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Numerous genetic testing options for individuals with epilepsy have emerged over the past decade without clear guidelines regarding optimal testing strategies. We performed a systematic evidence review (SER) and conducted meta-analyses of the diagnostic yield of genetic tests commonly utilized for patients with epilepsy. We also assessed nonyield outcomes (NYOs) such as changes in treatment and/or management, prognostic information, recurrence risk determination, and genetic counseling.We performed an SER, in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), using PubMed, Embase, CINAHL, and Cochrane Central through December of 2020. We included studies that utilized genome sequencing (GS), exome sequencing (ES), multigene panel (MGP), and/or genome-wide comparative genomic hybridization/chromosomal microarray (CGH/CMA) in cohorts (n ≥ 10) ascertained for epilepsy. Quality assessment was undertaken using ROBINS-I (Risk of Bias in Non-Randomized Studies of Interventions). We estimated diagnostic yields and 95% confidence intervals with random effects meta-analyses and narratively synthesized NYOs.From 5985 nonduplicated articles published through 2020, 154 met inclusion criteria and were included in meta-analyses of diagnostic yield; 43 of those were included in the NYO synthesis. The overall diagnostic yield across all test modalities was 17%, with the highest yield for GS (48%), followed by ES (24%), MGP (19%), and CGH/CMA (9%). The only phenotypic factors that were significantly associated with increased yield were (1) the presence of developmental and epileptic encephalopathy and/or (2) the presence of neurodevelopmental comorbidities. Studies reporting NYOs addressed clinical and personal utility of testing.This comprehensive SER, focused specifically on the literature regarding patients with epilepsy, provides a comparative assessment of the yield of clinically available tests, which will help shape clinician decision-making and policy regarding insurance coverage for genetic testing. We highlight the need for prospective assessment of the clinical and personal utility of genetic testing for patients with epilepsy and for standardization in reporting patient characteristics.

The COVID‐19 pandemic has ravaged the globe in the past year, demanding shifts in all aspects of life including health profession education. The New York City area was the first major United States epicenter and is home to four genetic counseling graduate programs. We set out to explore the multifaceted programmatic changes required from the four institutions in an early pandemic epicenter, providing the longest time horizon available for assessing the implications of this restructuring on graduate education in the profession. Using practitioner‐based enquiry, our iterative reflections identified three phases of COVID‐19 response within our programs from March through December 2020. The spring months were marked by significant upheaval and reactivity, with a focus on stabilizing our programs in an unstable environment that included a significant medical response required in our area. By summer, we were reinvesting time and energy into our programs and prioritizing best practices in online learning. Relative predictability returned in the fall with noticeable improvements in flexibility and proactive problem‐solving within our new environment. We have begun to identify changes in both curricula and operations that are likely to become more permanent. Telehealth fieldwork, remote supervision, simulated cases with standardized clients, and virtual recruitment and admission events are some key examples. We explored early outcome measures, such as enrollment, retention, course evaluations, and student academic and fieldwork progress, all indicating little change from prior to the pandemic to date. Overall, we found our programs, and genetic counseling graduate education more broadly, to be much more resilient and flexible than we would ever have realized. The COVID‐19 pandemic has awakened in us a desire to move ahead with reduced barriers to educational innovation.

The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including NF1, NF2, and schwannomatosis. This resource represents the opinions of a multi-center working group of Certified Genetic Counselors with experience in the care of individuals with NF, providing topics to be considered for the incorporation into a clinical genetic counseling session.

Graduation from a genetic counseling graduate program accredited by the Accreditation Council of Genetic Counseling and certification obtained by passing the American Board of Genetic Counseling (ABGC) certification examination are increasingly required to practice as a genetic counselor in the USA. Despite the ABGC certification examination serving as a gateway to the genetic counseling career, there have been no research studies to date that have examined what variables are associated with examination performance. Therefore, the Association of Genetic Counseling Program Directors established a Task Force to assess whether trainee demographics, Grade point average (GPA) and Graduate Record Exam (GRE®) percentile scores are associated with passing the ABGC certification examination on the first attempt. We surveyed accredited genetic counseling graduate programs in North America and gathered demographic data, admissions variables, and certification examination outcome data for 1,494 trainees from 24 training programs, representing approximately 60.5% of matriculants between 2007 and 2016. Univariable analysis was performed to assess associations between admissions variables and categorical outcome (pass vs. fail) on the certification examination using Wilcoxon rank-sum or Fisher's exact test. Variables significantly associated with the categorical board outcome were then entered in a stepwise model selection procedure. In stepwise logistic regression, trainees with higher GPA (OR = 3.41; 95% CI = 1.99, 5.83), higher verbal (OR = 1.02; 95% CI = 1.01, 1.03) and quantitative (OR = 1.02; 95% CI = 1.01, 1.03) GRE® scores, female trainees (OR = 2.95; 95% CI = 1.70, 5.12), and White trainees (OR 3.37; 95% CI = 2.14, 5.30) had higher odds of passing the certification examination on the first attempt. As programs move to a holistic approach to graduate admissions in order to improve access to the genetic counseling profession, our results may influence programs to provide additional preparation for the certification examination for all trainees. In addition, genetic counseling professional organizations should continue to work together to assess and eliminate outcome disparities in admissions, training, and certification processes.

