurofibromatosis and Schwannomatosis rating procedures. Of the 19 identified patient-reported outcome measures, 3 measures were excluded because they were not validated as an outcome measure or could not have been used as a single outcome measure for a clinical trial. Sixteen published patient-reported outcome measures for the domain of tinnitus were scored and compared on their participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials. RESULTS: The Tinnitus Functional Index was identified as the most highly rated measure for the assessment of tinnitus in populations with neurofibromatosis type 2, due to strengths in the areas of item content, psychometric properties, feasibility, and available scores. DISCUSSION: Response Evaluation in Neurofibromatosis and Schwannomatosis currently recommends the Tinnitus Functional Index for the assessment of tinnitus in neurofibromatosis type 2 clinical trials.

Concurrent spinal meningioma and giant invasive schwannoma without neurofibromatosis in children: A case report and literature review.

BACKGROUND: Spinal meningiomas coexisting with schwannomas in patients without neurofibromatosis are extremely rare lesions. There were only 15 cases reported to date, which were concurrent intradural tumors of different pathological types. CASE PRESENTATION: Herein, we present a rare case of a 15-year-old child with concurrent spinal dorsal meningioma and ventral giant invasive schwannoma at C7-T3 and T10-S5 spinal levels. Preoperative magnetic resonance imaging and computed tomography indicated the schwannoma across the thoracic and lumbosacral transitional vertebra, with extensive bony erosion of the sacrum. The results of surgical resection were mostly satisfactory. CONCLUSIONS: The present case is the youngest patient diagnosed with concurrent intradural tumors at different spinal levels. The pathogenetic mechanism remains unclear. The clinical presentations are always atypical. Surgical resection of the tumors is the first choice. We use the non-fusion surgery to preserve the function of the lumbar spine.

Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.

A simplified technique for correction of complete ptosis secondary to palpebral neurofibromatosis.

PURPOSE: To present a simplified technique in management of complete ptosis secondary to neurofibromatosis. METHODS: This prospective, non-comparative, clinical interventional study included 13 patients with complete ptosis secondary to histologically proved plexiform neurofibromas. It was conducted at the Orbital Unit of Assiut University Hospital, the referral center of Upper Egypt in the period between June 2013 and October 2021. In all cases, a simplified technique of 5 surgical steps was applied: (A) Division of the involved eyelid surgically into three parts by drawing 2 curvilinear lines, the superior line 11 mm below and parallel to the lower eyebrow hairline and the inferior one 10 mm above the lid margin, (B) Resection (full-thickness) of the large middle part which involves the main pathology and lies between the 2 lines, (C) Preservation of the upper part with identification, dissection and clamping of the levator muscle, (D) Refinement of the lower part by removal of any tissue between the skin and the debulked tarsus and (E) Re-suturing of the upper and lower parts in layers; conjunctiva to conjunctiva, levator to tarsus (after resection of a part that corrects the ptosis) and skin to skin. RESULTS: Ptosis was completely corrected in 8 cases (61.5%) and residual mild ptosis occurred in 5 patients (38.5%). No exposure keratopathy or tumor growth was reported during the follow-up period of minimum 1 year. CONCLUSIONS: This simplified technique could be considered as a surgical basis for correction of complete ptosis in neurofibromatosis.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Neurofibroma: Case Series with Clinical Features and Recommendations.

Neurofibroma is an autosomal benign disorder. It can be localized, diffuse or invasive like plexiform neurofibroma that involves the nerves, muscle, tissues, skeleton. It represents itself as a destructive variant of neurofibroma, mostly present as orbital or periorbital neurofibroma or may be associated with autosomal dominant disease. Clinical diagnosis of neurofibromatosis (NF) according to National Institutes of Health (NIH) criteria should have more than two of the seven features including lisch nodules, cafe'- au-lait spots, plexiform neurofibroma, optic glioma, freckling, first degree relative with NF or dysplasia of cortical bones. However, proper early diagnosis is still crucial due to its various presentation such as cheek mass, painless swelling on skin, chalazion, intratracheal tumor, genital swelling or ptosis. It is reported that neurofibroma often represents as ocular or facial swelling. Here we are presenting features of neurofibroma of eight cases of patients from Civil Hospital, Karachi. These cases had main complain of overhanging skin mass mainly on orbital or periorbital region that damage the area and with poor daily activities. Multiple nodules on face and body along with them Cafe'-au-lait spots and lisch nodules were main signs. While, other signs i.e. ptosis, pterygium, telecanthus and muddy discoloration of conjunctiva need further evaluation for correlation with neurofibromatosis. Debulking surgery was planned for most of the cases but the huge disfigurement caused by overhanging skin mass and nodules made it a challenge for plastic surgeons to provide good outcomes with minimum damage. Keywords: neurofibroma; lisch nodules; ptosis; Cafe'-au-lait spot; periorbital; overhanging skin.

