Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.

https://jmg.bmj.com/content/jmedgenet/early/2006/11/14/jmg.2006.045906.full.pdf

Guidelines for the diagnosis and management of individuals with neurofibromatosis 1

Autosomal dominantly inherited tumor-prone syndromes are a substantial health problem and are amenable to epidemiologic studies by combining cancer surveillance registries with a genetic register (GR)-based approach. Knowledge of the frequency of the conditions provides a basis for appropriate health-resources allocations. GRs for five tumor-prone syndromes were established in the Manchester region of North West England in 1989 and 1990. Mapping birth dates of affected individuals from families onto regional birth rates has allowed an estimate of birth incidence, disease prevalence, and de novo mutation rates. Disease prevalence in order of frequency were for neurofibromatosis type 1 (NF1): 1 in 4,560; familial adenomatous polyposis (FAP): 1 in 18,976; nevoid basal cell carcinoma [Gorlin syndrome (GS)]: 1 in 30,827; neurofibromatosis type 2 (NF2) 1 in 56,161; and von Hippel Lindau (VHL) 1 in 91,111. Best estimates for birth incidence were: 1 in 2,699; 1 in 8,619; 1 in 14,963, 1 in 33,000; and 1 in 42,987, respectively. The proportions due to de novo mutation were: 42% (NF1); 16% (FAP); 26% (GS); 56% (NF2); and 21% (VHL). Estimates for NF1, NF2, FAP, and VHL are in line with previous estimates, and we provide the first estimates of birth incidence and de novo mutation rate for GS.

Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service.

Overview All cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair,1,2 but not all of these mutations are inherited from a parent. For example, sporadic mutations can occur in somatic/ tumor cells only, and de novo mutations can occur for the first time in a germ cell (i.e., egg or sperm) or in the fertilized egg itself during early embryogenThe NCCN

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Genetic/familial high-risk assessment: breast and ovarian.

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (cafe-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

Neurofibromatosis type 1.

Several nerve guidance conduits (NGCs) and nerve protectant wraps are approved by the US Food and Drug Administration (FDA) for clinical use in peripheral nerve repair. These devices cover a wide range of natural and synthetic materials, which may or may not be resorbable. This review consolidates the data pertaining to all FDA approved materials into a single reference, which emphasizes material composition alongside pre-clinical and clinical safety and efficacy (where possible). This article also summarizes the key advantages and limitations for each material as noted in the literature (with respect to the indication considered). In this context, this review provides a comprehensive reference for clinicians which may facilitate optimal material/device selection for peripheral nerve repair. For materials scientists, this review highlights predicate devices and evaluation methodologies, offering an insight into current deficiencies associated with state-of-the-art materials and may help direct new technology developments and evaluation methodologies thereof.

FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy

Background: Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk. Methods: NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry. Results: Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p Conclusion: The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.

https://jmg.bmj.com/content/jmedgenet/39/5/311.full.pdf

Malignant peripheral nerve sheath tumours in neurofibromatosis 1

Background: Malignancy risks in neurofibromatosis 1 (NF1) patients are elevated but those occurring outside of the nervous system have not been clearly defined. We evaluated the risk of breast cancer in women with NF1 in a population-based study. 

Methods: The risk of breast cancer in a cohort of 304 NF1 women aged ≥20 years was assessed and compared to population risks over the period 1975-2005 using a person years at risk analysis. 

Results: There were 14 breast cancers in the follow up period yielding a Standard Incidence Ratio (SIR) of 3.5 (95% CI 1.9-5.9). However, 6 breast cancers occurred in the forties and the SIR of breast cancer aged <50 years was 4.9 (95% CI 2.4-8.8). 

Interpretation: Women with NF1 have a five-fold risk of breast cancer <50 years of age, are in the moderate risk category and should be considered for mammography from 40 years of age.