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

Genetic counselors working in a clinical setting may find themselves recruiting, enrolling, and returning results for genomic research, and existing clinical relationships with study participants may impact these research interactions. We present a qualitative study using semi-structured interviews of participants enrolled in a genome sequencing/exome sequencing (GS/ES) study at the same institution where they receive clinical care. Interviews were coded for motivations to participate and expectations of this research. The interviews revealed common motivations for participation, including altruism and hope for benefit for themselves, family members, and/or others with their condition. Additionally, themes emerged related to unintentional influence based on trust of the clinical provider that recruited them to the study. Participant trust in the enrolling provider at times appeared to extend to the study team to decide which research results to return and to do so in an appropriate format. Participants also based expectations for research results return on previous clinical genetic testing experiences, which may or may not be realistic depending on study design. It is imperative that genetic counselors enrolling patients into research studies be aware of the potential influence of their clinical relationship on potential subjects, be transparent about their role on the study team, and help set expectations about the study process, including results return.

Through self-reflection, self-education, and with a learning mindset each of us has embarked on a personal path to understand the impact of racism in our personal and professional lives. This personal work is ongoing, though it was through our individual paths that led us to engage in dialogue on race and racism at the 38th National Society of Genetic Counselors Annual Conference. We initially did not know each other; however, we were drawn by a mutual desire to further the conversation and sought connection with each other after the Conversations Around Diversity Platform Presentations. Through sustained, open dialogue we created a brave space for sharing our emotional and intellectual responses to the conference. Through this dialogue and through written reflections, we recognized an emboldened urgency to author a joint reflection on our shared responsibility as genetic counseling training program leaders to use our privilege in service to our students and future students. We have the evidence that we are not a diverse profession. We have more evidence now than we did before that our profession performs poorly with regards to inclusivity. Our inability to acknowledge, address, and discuss racism and other forms of oppression is damaging to each of us individually and as a group of professionals. We owe it to ourselves, our students, our patients, and colleagues to name our learned biases and behaviors, own them and interrupt them.

Although consensus is building that primary (PR) and secondary findings (SF) from genomic research should be offered to participants under some circumstances, data describing (1) actual choices of study participants and (2) factors associated with these choices are limited, hampering study planning. We conducted a cross-sectional analysis of choices made for return of PR and SF during informed consent by members of the first 247 families (790 individuals) enrolled in the Baylor-Hopkins Center for Mendelian Genomics, a genome sequencing study. Most (619; 78.3%) chose to receive SF and PR, 66 (8.4%) chose PR only, 65 (8.2%) wanted no results, and 40 (5.1%) chose SF only. Choosing SF was associated with an established clinical diagnosis in the proband (87.8 vs 79%, P=0.009) and European ancestry (EA) (87.7 vs 73%, P

Supervision is a practice that is utilized by a variety of practitioners to hone their counseling skills. Genetic counselors have embraced the supervision process, and some seek out supervision in a group setting with peers. Researchers have described the structure and content of genetic counseling peer supervision groups, and provided evidence for the benefits of seeking peer supervision. This study aimed to describe the interpersonal aspects of one genetic counseling peer supervision group, including personality traits and group dynamics, and how those factors influenced our experiences within the group. We also describe how the process of evaluating these factors impacted us individually and collectively. There was consensus that the group was a safe and trusting one, which was united by similar goals and mutual respect. Members reported gaining insights about how their own personality functioned within the group milieu, and also how the group setting impacted them. Based on our experiences, we recommend that other peer supervision groups consider similar self-evaluations on a periodic basis, both to enhance group functioning and to allow for increased self-awareness and professional growth.

