Consulta Multidisciplinar de Doenças Neurocutâneas: Experiência de Cinco Anos num Hospital Pediátrico Terciário em Portugal

Introduction: Neurocutaneous syndromes (NCS) are a heterogeneous group of conditions with multiorgan involvement and diverse manifestations, evolving throughout life with significant morbidity. A multidisciplinary approach to NCS patients has been advocated, although a specific model is not yet established. The aim of this study was 1) to describe the organization of the recently created Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases (MOCND) at a Portuguese pediatric tertiary hospital; 2) to share our institutional experience focusing on the most common conditions, neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC); 3) to analyze the advantages of a multidisciplinary center and approach in NCS. Methods: Retrospective analysis of 281 patients enrolled in the MOCND over the first five years of activity (October 2016 to December 2021), reviewing genetics, family history, clinical features, complications, and therapeutic strategies for NF1 and TSC. Results: The clinic works weekly with a core team of pediatricians and pediatric neurologists supported by other specialties as needed. Of the 281 patients enrolled, 224 (79.7%) had identifiable syndromes such as NF1 (n = 105), TSC (n = 35), hypomelanosis of Ito (n = 11), Sturge-Weber syndrome (n = 5), and others. In NF1 patients, 41.0% had a positive family history, all manifested café-au-lait macules, 38.1% neurofibromas with 45.0% being large plexiform neurofibromas. Sixteen were under treatment with selumetinib. Genetic testing was performed in 82.9% of TSC patients with pathogenic variants found in TSC2 gene in 72.4% patients (82.7% if considered contiguous gene syndrome). Family history was positive in 31.4%. All TSC patients presented hypomelanotic macules and fulfilled diagnostic criteria. Fourteen patients were being treated with mTOR inhibitors. Conclusion: Offering a systematic and multidisciplinary approach to NCS patients enables timely diagnosis, promotes a structured follow-up, and encourages discussion to outline management plans for optimal care to every patient, with significant impact on the quality of life of patients and families.info:eu-repo/semantics/publishedVersio

Case report: Gene mutation analysis and skin imaging of isolated café-au-lait macules

Background: Café-au-lait macules (CALMs) are common birthmarks associated with several genetic syndromes, such as neurofibromatosis type 1 (NF1). Isolated CALMs are defined as multiple café-au-lait macules in patients without any other sign of NF1. Typical CALMs can have predictive significance for NF1, and non-invasive techniques can provide more accurate results for judging whether café-au-lait spots are typical.Objectives: The study aimed to investigate gene mutations in six Chinese Han pedigrees of isolated CALMs and summarize the characteristics of CALMs under dermoscopy and reflectance confocal microscopy (RCM).Methods: In this study, we used Sanger sequencing to test for genetic mutations in six families and whole exome sequencing (WES) in two families. We used dermoscopy and RCM to describe the imaging characteristics of CALMs.Results: In this study, we tested six families for genetic mutations, and two mutations were identified as novel mutations. The first family identified [NC_000017.11(NM_001042492.2):c.7355G>A]. The second family identified [NC_000017.11(NM_001042492.2):c.2739_2740del]. According to genotype-phenotype correlation analyses, proband with frameshift mutation tended to have a larger number of CALMs and a higher rate of having atypical CALMs. Dermoscopy showed uniform and consistent tan-pigmented network patches with poorly defined margins with a lighter color around the hair follicles. Under RCM, the appearance of NF1 comprised the increased pigment granules in the basal layer and significantly increased refraction.Conclusion: A new heterozygous mutation and a new frameshift mutation of NF1 were reported. This article can assist in summarizing the properties of dermoscopy and RCM with CALMs

Bone Health, Osteoporosis and Fracture Risk in Neurofibromatosis 1 - An Emphasis on Osteoclasts

Neurofibromatosis 1 (NF1) is an autosomal dominant hereditary syndrome, affecting skin, neural tissues and skeleton. Hallmarks of NF1 include benign cutaneous neurofibroma tumors, pigmentation lesions on the skin and in the iris, learning disabilities and predisposition to selected malignancies. Low bone mineral density (BMD) and osteopenia/osteoporosis are common in NF1. Osteoporosis is a systemic disorder characterized by low bone mineral density and increased fracture risk. Treatment of osteoporosis aims to prevent falls and decrease fracture risk. Osteoporosis is diagnosed in adults by measuring BMD and evaluating clinical risk factors of the patient. Bone turnover is a process of old bone resorbed by osteoclasts and new bone formed by osteoblasts. Multinuclear osteoclasts are derived from osteoclast progenitors, which can be isolated from peripheral blood. Osteoclast progenitors were isolated from 17 NF1 patients and healthy controls, and cultured in vitro to osteoclasts. NF1 osteoclasts are hyperactive, displaying increased differentiation and resorption capacity, abnormal morphology and tolerance to serum deprivation compared to control osteoclasts. These findings expanded the study to evaluate the effects of bisphosphonates, drugs designed to treat osteoporosis, in osteoclasts derived from blood samples of 20 NF1 and control persons. The number of control osteoclasts was expectedly reduced after bisphosphonate treatment. However, NF1 osteoclasts tolerated the apoptotic effect of alendronate, zoledronic acid and clodronate in vitro compared to controls. NF1-related osteoporosis was found in ~20 % of the patients, and selected laboratory parameters were measured. Patients with NF1 have increased levels of serum CTX and PINP, reflecting increased bone turnover in vivo. BMD decreases progressively in NF1 as evaluated in 19 NF1 patients 12 years after their initial BMD measurement. Patients with NF1-related osteopenia often progress to osteoporosis. This was found in patients aged 37-76.Siirretty Doriast

Neurofibromatosis Type 1: Optimizing Management with a Multidisciplinary Approach

Shaan Lalvani, Rebecca M Brown Department of Neurology, The Mount Sinai Hospital, New York, NY, USACorrespondence: Rebecca M Brown, MD, PhD, The Mount Sinai Hospital, Department of Neurology, 1216 5th Avenue, New York, NY, 10029, USA, Tel +1 2128248579, Email [email protected]: Neurofibromatosis Type I (NF1) is a complex genetic condition that affects multiple organ systems and presents a unique set of challenges for clinicians in its management. NF1 is a tumor predisposition syndrome that primarily affect the peripheral and central nervous systems via the impact of haploinsufficiency upon neural crest lineage cells including Schwann cells, melanocytes, fibroblasts, etc. NF1 can further lead to pathology of the skin, bones, visual system, and cardiovascular system, all of which can drastically reduce a patient’s quality of life (QOL). This review provides a comprehensive examination of the many specialties required for the care of patients with Neurofibromatosis Type 1 (NF1). We delve into the pathogenesis and clinical presentation of NF1, highlighting its diverse manifestations and the challenges they pose in management. The review underscores the importance of a multidisciplinary approach to NF1, emphasizing how such an approach can significantly improve patient outcomes and overall QOL. Central to this approach is the role of the NF expert, who guides a multidisciplinary team (MDT) comprising healthcare professionals from many areas of expertise. The MDT collaboratively addresses the multifaceted needs of NF1 patients, ensuring comprehensive and personalized care. This review highlights the need for further investigation to optimize the workflow for NF1 patients in an MDT setting, and to improve implementation and efficacy.Keywords: multisystemic, multidisciplinary team, quality of life, neurofibromatosis, NF expert, NF1, tumor predisposition syndrom

Neurofibromatosis type 1: From gene to population and cancer

Neurofibromatosis type 1 (NF1) is an autosomal dominant syndrome caused by mutations in the large and complex NF1 tumor suppressor gene on chromosome 17. NF1 is the most frequent hereditary tumor predisposition syndrome. The diagnosis of NF1 is usually based on clinical findings, such as tumors of the peripheral nervous system called neurofibromas and hyperpigmentary abnormalities such as café-au-lait pigment spots. This thesis investigated the molecular diagnostics, epidemiology, and cancer biology associated with the NF1 cancer syndrome. In this thesis, a new method for NF1 molecular diagnostics exploiting nextgeneration sequencing was developed. This is important, because mutation analysis is currently not available for every patient, and in the majority of the patients, the diagnosis is still merely based on clinical manifestations. A national NF1 cohort of 1,404 patients was used in this thesis, and a retrospective register-based total population study was carried out to evaluate the epidemiology and cancer incidence of NF1 in Finland. The results revealed that NF1 incidence is higher than previously accepted. The results with a birth incidence of 1/2,000 challenge the generally accepted NF1 incidence of ~1/3,000. The NF1 cancer incidence was studied with data from the Finnish Cancer Registry. A five-fold increase in cancer incidence was observed, which is the highest cancer incidence reported so far. In addition, cancers in the NF1 patients have a worse prognosis than the corresponding cancers in the general population. In NF1 patients the risk for breast cancer is also elevated, particularly under the age of 40. NF1-related breast cancer has poor prognosis, which is not solely explained by occurrence at young age or by histopathological type. Our results suggest that NF1 mutations are an independent factor contributing to low survival of patients with breast cancer. Active surveillance of NF1 patients and awareness of the NF1-related cancer risk are needed for early detection of the tumors and improved prognosis

The NF1 somatic mutational landscape in sporadic human cancers

Abstract Background Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1. Main body Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context. Conclusion As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1

Morbidity in neurofibromatosis 1: Epidemiological perspectives on breast cancer and diabetes

Neurofibromatosis type 1 (NF1) is a dominantly inherited rare disorder caused by pathogenic variants of the NF1 tumor suppressor gene. The syndrome can be diagnosed based on its clinical manifestations, such as café-au-lait macules, skinfold freckling, and benign cutaneous neurofibroma tumors. NF1 affects several organ systems, yet it is best known as a tumor predisposition syndrome. In this thesis, a Finnish cohort of 1,476 individuals with NF1 was used to study the prevalence of NF1 and the risks for breast cancer and diabetes among individuals with NF1. For a more precise assessment of the risk for contralateral breast cancer in NF1, the Finnish NF1 cohort was analyzed together with four other European NF1 cohorts. Moreover, the effect of NF1 on the concentration of circulating free plasma DNA (cfDNA) was assessed in a small-scale clinical study. Breast cancer diagnoses of individuals with NF1 were obtained from the Finnish Cancer Registry. Diagnoses of diabetes were inferred from drug purchases and hospital visits and hospital stays. The characteristics of NF1-related breast cancer were also analyzed. The results demonstrate that the overall prevalence of NF1 may be as high as 1/2,052. NF1 is associated with increased mortality throughout the lifetime, and the age-specific prevalence of NF1 declines in older age groups. Women with NF1 face a marked risk for breast cancer, and the risk for being diagnosed with breast cancer is 7.8% by 50 years of age. The survival after NF1-related breast cancer is worse compared to breast cancer in the general population. Breast cancers diagnosed in individuals with NF1 also exhibit poor prognostic factors, such as hormone receptor negativity. Moreover, women with NF1 and breast cancer have a 16% risk for contralateral breast cancer within 20 years. In contrast, the risk for diabetes and type 2 diabetes, in particular, is decreased among individuals with NF1. The NF1 syndrome, as such, may not significantly alter plasma cfDNA concentration. The results highlight the need for identifying all individuals with NF1 in order to provide them surveillance for NF1-related complications, such as breast cancer. The findings demonstrate the role of the NF1 gene in the pathogenesis of two common diseases, namely breast cancer and diabetes. Sairastavuus tyypin 1 neurofibromatoosissa: epidemiologisia näkökulmia rintasyöpään ja diabetekseen Tyypin 1 neurofibromatoosi (NF1) on vallitsevasti periytyvä harvinaissairaus, joka aiheutuu muutoksista NF1-kasvunrajoitegeenissä. Sairaus voidaan diagnosoida kliinisten oireiden, kuten ihon maitokahviläiskien, taivealueiden kesakoiden ja hyvänlaatuisten neurofibrooma-ihokasvainten perusteella. NF1 vaikuttaa moniin elinjärjestelmiin, mutta parhaiten se tunnetaan kasvainalttiusoireyhtymänä. Tässä tutkimuksessa tarkasteltiin NF1:n yleisyyttä sekä potilaiden alttiutta sairastua rintasyöpään ja diabetekseen. Tutkimuksessa käytettiin 1476 henkilön suomalaista NF1-kohorttia. Vastakkaisen rinnan rintasyövän riskiä tutkittaessa hyödynnettiin tietoja myös neljästä muusta eurooppalaisesta NF1-kohortista. Lisäksi tarkasteltiin NF1:n vaikutusta plasman vapaiden nukleiinihappojen pitoisuuteen. NF1-potilaiden rintasyöpädiagnoosit haettiin Suomen Syöpärekisteristä. Diabetesdiagnoosit pääteltiin lääkeostotiedoista sekä sairaalakäynneistä ja -jaksoista. Lisäksi tarkasteltiin NF1:een liittyvän rintasyövän ominaisuuksia. Tulokset osoittavat, että NF1:n vallitsevuus on jopa 1/2052. NF1 aiheuttaa lisääntynyttä kuolleisuutta kaikissa ikäryhmissä, minkä vuoksi NF1:n vallitsevuus laskee vanhemmissa ikäryhmissä. NF1:een liittyy merkittävä rintasyöpäriski, ja NF1:tä sairastavilla naisilla on 7,8 %:n todennäköisyys sairastua rintasyöpään ennen 50 vuoden ikää. NF1 huonontaa rintasyövän ennustetta, ja NF1-naisten rintasyövät ovat usein hormonireseptorinegatiivisia. Lisäksi rintasyöpään sairastuneilla NF1- naisilla on 16 %:n riski sairastua vastakkaisen rinnan rintasyöpään 20 vuoden kuluessa. Sen sijaan erityisesti tyypin 2 diabeteksen riski on NF1:ssä pienempi kuin vertailuväestössä. NF1-sairaus itsessään ei vaikuta merkittävästi muuttavan plasman vapaiden nukleiinihappojen pitoisuutta. Tulokset korostavat tarvetta tunnistaa kaikki NF1:tä sairastavat henkilöt, jotta he pääsevät taudin edellyttämän seurannan piiriin. Tulosten perusteella NF1-geeni vaikuttaa kahden yleisen sairauden, rintasyövän ja diabeteksen, kehityksee

Non-malignant features of cancer predisposition syndromes manifesting in childhood and adolescence: a guide for the general pediatrician

Purpose Cancer predisposition syndromes are genetic disorders that significantly raise the risk of developing malignancies. Although the malignant manifestations of cancer predisposition syndromes are well-studied, recognizing their non-malignant features is crucial for early diagnosis, especially in children and adolescents. Methods A comprehensive literature search was conducted using the PubMed database, focusing on non-malignant manifestations of cancer predisposition syndromes in children and adolescents. Key sources included the Clinical Cancer Research pediatric oncology series and ORPHANET. Studies that described clinical signs and symptoms affecting specific organ systems were included. Results Non-malignant dermatological features often serve as early indicators of cancer predisposition syndromes, including café-au-lait spots in Neurofibromatosis Type 1 and facial angiofibromas in Tuberous Sclerosis Complex. Neurological and developmental anomalies such as cerebellar ataxia in ataxia-telangiectasia and intellectual disabilities in neurofibromatosis type 1 and tuberous sclerosis complex are significant indicators. Growth and metabolic anomalies are also notable, including overgrowth in Beckwith–Wiedemann syndrome and growth hormone deficiency in neurofibromatosis Type 1. In addition, facial anomalies, ocular manifestations, hearing issues, and thyroid anomalies are prevalent across various cancer predisposition syndromes. For instance, hearing loss may be significant in neurofibromatosis Type 2, while thyroid nodules are common in PTEN hamartoma tumor syndrome and DICER1 syndrome. Cardiovascular, abdominal, musculoskeletal, pulmonary, genitourinary manifestations, and prenatal deviations further complicate the clinical picture. Conclusions Recognizing non-malignant features of cancer predisposition syndromes is essential for early diagnosis and management. This organ-specific overview furthers awareness among healthcare providers, facilitating timely genetic counseling, surveillance programs, and preventive measures, ultimately improving patient outcomes

Genodermatoses with behavioural sequelae

Children with genodermatoses are at an increased risk of developing behavioural disorders which may impart lasting damage on the individual and their family members. As such, early recognition of childhood mental health disorders via meticulous history taking, thorough physical examination, and disorder-specific testing is of paramount importance for timely and effective intervention. If carried out properly, prompt psychiatric screening and intervention can effectively mitigate, prevent or even reverse, the psychiatric sequela in question. To that end, this review aims to inform the concerned physician of the manifestations and treatment strategies relevant to the psychological sequelae of genodermatoses. © Author(s) (or their employer(s)) 2022