A case report of giant malignant schwannoma of the sciatic nerve associated with neurofibromatosis-1: A CARE-compliant article.

RATIONALE: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous syndrome that causes multiple central and peripheral nerve sheath tumors. People with NF1 have a 10% chance of developing malignant peripheral nerve sheath tumors (MPNSTs). Here we report a unique instance of a malignant schwannoma that has remained free of metastasis since its initial removal a decade ago. The malign schwannoma has been infrequently documented in the literature, and remarkably, no instances of such an extensive postoperative time without metastases have ever been described. PATIENT CONCERNS: A 46-year-old male patient with NF had multiple neurofibromas in different parts of his body, underwent surgery about 10 years ago (2013), and was diagnosed histopathologically as MPNST. DIAGNOSES: He was admitted to our institution with a recurrent mass in the posterior third of the proximal thigh and severe pain radiating to the left lower extremity, which presented as sciatic pain (2021). A magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography examination revealed that the tumor was likely malignant. INTERVENTIONS: Surgical excision was performed. OUTCOME: A 10-year follow-up revealed no metastases or neurologic impairment. LESSONS: When articles about benign schwannomas are placed in a separate category, little is written about NF-1-related malignant schwannomas of the sciatic nerve. MPNSTs are high-grade, aggressive sarcomas with a high risk of local recurrence (40%-65%) and metastasis to other body parts. Therefore, among the various benign peripheral nerve sheath tumors in NF-1 patients, the diagnosis of MPNST is crucial.Orthopedic surgeons should be aware that neurofibromas in NF-1 have a significant risk of developing MPNSTs. This study reports the successful treatment of a giant malignant sciatic nerve schwannoma with a long follow-up period without metastasis.

Management of Central and Peripheral Nervous System Tumors in Patients with Neurofibromatosis.

Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.

Neurofibromatosis Type I Presenting with Incomplete Ileal Volvulus in a Pediatric Patient.

BACKGROUND Neurofibromatosis 1 is a neurocutaneous disorder with multisystemic manifestations. When patients are lacking overt cutaneous manifestations, diagnosis may be delayed and may complicate diagnosis and management of atypical presentations of this disease. It is thus important to strive to obtain relevant and/or complete history to arrive at the appropriate diagnosis. Furthermore, maintaining an index of suspicion in cases of vague abdominal pain may guide the clinician in establishing the correct diagnosis of mesenteric plexiform neurofibroma in the setting of known/presumed neurofibromatosis 1 patients presenting with acute and/or chronic vague abdominal symptoms. CASE REPORT This is a case of a teenage boy who presented with acute, vague abdominal pain over a period of 2 weeks. Laboratory tests and physical exam findings in primary and secondary care settings were unremarkable, and thus the patient was discharged home only to continue with abdominal pain, thus seeking additional medical care. After admission to our facility and exhaustive history taking, physical examination, and imaging, a prospective diagnosis of neurofibromatosis with mesenteric neurofibroma was made. Upon surgical exploration, a mesenteric mass with corresponding volvulized, ischemic small bowel was removed. Histopathology confirmed a plexiform neurofibroma. The patient recovered adequately and was discharged home without complications. CONCLUSIONS This case highlights the importance of exhaustive history taking to obtain an accurate diagnosis as well as the importance of a high index of clinical suspicion for mesenteric neurofibromatosis in patients with presumed or known neurofibromatosis and presenting with vague abdominal symptoms.

Approaches to Incidental Intradural Tumors of the Spine in the Pediatric Population.

BACKGROUND: Incidental intradural tumors of the spine in the pediatric population are rare lesions whose management remains unclear. Surgeons must balance the risks of iatrogenic deficits and complications after surgical resection against the risks from progressive growth of the tumor. Moreover, the natural history of an incidental finding can be difficult to predict. Here, we review the literature on incidental intradural tumors of the spine and present considerations for their management. SUMMARY: Growth of the tumor or changes in radiographic features are usually indications for resection. Asymptomatic lesions can be found in patients with genetic syndromes that predispose to tumor formation, such as neurofibromatosis type 1 and 2, schwannomatosis, and Von-Hippel-Lindau syndrome, and careful workup of a genetic cause is warranted in any patient presenting with multiple tumors and/or cutaneous features. Close follow-up is generally favored given the heavy tumor burden; however, some recommend pre-emptive resection to prevent permanent neurological deficits. Incidental intradural tumors can also occur in association with hydrocephalus, significant syringomyelia, and cord compression, and surgical treatment is usually warranted. Tumors may also be discovered as part of the workup for scoliosis, where they are not truly incidental to the scoliosis but rather are contributing to curve deformation. KEY MESSAGES: Thorough workup of patients for associated genetic syndromes or comorbidities should be undertaken in pediatric patients with incidental intradural tumors. Further research is needed into the natural history of these incidental lesions. Incidental tumors can often be managed conservatively with close follow-up, with surgical intervention warranted for expanding tumors or new-onset symptoms.

Treatment of L5-S1 spondyloptosis with stand-alone anterior lumbar interbody fusion in a patient with neurofibromatosis.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a multisystem disorder that causes multiple tumor formations throughout the nervous system. Common spinal dysplasias seen with NF1, such as dural ectasia (DE), often undergo modulation and predispose these patients to spondylolisthesis, making surgical treatment challenging. CASE DESCRIPTION: A patient with NF1 presented with a 12-year-history of back and left lower extremity radicular pain. Lumbar spine magnetic resonance imaging revealed developmental anomalies with severe DE and associated scalloping of the L4-S1 vertebral bodies and severe L5-S1 Meyerding grade 4 spondylolisthesis. During surgery, post-positioning x-rays demonstrated a grade 5 spondyloptosis. The patient underwent an L5-S1 stand-alone anterior lumbar interbody fusion (ALIF). The final construct was an ALIF cage with one screw into S1, without an anterior plate. By 3-months post-operative, there was complete resolution of preoperative symptoms and at 2 year follow-up the patient was asymptomatic with stable hardware and solid bony fusion. To the authors' knowledge, this is the first report of spondyloptosis treated with a stand-alone ALIF in a patient with NF1 and severe DE.

COVID-19 in people with neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis.

PURPOSE: People with pre-existing conditions may be more susceptible to severe COVID-19 when infected by SARS-CoV-2. The relative risk and severity of SARS-CoV-2 infection in people with rare diseases such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown. METHODS: We investigated the proportions of people with NF1, NF2, or SWN in the National COVID Cohort Collaborative (N3C) electronic health record data set who had a positive test result for SARS-CoV-2 or COVID-19. RESULTS: The cohort sizes in N3C were 2501 (NF1), 665 (NF2), and 762 (SWN). We compared these with N3C cohorts of patients with other rare diseases (98-9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who had a positive test result for SARS-CoV-2 or COVID-19 (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population. CONCLUSION: Having NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a patient with COVID-19 or of developing severe complications from SARS-CoV-2.

A Review of Spinal Lesions in Neurofibromatosis Type 1 in a Large Neurofibromatosis Type 1 Center.

BACKGROUND: Spinal lesions are a known manifestation of neurofibromatosis type 1 (NF1). The aim of this retrospective review was to analyze and report the prevalence of spinal lesions on imaging in a large NF1 center. METHODS: The data were collected from a period of 62 months from a cohort of 514 patients. Data were collected from multidisciplinary team meeting reports that included radiologic reports of each patient investigating 20 distinct variables. The prevalence of each of these lesions was calculated, and any statistically significant associations were investigated using the χ2 test. RESULTS: Four-hundred forty-seven patients had classic NF1, and 67 patients had spinal NF1. Many of the patients had spinal abnormalities; 25.7% of these patients were found to have dural ectasia, whereas 44.9% of patients had a spinal deformity. A statistically significant association between dural ectasia and spinal neurofibromatosis was established (P < 0.05). An additional statically significant association was established between dural ectasia and spinal deformity (P < 0.00001). The patients with spinal nerve root tumors were identified, and it was found that 49.8% of patients possessed these tumors, whereas 56.3% of these tumors were intraspinal tumors. The most common region affected was the cervical spine, and the most common spinal level was C2. CONCLUSIONS: This high prevalence of spinal tumours in mobile areas of the spine is possibly the result of a combination of genetic predisposition and repeated microtraumas resulting in tumor formation. This is the largest reported study of spinal lesions in NF1 based on imaging and offers insights into the etiology and relationships between lesions.

Intraoral neurofibroma: A case report with emphasis on immunohistochemical markers.

ABSTRACT: A neurofibroma is a benign peripheral nerve sheath tumor. They occur in combination with neurofibromatosis or as a solitary mass. Intraoral neurofibromas pose diagnostic difficulties, suggesting the appropriate use of diagnostic markers and clinical knowledge. Here, we report a case of intraoral neurofibroma in a 57-year-old female who reported with the complaint of painless growth in the lower left back tooth region for the past three years. Based on the clinical features, provisional diagnosis of traumatic fibroma was made. However, histopathology proved it to be a benign spindle cell lesion; upon further investigation by immunohistochemistry, it was diagnosed to be a case of neurofibroma.