Objective: Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials. Methods: The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials. Results: The REiNS PRO group chose the Numeric Rating Scale–11 (≥8 years) to assess pain intensity, the Pain Interference Index (6–24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (≥18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (≥5 years) for NF clinical trials. Conclusions: The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research.

To explore health-related quality of life (HRQoL) reported by individuals with neurofibromatosis type 2 (NF2) and to assess for correlations between HRQoL and objective measures of disease manifestations.Prospective observational study.Seven international NF2 centers.Eighty-one individuals with NF2, 73 adults (18 years) and 8 children/adolescents (10-17 years).Quality of life was measured by Short Form-36 (SF-36) norm-based scores. Objective clinical measures were hearing (categorized by word-recognition scores), facial function (categorized by the House-Brackmann scale) and the volume of subjects' larger vestibular schwannoma (VS).At baseline, adults showed significant deficits in all but two subscales of the SF-36 compared with age- and gender-adjusted United States population norms. In linear regression models including age, gender, inheritance status, hearing, facial weakness and VS volume, demographic and functional measures showed no relationship to any SF-36 subscale. Larger baseline VS volume was significantly related to reduced physical role performance, reduced mental health, and increased pain (p 0.05). In bivariate analysis, previous VS surgery was not significantly associated with baseline HRQoL; receipt of VS surgery or tumor growth during the observation period was not significantly associated with changes in HRQoL.NF2 patients report reduced HRQoL in physical, social, and mental domains, but this was not significantly related to objective measures of hearing or facial functioning. Larger baseline VS volume negatively impacted patient-reported HRQoL whereas VS surgery or tumor growth did not. Future studies should explore the relationship between tumor volume and HRQoL and psychosocial factors that may moderate this relationship.

Purpose Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. Patients and Methods Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. Results Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell–derived factor 1α (P = .037 and .025, respectively). Conclusion Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.

Objective Assess patient-reported outcomes (PRO) for hearing and tinnitus relative to clinical hearing assessment in people with neurofibromatosis 2 (NF2) associated hearing loss. Study design Prospective, open label, phase-II clinical trial with PRO administered pre-, post-, and after treatment. Setting Three tertiary referral centers. Patients Fourteen patients with NF2, median age of 30 years (range, 14-79 yr) and progressive hearing loss (median baseline word recognition score, 60%; range, 13-82%). Half of these patients achieved objective hearing response (word recognition score improved beyond the 95% critical difference versus baseline). Intervention Bevacizumab 7.5 mg/kg was administered every 3 weeks for 48 weeks, followed by surveillance for 24 weeks off-drug. Main outcome measures Speech, spatial, and qualities of hearing scale (SSQ) and tinnitus reaction questionnaire (TRQ) to assess hearing difficulties in life situations and tinnitus related distress. Results Patient-reported speech understanding and auditory quality improved with bevacizumab treatment and were significantly correlated with word recognition scores, but not pure tone threshold average. There was no change in spatial perception after treatment. Reduction in tinnitus distress after treatment with bevacizumab did not reach statistical significance. Conclusion Participants had reductions in hearing difficulty during treatment with bevacizumab, suggesting that patients subjectively experience hearing-related benefit mirroring clinical hearing assessments. We suspect the lack of significant reduction in tinnitus distress is related to small sample size and low intensity of distress in our sample. These data highlight the usefulness of PRO measures to assess benefits of treatment in the setting of NF2-associated hearing loss.

Genomic sequencing technology is increasingly used in genetic research. Studies of informed consent for exome and genome sequencing (ES/GS) research have largely involved hypothetical scenarios or healthy individuals enrolling in population-based studies. Studies have yet to explore the consent experiences of adults with inherited disease. We conducted a qualitative interview study of 15 adults recently enrolled in a large-scale ES/GS study (11 affected adults, four parents of affected children). Our study had two goals: (1) to explore three theoretical barriers to consent for ES/GS research (interpretive/technical complexity, possibility of incidental findings, and risks of loss of privacy); and (2) to explore how interviewees experienced the consent process. Interviewees could articulate study goals and processes, describe incidental findings, discuss risks of privacy loss, and reflect on their consent experience. Few expected the study would identify the genetic cause of their condition. All elected to receive incidental findings. Interviewees acknowledged paying little attention to potential implications of incidental findings in light of more pressing goals of supporting research regarding their own medical conditions. Interviewees suggested that experience living with a genetic condition prepared them to adjust to incidental findings. Interviewees also expressed little concern about loss of confidentiality of study data. Some experienced the consent process as very long. None desired reconsent prior to return of study results. Families with inherited disease likely would benefit from a consent process in which study risks and benefits were discussed in the context of prior experiences with genetic research and genetic disease.

