Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation.

PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.

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.

The development of the PlexiQoL: A patient-reported outcome measure for adults with neurofibromatosis type 1-associated plexiform neurofibromas.

BACKGROUND: To develop and validate a patient-reported outcome (PRO) measure of quality of life (QoL), specific to patients with Neurofibromatosis Type 1 (NF1)-associated plexiform neurofibromas (pNFs), suitable for use in clinical efficacy trials. The study was conducted in parallel in the UK and US. METHODS: Qualitative interviews were conducted with patients to generate questionnaire content. Face and content validity of the draft scale was assessed by cognitive debriefing interviews (CDIs). A postal validation survey was conducted to identify the final version of the questionnaire (the PlexiQoL), establish its unidimensionality, and assess its psychometric properties. RESULTS: Thematic analysis was performed on 42 interview transcripts. Thirty-one CDIs revealed that patients found the draft scale to be comprehensible, relevant, and easy to complete. The postal validation survey was completed by 273 patients. Rasch analysis identified an 18-item unidimensional scale that showed excellent internal consistency, reproducibility, and sensitivity to differences in patient-perceived pNF severity, general health, and the use of pain medication. CONCLUSIONS: The PlexiQoL is the first disease-specific PRO assessing the ability of adults with NF-1 associated pNFs to meet their basic human needs. Clinical trials are planned to assess the sensitivity to change of the PlexiQoL in people undergoing treatment for pNFs.

A retrospective regional study of aqueduct stenosis and fourth ventricle outflow obstruction in the paediatric complex neurofibromatosis type 1 population; Aetiology, clinical presentation and management.

OBJECTIVES: Aqueduct stenosis (AS) and fourth ventricle outflow obstruction are rare associations of neurofibromatosis type 1 (NF1), resulting in ventriculomegaly and hydrocephalus requiring surgical treatment. This study aims to identify the prevalence of AS and its patterns of clinical presentation, aetiology and treatment in the paediatric complex NF1 population. PATIENTS AND METHODS: Patients with NF-1 aged 0-18 years were recruited from the Regional Genetic Family Register, following institutional review board approval. Magnetic resonance imaging data and clinical documents were reviewed with respect to clinical presentation, degree of ventriculomegaly, aetiological factors and management of AS and fourth ventricle outflow obstruction. RESULTS: 24 of the 233 paediatric patients seen within the NHS highly specialised service for complex NF1 were found to have AS or and fourth ventricle outflow obstruction. This included 13 males and 11 females with a mean age of 9 years 5 months (range 8 months - 17 years). The majority of patients with AS or fourth ventricle outflow obstruction presented with symptoms of raised intracranial pressure associated with ventriculomegaly and/or hydrocephalus (n = 18). However, in 25 % of patients, AS was an incidental finding on MRI and was observed both in the presence (n = 2) and absence (n = 4) of ventriculomegaly. In the majority of cases a single cause of AS was identified (n = 16), of which tectal plate thickening (n = 7) was most frequently observed. The remaining 8 patients had multiple causes of AS, in which tectal plate thickening (n = 7) and aqueductal webs (n = 5) were the most common observations. Surgery was performed on all patients with evidence of raised pressure (n = 8) by performing endoscopic third ventriculostomy (ETV) (n = 5) or ventriculoperitoneal (VP)-shunting (n = 3). Tectal plate thickening was most frequently observed in patients who underwent ETV (n = 3), followed by aqueductal web (n = 1) and T2-signal changes in the tectal plate (n = 1). Patients treated with VP-shunt had 4th ventricle outflow obstruction (n = 2) and a tectal plate tumour (n = 1). CONCLUSION: This study identifies that AS is more prevalent amongst the paediatric complex NF-1 population than previously reported, occurring in 10 % of cases. Our findings demonstrate that AS is most commonly symptomatic in presentation but can be asymptomatic in 25 % of paediatric complex NF1 patients. In this population, AS can occur both in the presence and absence of ventriculomegaly and therefore requires careful monitoring for development of hydrocephalus. In this study, over one third of patients (9 of 24 patients) with AS eventually required treatment.

Autism Spectrum Disorder Symptom Profile Across the RASopathies.