Large, linear pigmentation anomaly: an unusual dyspigmentation case.

Segmental pigmentation anomalies can be further divided into segmental pigmentation disorder (SPD) complex and café-au-lait macules (CALMs). Both are congenital skin conditions characterized by hyper- or hypopigmentation. Segmental pigmentation disorder is a rare entity, whereas CALMs are common skin lesions that may be associated with various genetic conditions, especially when several are present and the patient has other indicators of a genetic abnormality. When the CALM is segmental, segmental neurofibromatosis (type V) may be considered in the differential diagnosis. Herein we present a 48-year-old woman with a history of malignant melanoma who presented with a large, linear, hyperpigmented patch on her shoulder and arm, present since around birth. The differential diagnosis consisted of CALM versus hypermelanosis (a subtype of SPD). Given a family history of a similar lesion, in addition to a personal and family history of melanoma and internal cancers, a hereditary cancer panel was completed demonstrating genetic variance of uncertain significance. This case brings attention to a rare dyspigmentation disorder and questions a possible association with melanoma.

Depression explains the association between pain intensity and pain interference among adults with neurofibromatosis.

INTRODUCTION: Neurofibromatoses (NFs; NF1, NF2 and Schwannomatosis) are incurable genetic syndromes characterized by nerve sheath tumors and often accompanied by substantial emotional distress (e.g., depression and anxiety). Pain is also common but understudied in adults with NF and interferes with daily living. In other medical populations, depression and anxiety have a strong association with pain interference. However, research has not explored the relationship of depression and anxiety to pain interference among adults with NF experiencing pain. The aim of this study was to test the hypothesis that depression and anxiety will mediate the association between pain intensity and pain interference among geographically diverse adults with NF who endorse pain. METHODS: We used baseline data from an RCT of a mind-body intervention aimed at improving quality of life in adults with NF. Participants (N = 214) who endorsed pain completed measures of demographics, clinical characteristics, baseline pain intensity, pain interference, depression, and anxiety. We constructed a multiple mediation model in R using the lavaan package to test our hypothesis. RESULTS: Preliminary analyses showed differences in pain interference by NF diagnostic subtype (F(2, 206) = 6.82, p = 001). In a model that controlled for NF diagnostic subtype, we found that depression (ß = .07, p = .017), but not anxiety (ß = -.003, p = .878), partially mediated the association between pain intensity and pain interference. CONCLUSION: Improving depression has the potential to decrease pain interference among people with NF who experience pain. TRIAL REGISTRATION: Clinicaltrials.gov Registration #: NCT03406208.

Recommendations for Social Skills End Points for Clinical Trials in Neurofibromatosis Type 1.

OBJECTIVE: To review parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6-18 years) with neurofibromatosis type 1 (NF1). METHODS: Searches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials. RESULTS: Two measures were ultimately recommended by the committee: the Social Responsiveness Scale-2 (SRS-2) and the Social Skills Improvement System-Rating Scale (SSIS-RS). CONCLUSIONS: Each of the 2 measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning; the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

Recommendations for Measurement of Attention Outcomes in Preschoolers With Neurofibromatosis.

Children with neurofibromatosis type 1 (NF1) are at increased risk for attention problems. While most research has been conducted with school-aged cohorts, preschool-aged children offer a novel developmental window for clinical studies, with the promise that treatments implemented earlier in the developmental trajectory may most effectively modify risk for later difficulties. Designing research studies around the youngest children with NF1 can result in intervention earlier in the developmental cascade associated with NF1 gene abnormalities. Furthermore, clinical trials for medications targeting physical and psychological aspects of NF1 often include individuals spanning a wide age range, including preschool-aged children. In a prior report, the REiNS Neurocognitive Subcommittee made recommendations regarding performance-based and observer-rated measures of attention for use in clinical trials and highlighted the need for separate consideration of assessment methods for young children. The observer-rated Attention-Deficit/Hyperactivity Disorder Rating Scale-Preschool version is recommended as a primary outcome measure. The NIH Toolbox Flanker, Dimensional Change Card Sort, and List Sort Working Memory tasks and Digits Forward from the Differential Ability Scales-2nd Edition (performance-based measures) are recommended as secondary outcome measures. Specific methodologic recommendations for inclusion of preschoolers in clinical trials research are also offered.