Purpose Whereas T2 hyperintensities known as NF-associated bright spots are well described in patients with neurofibromatosis type I (NF-1), there is a paucity of data on incidental findings in patients with neurofibromatosis type II (NF-2). We aim to characterize unexplained imaging findings in the brains of patients with NF-2. Materials and methods This study is retrospective, HIPAA-compliant and approved by the institutional review board. 34 patients with NF-2 underwent brain magnetic resonance imaging (MRI) between January 2000 and December 2012. T2 and T1-weighted imaging characteristics, diffusion weighted imaging (DWI) characteristics, and enhancement patterns were analyzed by visual inspection. Clinical information at time of imaging was available for all patients. Neuropathologic data was available for one patient. Results We found unexplained T2 hyperintensities present on initial imaging in 23/34 patients (67%). Of the 23 patients with unexplained MRI findings, 15 (65%) had wedge-shaped T2 hyperintensities in the subcortical white matter extending to the cortex suggestive of a cortical dysplasia. 3 additional cases (17%) had a lesion within the cerebellum suggestive of a neuronal migration anomaly. In one patient where the MRI was suggestive of focal cortical dysplasia, histopathologic analysis revealed dysplastic glial foci without other alterations of cortical architecture or other cytologic abnormalities. Conclusion Unexplained T2 hyperintensities occur frequently in patients with NF-2. While they may not be the NF-2 equivalent of NF-associated bright spots seen in NF-1, some of these T2 hyperintensities in patients with NF-2 may represent underlying disorders of neuronal migration. Further studies are needed to validate our findings., Highlights • 34 patients with NF2 underwent consecutive brain magnetic resonance imaging (MRI). • 67% had brain MRI findings suggestive of a focal cortical dysplasia. • 17% had a lesion within the cerebellum suggestive of a neuronal migration anomaly. • One patient was found to have micro-hamartomas involving the cortex. • Patients with NF-2 may have radiographic findings suggestive of cortical dysplasia.

Constitutional SMARCB1 mutations at 22q11.23 have been found in ~50% of familial and

To describe the spectrum and associated clinical features of peripheral and cerebral vasculopathy in pediatric patients with neurofibromatosis type 1, children seen at a single center from 2000 to 2010 with appropriate imaging studies were identified. Scans were assessed for vascular disease by 2 pediatric neuroradiologists. Of 181 children, 80 had pertinent imaging studies: 77 had brain imaging, 6 had peripheral imaging, and 3 had both. Vasculopathy was identified in 14/80 children (18%, minimum prevalence of 14/181; 8%). Of those with vascular abnormalities, 2/14 had peripheral vasculopathy (1% minimum prevalence) and 12/14 had cerebrovascular abnormalities (7% minimum prevalence). No associations were found between vasculopathy and common clinical features of neurofibromatosis type 1, including optic pathway glioma, plexiform neurofibroma, skeletal abnormalities, attention-deficit hyperactivity disorder (ADHD), or suspected learning disability. Both peripheral and cerebral vasculopathy are important complications of pediatric neurofibromatosis type 1 and should be considered in the management of this complex disease.

Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. © 2016 Wiley Periodicals, Inc.

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non-clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors’ roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre-defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force’s work, key changes and the 2013 PBCs are presented herein.

Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.

As genetic testing technology has evolved, the landscape of hereditary brain tumors is expanding beyond syndromes such as Li-Fraumeni, von-Hippel-Lindau, neurofibromatosis, and tuberous sclerosis. Anecdotally, many consider benign brain tumors to have less of a germline component than malignant tumors. Based on published literature, it is unclear if there are differences between benign and malignant tumors in terms of the germline contribution to causation and this study examines that gap. All sequential cases with at least one diagnosis of a primary brain tumor (PBT) submitted to a single laboratory for hereditary cancer multigene panels between March 2012 and December 2016 were retrospectively reviewed. Cases were grouped as benign or malignant/malignant potential based on the reported pathology. Age at diagnosis and genetic testing, and mutation distribution were analyzed. Of 610 PBT cases, about half (51.8%) were benign. Germline mutations were identified in 14.2% (n=316) of benign cases and 17.4% (n=294) of malignant cases. Overall, 62.1% had multiple primary tumors; 75.3% in the benign subgroup had >1 primary cancer diagnosis compared to 48.0% in the malignant group. In the benign subgroup, 53.3% had their PBT as the initial or concurrent diagnosis compared to 61.0% in the malignant subgroup. The average length of time from PBT diagnosis to genetic testing was similar for benign and malignant subgroups (9y and 8y, respectively). Though this cohort was enriched for patients with multiple primary cancer diagnoses, germline mutations were frequent among both benign and malignant subgroups. In the malignant subgroup, over half presented with a PBT as their first diagnosis, however, genetic testing was delayed for close to a decade on average. Clinician awareness of germline genetic findings among both benign and malignant PBT cases, and the utilization of genetic testing to assist with appropriate and comprehensive screening are important.

Schwannomatosis is a neurogenetic syndrome characterized by schwannomas throughout the peripheral nervous system without bilateral vestibular schwannomas (VS) or germline neurofibromatosis 2 (NF2) mutation.1 Management is difficult due to large tumor burden and treatment-resistant pain. Patients require multiple surgical procedures (average of 3.4 per decade) for pain, focal neurologic deficits, or myelopathy.1 There are no known effective drug therapies.

The neurocutaneous syndromes are a heterogeneous group of conditions affecting the nervous system and the skin, as well as other organ systems including the eyes, kidneys, and heart. This section discusses the most common inherited syndromes, neurofibromatosis and tuberous sclerosis. Diagnosis of these disorders is based on clinical criteria. Genetic testing may assist diagnosis and give information for family members. Genetic counseling is complicated by the frequent presence of de novo mutations, mosaicisms, and variable expression and severity. Additionally patients often experience stigma and discrimination, and may have psychiatric symptoms. All of these factors should be considered during counseling.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with increased risk for neoplasms. Two studies in the United Kingdom have indicated that women with NF1 (particularly women under 50) may also be at increased risk of breast cancer. No such study has been done to date in the United States. Chart review for breast cancer diagnoses was undertaken for 126 women with NF1 followed at Johns Hopkins who were 20 years of age or older. Four of 126 women who met eligibility criteria were diagnosed with breast cancer (3.2% over 15 years). The unadjusted standardized incidence ratio (SIR) for breast cancer in the NF1 population between the ages of 20 and 49 was 2.68 (P=0.076, 95% CI: 0.68-7.29) based on incidence rates of breast cancer in the general population taken from the Surveillance Epidemiology and End Results (SEER) database. The unadjusted SIR for women with NF1 ≥50 was 0.81 (P=0.84, 95% CI: 0.041-4.01). When adjusted for race, the rate of NF1 in the general population and time of diagnosis, the SIR was 4.41 (P=0.0049, 95% CI: 1.12-12.00) for women

Metanephric stromal tumor (MST) is a recently recognized benign renal stromal tumor. MST is thought to be part of a spectrum of benign metanephric renal lesions, which also includes the epithelial lesion metanephric adenoma and the mixed stromal–epithelial lesion metanephric adenofibroma. Metanephric lesions may represent hyperdifferentiated counterparts to Wilms’ tumor (WT). MST characteristically shows renovascular angiodysplasia and juxtaglomerular (JG) cell hyperplasia. This is remarkably similar to the renal pathology described in neurofibromatosis-1 (NF-1) syndrome, a condition which is also associated with WT. Here, we report the first case of MST arising in a patient with NF-1. The patient presented with hypertension, and the MST was associated with florid angiodysplasia and JG cell hyperplasia. This case tightens the link between NF-1, WT, and MST.

Peters Plus syndrome comprises ocular anterior segment dysgenesis (most commonly Peters anomaly), short stature, hand anomalies, distinctive facial features, and often other additional defects and is inherited in an autosomal-recessive pattern. Mutations in the beta1,3-glucosyltransferase gene (B3GALTL) were recently reported in 20 out of 20 patients with Peters Plus syndrome. In our study, B3GALTL was examined in four patients with typical Peters Plus syndrome and four patients that demonstrated a phenotypic overlap with this condition. Mutations in B3GALTL were identified in all four patients with typical Peters Plus syndrome, while no mutations were found in the remaining four patients that demonstrated some but not all characteristic features of the syndrome. The previously reported common mutation, c.660 + 1G > A, accounted for 75% of the mutant alleles in our Peters Plus syndrome population. In addition, two new mutant alleles, c.459 + 1G > A and c.230insT, were identified and predicted to result in truncated protein products. These data confirm an important role for B3GALTL in causing typical Peters Plus syndrome, and suggest that this gene may not be implicated in syndromic cases that involve Peters anomaly but lack other classic features of this complex condition.