Dysregulation of the Ras MAPK signaling pathway is implicated in the pathogenesis of autism spectrum disorder (ASD). The RASopathies, a group of disorders caused by mutations of the Ras/MAPK pathway genes, share many overlapping clinical features. Studies suggest a high prevalence of ASD in the RASopathies, but detailed characterization of the ASD profile is lacking. The aim of this study was to compare the ASD symptom profile of three distinct RASopathies associated with both gain-of-function and loss-of-function mutations: neurofibromatosis type 1 (NF1), Noonan syndrome (NS), and cardiofaciocutaneous syndrome (CFC). Participants were drawn from existing databases if they had a diagnosis of a RASopathy, met the criteria for ASD, and were able to communicate verbally. We compared the phenotypic profile of NF1 + ASD (n = 48), NS + ASD (n = 11), and CFC + ASD (n = 7) on the Autism Diagnostic Inventory (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). We found subtle but non-significant group differences with higher levels of social impairments and lower restricted repetitive behaviors in the NF1 group as compared with the NS and CFC groups. We observed group differences in developmental milestones with most severe delays in CFC, followed by NS and NF1. Our results suggest that despite developmental differences, the ASD profile remains relatively consistent across the three RASopathies. Though our results need confirmation in larger samples, they suggest the possibility that treatment and mechanistic insights developed in the context of one RASopathy may be generalizable to others and possibly to non-syndromic ASD associated with dysregulation of Ras/MAPK pathway genes.

First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics.

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.

A qualitative study of the impact of plexiform neurofibromas on need fulfilment in adults with neurofibromatosis type 1.

OBJECTIVE: To explore the impact of plexiform neurofibromas on the lives of adults with neurofibromatosis type 1. BACKGROUND: Neurofibromatosis type 1 is a complex neurogenetic syndrome that affects many aspects of health and functioning. A common manifestation of neurofibromatosis type 1 is plexiform neurofibromas, non-cancerous tumours that can cause disfigurement, pain and neurologic disability. Patient-reported outcome measures used in this condition have addressed symptoms and functional ability but not how the condition affects patients' lives, particularly, their ability to meet their human needs. METHODS: Unstructured qualitative interviews were conducted with adults with neurofibromatosis type 1-associated plexiform neurofibromas in the United Kingdom and United States. Interviewees were encouraged to describe how plexiform neurofibromas affected their ability to meet their needs. Interviews were audio-recorded and transcribed verbatim. The UK and US transcripts were combined and theoretical thematic analysis was conducted. RESULTS: In all, 42 interviews (United Kingdom = 20, United States = 22) were conducted. Transcripts revealed 696 statements on the impact of plexiform neurofibromas on need fulfilment. Five major themes emerged: appearance, relationships, independence, role fulfilment and pleasure. CONCLUSION: Neurofibromatosis type 1-associated plexiform neurofibromas have a major effect on individuals' ability to meet their needs. An understanding of need fulfilment will complement information generated from traditional patient-reported outcome measures, particularly in a multi-faceted syndrome such as neurofibromatosis type 1.

C2 neurofibromas in neurofibromatosis type 1: genetic and imaging characteristics.

OBJECTIVEC2 nerve root neurofibromas have been reported frequently in patients with neurofibromatosis type 1 (NF1), although their genetic and imaging characteristics are unexplored. The aim of this study was to characterize genetic and spinal imaging findings in a large cohort of NF1 patients with C2 neurofibromas.METHODSThe authors performed a review of national NF1 referrals between 2009 and 2016. Inclusion criteria were at least 1 C2 root neurofibroma and cervical-spine or whole-spine MRI scans available for analysis. Blinded imaging review was performed by a neuroradiologist with an interest in NF1.RESULTSFifty-four patients with 106 C2 neurofibromas were included. The median age was 32.5 years (range 15-61 years), and there were slightly more male patients (33 vs 21 female patients). Splice-site (30%) and missense (20%) variants were frequent. Spinal neurofibromas were distributed in all spine regions (65%) or in the cervical spine alone (22%). Most (93%) C2 neurofibromas were visible on MRI scans of the head. Intradural invasion and cord compression in the cervical spine included the C2 level in 95% and 80% of patients, respectively. Compared with all other cervical spine neurofibromas in these patients, C2 neurofibromas had higher rates of intraspinal extension (75% vs 32%; OR 6.20, 95% CI 3.85-9.97; p < 0.001), intradural invasion (53% vs 26%; OR 3.20, 95% CI 2.08-4.92; p < 0.001), and cord compression (25% vs 13%; OR 2.26, 95% CI 1.35-3.79; p = 0.002). However, C2 neurofibromas had lower rates of extraforaminal growth beyond the transverse process (12% vs 62%; OR 0.09, 95% CI 0.05-0.16; p < 0.001).CONCLUSIONSC2 neurofibromas are associated with an aggressive intraspinal phenotype, limited growth outside the spinal canal, and an uncommon genetic profile. These observations require future study.