/pdf/women-with-neurofibromatosis-1-are-at-a-moderately-increased-44ocjwtsst.pdf

Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening

PA01 More than meets the eye: a case of encephalocraniocutaneous lipomatosis Catriona Gallagher, Norah McGrath, Irene Timoney and Fiona Browne Temple Street Children’s Hospital, Dublin, Ireland Encephalocraniocutaneous lipomatosis (ECCL) is a rare and often overlooked neurocutaneous syndrome resulting from somatic mutations in FGFR1 and characterized by skin lesions with ocular and central nervous system (CNS) anomalies. A 2year-old girl presented for assessment of localized congenital alopecia. Parents reported a ‘fullness’ in the area from birth, with hair loss overlying the area. This had become more apparent with age as the remainder of her scalp hair thickened. Examination revealed an 8 9 6 cm, well-defined area of subcutaneous fullness in the frontal midline scalp with associated alopecia. Hair on the rest of the scalp was normal. The remainder of her examination revealed a yellow plaque on the left eye, confirmed by ophthalmology as a lipodermoid cyst. Magnetic resonance imaging of the brain showed a focal abnormality right of the midline of the anterior scalp extending from the skin to the external cortex of the skull. A general prominence of the scalp fat in the region was also noted. There was no intracranial extension of the scalp lesion or other CNS abnormalities noted. The constellation of ocular and cutaneous findings in our patient is in keeping with a diagnosis of ECCL (Moog U. Encephalocraniocutaneous lipomatosis. J Med Genet 2009; 46: 721–9). The characteristic cutaneous feature of ECCL, seen in 80% of cases, is a naevus psiloliparus that clinically presents as an alopecic fatty tissue naevus of the scalp. Other cutaneous findings include subcutaneous fatty lipomas, focal dermal hypoplasia, skin tags and blaschkoid pigmentary anomalies. Ocular features present as unilateral or bilateral choristomas in 80% of cases. CNS involvement includes intracranial or intraspinal lipoma, abnormal intracranial vessels, hydrocephalus or arachnoid cysts. Importantly, neurological symptoms such as seizures and intellectual impairment are common; low-grade gliomas have been observed less commonly. We present this case to highlight this rare neurocutaneous condition, which can be associated but serious neurological complications and the need for specialist assessment of children born with unexplained cutaneous features. PA02 (P28) Prediction of FLG genotype using human and computeraided phenotype extraction with random forest machine learning Bjorn R. Thomas, Lloyd Steele, Reiko J. Tanaka and Edel A. O’Toole Department of Dermatology, The Royal London Hospital, Barts Health NHS Trust, London, UK; Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London, UK; and Department of Bioengineering, Imperial College London, London, UK Palmar hyperlinearity is associated with FLG mutations and can be a feature of atopic eczema (AE). There are no consensus features of palmar hyperlinearity and these vary between studies. Using palmar hyperlinearity to predict loss-of-function FLG variants has proven difficult. In total, 503 participants with AE from the Tower Hamlets Eczema Assessment were used to train models to predict whether participants were wild-type (WT; n = 279), heterozygotes (n = 151) or compound heterozygotes/homozygotes (n = 25) for loss-of-function variants in FLG. Three main features were investigated: (i) computer-aided feature extraction of palmar photos were used to generate thenar hyperlinearity scores (thenar score); (ii) a Bernoulli mixture model was used to cluster whole-body binary eczema lesional distribution data into nine lesional distribution groups (cluster); and (iii) five human delineated palmar linearity groups (palmar pattern) previously created were used in the models. Seven models were used: thenar score, cluster and palmar pattern were modelled individually and then in combination to cover all permutations of these three features. All models were adjusted according to age, sex and body mass index. The dataset was split into a training and test set (90/10). Repeated K-fold cross-validation was used to choose the best-performing machine learning algorithm, using accuracy as a primary metric. Random forests were the bestperforming algorithm for all models. Models were then trained and tuned using the training dataset, and then validated on the test set. Up-sampling was used as there was significant class imbalance. The individual thenar score, palmar pattern and cluster models had an accuracy of 58 3%, 68 8% and 45 8%, respectively. The combination models with thenar score/cluster, palm pattern/cluster and thenar score/palm pattern had accuracies of 54 4%, 62 5% and 64 6%, respectively. The top-performing model, which included thenar score, palm pattern and lesion distribution clusters, had an accuracy of 70 8% (sensitivity/specificity of WT, heterozygote and compound heterozygote/homozygote was 90 0%/55 6%, 37 5%/90 6% and 93 5%/50%, respectively). With this model, only three of the of 30 WT participants in the test set were misclassified as having a loss-of-function variant in FLG, indicating that this model may already be reasonable at classifying whether a person has at least one loss-of-function variant in FLG. These data demonstrate that clinical phenotype can provide information on FLG genotype. To take this forward, implementation of Computer Vision on the dataset should significantly improve classification ability and remove observer British Association for Paediatric Adolescent Dermatology 195

https://academic.oup.com/bjd/article-pdf/187/S1/195/47374031/bjd0195a.pdf

E Howard

Papers

Malignant peripheral nerve sheath tumours in neurofibromatosis 1

Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening

PA02 (P28): Prediction of FLG genotype using human and computer‐aided phenotype extraction with random forest machine learning