Intracranial hemorrhage in a term neonate is a rare event in the absence of an identifiable precipitating factor such as severe thrombocytopenia, mechanical trauma, asphyxia, infections, or congenital vascular malformations. Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of multisystem disorders characterized by the abnormal glycosylation of a number of glycoproteins. Although bleeding caused by abnormal glycosylation of various coagulation factors is a well-known clinical complication of several types of congenital disorders of glycosylation, intracranial hemorrhage has not been reported as an initial manifestation of this entity. Here we report the detailed history of a family with 2 consecutive male infants, both born at term with intracranial hemorrhage diagnosed within the first 24 hours of life. The diagnosis of a congenital disorder of glycosylation was established in the second infant by an abnormal glycosylation of serum transferrin detected by electrospray-ionization mass spectrometry. Both infants showed significant neurologic deterioration during the first month of life, and both died at 5 months of age. Intracranial hemorrhage in a term neonate without a potential precipitating factor represents yet another clinical feature that should raise the suspicion for a congenital disorder of glycosylation.

Objective: This study proposes to estimate the frequency of gastrointestinal (GI) complications in the neurofibromatosis type 1 population known to the Comprehensive Neurofibromatosis Center at Johns Hopkins Hospital. Background Although the neurological complications associated with neurofibromatosis type 1 (NF1) are widely known, GI complications have been largely undocumented though they can greatly affect morbidity in this population. Plexiform neurofibromas can lead to intestinal obstruction. Central or peripheral neurofibromas may lead to autonomic instability compromising gut function. While patients with NF1 often report GI complications to their providers, the comprehensive study of these complications has not been undertaken. Design/Methods: Chart review on all patients with NF1 at Johns Hopkins Hospital. Subjects were separated by age (>18 years or Results: 309 subjects >18 years and 196 subjects Conclusions: GI complications are common in adults and children with NF1. None of the complications noted were due to a GI stromal tumor. Screening of GI complications should be included in adults and children with NF1. Disclosure: Dr. Wolf has nothing to disclose. Dr. Bergner has nothing to disclose. Dr. Obeng has nothing to disclose. Dr. Blakeley has nothing to disclose.

Objective: This study proposes to estimate the prevalence of central nervous system (CNS) vascular complications in the neurofibromatosis type 1 (NF1) population known to the Johns Hopkins Comprehensive Neurofibromatosis Center. Background Neurofibromatosis type 1 (NF1) affects approximately 1 in 3300 people. Though the neurological complications associated with NF1 are widely known, potentially harmful vascular effects have been largely undocumented. Due to the increasing number of incidental findings in the literature and our heightened clinical suspicion given the experience within our NF Center, a comprehensive study aimed at estimating the prevalence of widespread vasculopathy in the NF1 population is needed. Design/Methods: Retrospective chart review was undertaken for all patients with NF1 from our Center. Charts were screened for brain MRI scans either completed or formally reviewed at Johns Hopkins Hospital from 1980 until the present. MRI reports were reviewed for indication of a vascular anomaly. Results: 429 patients were screened for this study. 44 patients were found to have at least one CNS vasculopathy. The most common finding in patients >18 years were arteriovenous anomalies and ischemic stroke. The most common finding in patients Conclusions: Based on confirmed vasculopathy in 44 of 429 patients seen in a large neurofibromatosis clinic, we report the minimum prevalence rate of 10% for CNS vascular complications. The actual prevalence is likely higher, as only 41% of the clinic population underwent brain MRI. When controlled for age, the prevalence of CNS vascular complications within our population increases from 7% in childhood to 13% in adulthood. The majority of vascular complications seen were ischemic events or complications known to increase the likelihood of ischemic events in a population with a mean age of 36 years. This data indicates that patients with NF1 are at risk for vascular disease at a young age. Disclosure: Dr. Bergner has nothing to disclose. Dr. Kaas has nothing to disclose. Dr. Chance has nothing to disclose. Dr. Jordan has received personal compensation for activities with Berlin Heart. Dr. Blakeley has nothing to disclose.