Cutaneous neurofibromas: Current clinical and pathologic issues.

OBJECTIVE: To present the current terminology and natural history of neurofibromatosis 1 (NF1) cutaneous neurofibromas (cNF). METHODS: NF1 experts from various research and clinical backgrounds reviewed the terms currently in use for cNF as well as the clinical, histologic, and radiographic features of these tumors using published and unpublished data. RESULTS: Neurofibromas develop within nerves, soft tissue, and skin. The primary distinction between cNF and other neurofibromas is that cNF are limited to the skin whereas other neurofibromas may involve the skin, but are not limited to the skin. There are important cellular, molecular, histologic, and clinical features of cNF. Each of these factors is discussed in consideration of a clinicopathologic framework for cNF. CONCLUSION: The development of effective therapies for cNF requires formulation of diagnostic criteria that encompass the clinical and histologic features of these tumors. However, there are several areas of overlap between cNF and other neurofibromas that make distinctions between cutaneous and other neurofibromas more difficult, requiring careful deliberation with input across the multiple disciplines that encounter these tumors and ultimately, prospective validation. The ultimate goal of this work is to facilitate accurate diagnosis and meaningful therapeutics for cNF.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway.

AIM: To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD). METHOD: Fifty children were recruited over 10 months through the regional genetics service and advertisements. A range of parent, child, and observational measures were administered including Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale. RESULTS: Using the Collaborative Programme for Excellence in Autism criteria, 12 out of 40 children with Noonan syndrome (30%) showed ASD, and 12 out of 40 (30%) with partial ASD features and 16 out of 40 (40%) showed non-ASD. The Noonan syndrome ASD group showed male dominance in a ratio of 5:1. In the CFC group, eight out of nine children met the criteria for ASD, with equal sex distribution. Additionally 19 out of 40 (48%) of the Noonan syndrome group and eight out of nine (88.9%) of the CFC group scored met clinical criteria for ADHD. Only one child was in the Costello syndrome group. INTERPRETATION: This is the first systematic study to suggest a high prevalence of ASD in Noonan and CFC syndromes, and thus offers crucial evidence to support the importance of the Ras/MAPK pathway in the aetiology of ASD. Limitations include the inevitable possibility of a sampling bias in a rare disorder study of this kind.

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT).

IMPORTANCE: Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. OBJECTIVE: To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. DESIGN, SETTING, AND PARTICIPANTS: Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. MAIN OUTCOMES AND MEASURES: Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. RESULTS: Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. CONCLUSIONS AND RELEVANCE: This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

Auditory Brainstem Implantation in Neurofibromatosis Type 2: Experience From the Manchester Programme.

OBJECTIVE: To describe the experience of auditory brainstem implantation (ABI) in patients with Neurofibromatosis type 2 (NF2). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral centre. PATIENTS: Implanted with a Cochlear ABI22 or ABI24M between 1994 and 2009 because of NF2 disease. INTERVENTION(S): Rehabilitative. MAIN OUTCOME MEASURE(S): Surgical complication rate; audiological outcomes. RESULTS: There were 50 primary ABI insertions in 49 patients, including 16 inserted at the time of first side tumor removal as a sleeper, and two revision repositionings which failed to improve outcome. Postoperatively three patients had cerebrospinal fluid leaks which did not require reoperation, one patient had meningitis, and eleven patients suffered either temporary or permanent lower cranial nerve dysfunction. Twenty-nine patients became full time users; a further 12 patients became non-users. Three patients died while their device was inactive. Five patients retain serviceable contralateral hearing. Audiological open set testing of users showed means of: environmental sounds discrimination 51%; phoneme discrimination: with ABI alone 22%/lip reading (LR) 45%/ABI with LR 65%; sentence testing: with ABI alone 13%/LR 19%/ABI with LR 54%. CONCLUSIONS: The majority of patients with NF2 implanted with an ABI find the device a useful aid to communication in conjunction with LR and in recognizing common environmental sounds. A small proportion gain open set discrimination. Almost a third of patients may end up as non-users. There is probably an increased risk of postoperative lower cranial nerve dysfunction so careful preoperative assessment is advised.

Sex bias in autism spectrum disorder in neurofibromatosis type 1.

BACKGROUND: Despite extensive literature, little is known about the mechanisms underlying sex bias in autism spectrum disorder (ASD). This study investigates the sex differences in ASD associated with neurofibromatosis type 1, a single-gene model of syndromic autism. METHODS: We analysed data from n = 194 children aged 4-16 years with neurofibromatosis type 1. Sex differences were evaluated across the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS), verbal IQ, Social Responsiveness Scale (SRS) and Conners questionnaires. RESULTS: There was 2.68:1 male:female ratio in children meeting ASD criteria on the deep phenotyping measures. On symptom profile, males with neurofibromatosis type 1 (NF1) + ASD were more impaired on reciprocal social interaction and communication domains of the ADI-R but we found no differences on the restricted, repetitive behaviours (RRBs) domain of the ADI-R and no differences on the social on the ADOS. NF1 ASD males and females were comparable on verbal IQ, and the inattention/hyperactivity domains of the Conners questionnaire. CONCLUSIONS: There is a significant male bias in the prevalence of ASD in NF1. The phenotypic profile of NF1 + ASD cases includes greater social communication impairment in males. We discuss the implications of our findings and the rationale for using NF1 as a model for investigating sex bias in idiopathic ASD.

Cognition in children with neurofibromatosis type 1: data from a population-based study.

AIM: This study aimed to investigate the core cognitive deficits in children with neurofibromatosis type 1 (NF1). METHOD: The study recruited 49 children with NF1 (25 males, 24 females; mean age 11y 9mo [SD 3y 2mo]), 19 healthy siblings of children with NF1 (sibling comparisons; mean age 12y 7mo [SD 2y 7mo], 9 males, 10 females) and 29 healthy children from the community (community comparisons; mean age 11y [SD 2y 7mo], 12 males, 17 females). Participants completed a battery of cognitive tests including tests of intelligence, academic achievement, attention, visuoperceptual functioning, visual learning, executive functioning, and non-verbal working memory tests. RESULTS: Our study, using a population-based sample, confirmed previous findings from studies using variable sampling methods. Children with NF1 had significantly lower Full-scale IQs (p=0.04) and lower academic achievement (p=0.026-0.005) than their siblings. Compared with their siblings, they also had significantly poorer visuospatial processing (p=0.007), visual associate learning (p=0.014), non-verbal working memory (p=0.023), and executive function (p<0.001). Data from the community comparisons were not included because they were subject to significant selection bias. INTERPRETATION: Population-based frequencies for cognitive deficits in children with NF1 are similar to the frequencies in non-population based samples. This study highlights the heterogeneous nature of cognitive problems in children with NF1 and the need for monitoring and support at school.

Recent developments in neurofibromatoses and RASopathies: management, diagnosis and current and future therapeutic avenues.

Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues" chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collaborations directed towards the best practices and therapies for individuals with RASopathies.

Autism spectrum disorder profile in neurofibromatosis type I.

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant single-gene disorder, in which the co-occurrence of autism spectrum disorder (ASD) has attracted considerable research interest recently with prevalence estimates of 21-40%. However, detailed characterization of the ASD behavioral phenotype in NF1 is still lacking. This study characterized the phenotypic profile of ASD symptomatology presenting in 4-16 year old children with NF1 (n = 36) using evidence from parent-rated Social Responsiveness Scale and researcher autism diagnostic observation Scale-2. Compared to IQ-matched reference groups of children with autism and ASD, the NF1 profile shows overall similarity but improved eye contact, less repetitive behaviors and better language skills.

Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed.