Neurocutaneous Manifestations Research Articles

Co-occurrence of neurofibromatosis type 1, caused by Alu insertion, and 16p13.11 microduplication

BackgroundNeurofibromatosis type 1 (NF1), an autosomal dominant disorder, characterized by a spectrum of diverse neurocutaneous manifestations, is caused by heterozygous pathogenic variants in NF1 gene. While patients with NF1 often exhibit characteristic features, atypical phenotypes can arise, necessitating consideration of differential diagnoses or concurrent pathologies.Case presentationA seven-year-old boy with suspected NF1 underwent clinical evaluation. He presented hallmark café-au-lait spots, axillary freckling, and neurofibromas. Neuroimaging revealed a cranial plexiform neurofibroma. Additionally, he exhibited attention-deficit hyperactivity disorder and developmental delay. Genetic testing identified an Alu insertion variant within the NF1 gene, and subsequent array comparative genomic hybridization detected a 16p13.11 duplication.ConclusionsThis case underscores the intricate molecular bases of NF1 by identifying a rare Alu insertion variant. The patient's neurocognitive challenges and dysmorphic features prompted exploration of a potential overlapping genetic condition. Coexisting genetic disorders have been documented in NF1 patients, emphasizing the necessity of discerning atypical manifestations. The observed 16p13.11 duplication likely contributes to the patient's phenotype, enhancing the precision of diagnosis, prognosis, and genetic counseling.

Neurofibromatosis type 1 with three synchronous tumors

Neurofibromatosis type 1, resulting from dominantly inherited mutations affecting neurofibromin, is among the most common human genetic syndromes associated with many neurocutaneous manifestations. Neoplasms, neurogenic and non-neurogenic, are frequent, as are the gastrointestinal manifestations. Gastrointestinal tumors and vasculopathy are well-reported in individuals with neurofibromatosis type 1. A combination of somatostatioma and gastrointestinal stromal tumor is considered pathognomonic. We here report a case of neurofibromatosis type 1 with a triad of distinct neoplasms: gastrointestinal stromal tumor, neuroendoscrine tumor, and intra-ampullary papillary-tubular neoplasm. The trilogy of these neoplasms is unique and, to our knowledge, has never been reported in the literature. The report also emphasizes the role of advanced immunochemical staining in day-to-day practice, which has improved diagnostic accuracy and yield.

White epidermal nevus as an early sign of tuberous sclerosis complex-A case series.

Tuberous sclerosis complex (TSC) is a rare genetic disease with neurocutaneous manifestations, often presenting initially to the dermatology clinic. We report a cohort of neonates who presented with a novel finding of white epidermal nevus and were eventually diagnosed with TSC. White epidermal nevus may be yet another dermatological finding that may aid in the early diagnosis of TSC.

Neuropsychiatric Manifestations, Reduced Self-Esteem and Poor Quality of Life in Children and Adolescents with Neurofibromatosis Type 1 (NF1): The Impact of Symptom Visibility and Bullying Behavior.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, associated with neurocutaneous manifestations and neuropsychiatric manifestations. The present study explored the prevalence of bullying/cyberbullying behaviors and victimization behaviors in a cohort of children and adolescents with NF1. Possible gender differences and predictors of psychological symptoms, quality of life (QoL), and self-esteem were also examined. Thirty-eight school-aged participants with NF1 completed a psychological evaluation designed to assess anxiety and depression symptomatology, QoL, self-esteem, and the prevalence and extent of bullying/cyberbullying and victimization behaviors. We found that our participants frequently reported victimization behaviors rather than bullying/cyberbullying ones. Moreover, participants complained of depressive and anxiety symptomatology together with reduced self-esteem, and low psychosocial quality of life, with females reporting more severe performances than males. Furthermore, we found that reduced self-esteem was associated with more visibility of the NF1 symptoms, and victimization behaviors were found to mediate the relationship between anxiety and psychosocial QoL. Our findings indicated the presence of a maladaptive loop in children and adolescents with NF1 patients characterized by psychological symptoms, unfavorable self-perception, low self-esteem, and psychosocial difficulties that might be worsened by experiencing victimization behaviors. These results suggest the need to use a multidisciplinary approach in the diagnosis and treatment of NF1.

Neurofibromatosis 1 (von Recklinghausen Disease).

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.

Biotin supplementation in children with symptomatic profound biotinidase deficiency and their pregnant mothers

Background: Biotin is the coenzyme of multiple carboxylases involved in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotinidase (BTD) deficiency is an autosomal recessive disorder affecting the biotin cycle. It disrupts endogenous biotin recycling and results in multiple carboxylase deficiency depending upon the level of enzyme activity. Children with profound deficiency often present in infancy with neurocutaneous manifestations. Management of symptomatic children or screen-positive newborns is lifelong oral supplementation with biotin. There may be partial or complete resolution of symptoms in the former. Clinical Description: We describe two unrelated families diagnosed as profound BTD deficiency, with three affected children in each family. The first family had two symptomatic surviving children, a 2-year-old boy with seizures, developmental delay, and hearing loss, and a 1.5-month-old boy with seizures. Diagnosis was established while ascertaining etiology for seizures refractory to multiple anticonvulsant therapy. The second family was referred for postconceptional counseling following two infantile deaths with similar phenotype, early-onset seizures, encephalopathy, and acute metabolic decompensation. Management: The affected children in the first family showed a dramatic response in seizure controls with oral biotin though the other symptoms such as developmental delay and hearing loss remained unaffected. Mother was advised regarding prenatal diagnosis in the next pregnancy but was unwilling. In the second family, stored genetic material from the earlier affected infant revealed a pathogenic homozygous indel in the BTD gene, which was confirmed in utero in the subsequent pregnancy. Both women were started on oral biotin on the lines of antenatal management of holocarboxylase synthetase deficiency. After birth, therapy was continued on the confirmation of profound BTD deficiency in both babies. They have remained asymptomatic on follow-up; the first baby till a year and the second till 3 months. Conclusion: There is a considerable phenotypic variability in profound BTD deficiency. Early detection and prompt treatment with biotin may result in complete resolution of some symptoms and ameliorate others. Antenatal biotin supplementation in families at high risk or with prenatal diagnosis of BTD deficiency may have a favorable outcome in affected progeny.

Classical neurocutaneous manifestations of tuberous sclerosis complex.

Classical neurocutaneous manifestations of tuberous sclerosis complex.

Two Cases of Tuberous Sclerosis With Multiple Rhabdomyoma Succumbing to Sudden Cardiac Death

Tuberous sclerosis complex is an autosomal dominant condition with variable penetrance. It is characterized by tuberose deposits in various organ systems. Although clinical features predominate neurocutaneous manifestations, cardiac, kidney, and lung involvement are common. Cardiac involvement is marked by the presence of multiple rhabdomyomas and in some cases arrhythmias. In the absence of symptoms, rhabdomyomas require no specific treatment. However, cardiac arrhythmias are unpredictable and may be the cause of sudden cardiac death in some cases. Although treatment is mainly symptomatic, drugs like rapamycin have shown promise in the regression of astrocytomas and angiofibromas. Here, we are reporting two cases of tuberous sclerosis of which one succumbed to arrhythmias and the other to possible sudden cardiac death.

Case Report of Hereditary Coproporphyria Accompanied by Nystagmus and Vestibular Dysfunction

Porphyria is a collection of disorders resulting from a breakdown in heme synthesis. The most common form is acute intermittent porphyria (AIP), and the other disorders are less common and therefore more difficult to diagnose. Our case study focuses on a 39-year-old male with a combination of gastrointestinal symptoms as well as neurocutaneous manifestations. Failing to recognize this disorder in the primary care setting can lead to additional, sometimes repetitive, clinical investigation and negative outcome for patients. The authors believe strongly in the teamwork model for today's medicine. Close communication between specialty and primary care, as well as a broader differential, could have helped achieve an earlier diagnosis and treatment for the patient. J Med Cases. 2018;9(11):355-359 doi: https://doi.org/10.14740/jmc3158w

Case Report of Hereditary Coproporphyria Accompanied by Nystagmus and Vestibular Dysfunction

Porphyria is a collection of disorders resulting from a breakdown in heme synthesis. The most common form is acute intermittent porphyria (AIP), and the other disorders are less common and therefore more difficult to diagnose. Our case study focuses on a 39-year-old male with a combination of gastrointestinal symptoms as well as neurocutaneous manifestations. Failing to recognize this disorder in the primary care setting can lead to additional, sometimes repetitive, clinical investigation and negative outcome for patients. The authors believe strongly in the teamwork model for today's medicine. Close communication between specialty and primary care, as well as a broader differential, could have helped achieve an earlier diagnosis and treatment for the patient. J Med Cases. 2018;9(11):355-359 doi: https://doi.org/10.14740/jmc3158w

Growing Cyst-Like White Matter Lesions in Children With Neurofibromatosis Type 1

BackgroundNeurofibromatosis type 1 (NF1) is an autosomal dominant disease with prominent neurocutaneous manifestations. The most common intracranial imaging finding of NF1 on brain magnetic resonance imaging (MRI) is the high-signal intensity foci without a mass effect or growth in size. Patient DescriptionWe describe two children with NF1 in whom brain MRI showed growing cystic lesions and adjacent white matter signal abnormalities, which were confirmed as non-neoplastic cystic degeneration and reactive gliosis. ConclusionGrowing cyst-like white matter lesions can be seen on serial brain MRI in children with NF1. Reactive gliosis with cystic degeneration could be a pathogenic basis of these cystic lesions.

Simultaneous Presentation of Cerebellopontine Angle Pleomorphic Xanthoastrocytoma and Malignant Melanoma in a Known Case of Neurofibromatosis 1; Probable Role of BRAF Gene: A Case Report and Review of Literature

Introduction: Pleomorphic Xanthoastrocytoma (PXA) is a rare astrocytic neoplasm which mostly affects supratentorial region. The vast majority are sporadic, with only rare examples described in association with neurofibromatosis 1 (NF1), a genetic disorder with neurocutaneous manifestations. Co-occurrence of these 2 rare entities with neoplasm of melanocytes, Cutaneous Malignant Melanoma (CMM), is described in this report for the first time. Case Presentation: A 34-year-old female with established diagnosis of NF1 and left optic nerve glioma from childhood was presented with visual field impairment, decreased level of consciousness and right VI and VII cranial nerves paresis. An irregular hyperpigmented skin lesion was also noted on thoracic area, which histopathological and immunohistochemistry (IHC) study with S100 confirmed CMM. Brain MRI demonstrated high signal intensity mass in right cerebellopontine. Right retro-mastoid craniectomy and total resection of tumor was performed and histopathological investigation of excised lesion along with IHC study with glial fibrillary acidic protein (GFAP), confirmed PXA. Sanger sequencing showed positive BRAF T1799A mutation in both PXA and melanoma’s tissue. Conclusions: The association between BRAF gene mutations and human cancers such as PXA and CMM was discovered. This first ever co-occurrence of mentioned rare disorders emphasizes on probable role of BRAF gene in pathogenesis and whether its inhibitors could serve as an adjuvant agent to facilitate surgical approaches to complex lesions.

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis related to or comparable with mechanisms seen in inflammatory pathways? Part II: angiogenesis- and inflammation-related molecular pathways, tumor-associated macrophages, and possible therapeutic implications: a comprehensive review.

Phacomatoses are a special group of familial hamartomatous syndromes with unique neurocutaneous manifestations as well as characteristic tumors. Neurofibromatosis type 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. A vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with these syndromes, related to NF2 and TSC, respectively. These tumors can present with an obstructive hydrocephalus due to their location adjacent to or in the ventricles. Remarkably, both tumors are also known to have a unique association with elevated protein concentrations in the cerebrospinal fluid (CSF), sometimes in association with a non-obstructive (communicating) hydrocephalus. Of the two, SGCT has been shown to be associated with a predisposition to CSF clotting, causing a debilitating recurrent shunt obstruction. However, the exact relationship between high protein levels and clotting of CSF remains unclear, nor do we understand the precise mechanism of CSF clotting observed in SGCT. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiological processes for that in the context of tumorigenesis are angiogenesis and inflammation. Both these processes are correlated to the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin pathway which is tumorigenesis related in many neoplasms and nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation pathways on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I described the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating hydrocephalus. Part II hereafter describes the different cellular and molecular pathways involved in angiogenesis and inflammation observed in both tumors and explores the existing metabolic overlap between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both tumors, inflammatory processes seem significantly more prominent in SGCT. Both SGCT and VS are characterized by different subgroups of tumor-associated macrophages (TAMs): the pro-inflammatory M1 type is predominating in SGCTs, while the pro-angiogenetic M2 type is predominating in VSs. We suggest that a lack of NF2 protein in VS and a lack of TSC1/TSC2 proteins in SGCT significantly influence this fundamental difference between the two tumor types by changing the dominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, the pro-inflammatory state of SGCT may also explain the associated tendency for CSF clotting. The underlying cellular and molecular differences observed can potentially serve as an access point for direct therapeutic interventions for tumors that are specific to certain phacomatoses or others that also carry such genetic changes.

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis comparable with mechanisms seen in inflammatory pathways? Part I: historical observations and clinical perspectives on the etiology of increased CSF protein levels, CSF clotting, and communicating hydrocephalus: a comprehensive review.

Phacomatoses are a special group of familial hamartomatous syndromes with unique neuro-cutaneous manifestations as well as disease characteristic tumors. Neurofibromatosis 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. Vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with NF2 and TSC, respectively. These tumors can present with obstructive hydrocephalus due to their location adjacent to or in the ventricles. However, both tumors are also known to have a unique association with an elevated protein concentration in the cerebrospinal fluid (CSF), sometimes in association with non-obstructive (communicating) hydrocephalus (HCP), the causality of which has been unclear. Furthermore, SGCTs have repeatedly been shown to have a predisposition for CSF clotting, causing debilitating obstructions and recurrent malfunctions in shunted patients. However, the exact relation between high protein levels and spontaneous clotting of the CSF is not clear, nor is the mechanism understood by which CSF may clot in SGCTs. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiologic mechanisms for that, in the context of tumorigenesis, are angiogenesis and inflammation. Both mechanisms are correlated to the Pi3K/Akt/mTOR pathway which is a major tumorigenesis pathway in nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I describes the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating HCP. Part II describes different cellular and molecular pathways involved in angiogenesis and inflammation in these two tumors and the correlation between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both VS and SGCT, inflammatory processes seem more prominent in SGCT. Both pathologies are characterized by different subgroups of tumor-associated macrophages (TAM): the pro-inflammatory, M1 type is predominating in SGCTs while pro-angiogenetic, M2 type is predominating in VSs. We suggest that lack of NF2 protein in VS and lack of TSC1/2 proteins in SGCT determine this fundamental difference between the two tumor types, by defining the predominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, a "pro-inflammatory state" of SGCT can be used to explain the observed associated enhanced CSF clotting process. These distinct cellular and molecular differences may have direct therapeutic implications on tumors that are unique to certain phacomatoses or those with similar genetics.

Further Delineation of Speckled Lentiginous Nevus Syndrome

Speckled lentiginous nevus syndrome is a recently described condition, characterized by unilateral neurocutaneous manifestations consisting of: speckled lentiginous nevus, hyperhidrosis, muscular weakness and dysesthesia. Skeletal anomalies such as scoliosis, limb asymmetry, and psychiatric manifestations have been also reported. Herein, we report a case of speckled lentiginous nevus syndrome with skeletal anomalies and a pseudo-marfanoid phenotype.

Neurocutaneous Disorders for the Practicing Neurologist: a Focused Review.

The neurocutaneous disorders (NCDs) embrace an extensive group of developmental disorders associated with involvement of the skin, central nervous system (CNS), and/or the peripheral nervous system (PNS). The neurocutaneous manifestations relate to the common ectodermal origin of these organs. This review intended for the practicing clinical neurologist focuses on selected aspects of the NCDs primarily those associated with cerebrovascular disease. Our emphasis is primarily on those NCDs with genetic heterogeneity and their neurological manifestations.

Neurocutaneous Manifestations of Genetic Mosaicism.

Genetic mosaicism is defined as the presence of two or more genetically distinct cell populations in a single individual. Ever more disorders are found to be manifestations of mosaicism and together constitute a significant proportion of the morbidity confronting pediatric specialists. An emerging category is that of overgrowth syndromes with skin manifestations and neurological or developmental abnormalities, such as the well-known Proteus syndrome. In recent years, we have seen dramatic advances in our understanding of these disorders and we now know the genetic basis of many of them. This has profound consequences for diagnosis, counselling, and even treatment, with therapies targeted to specific pathways becoming available for clinical use. Recognizing such overgrowth syndromes, therefore, is more important than ever. Fortunately, their skin manifestations can provide important diagnostic clues when evaluated in the entire phenotypic context. In this review, I provide an overview of the most frequently seen mosaic neurocutaneous phenotypes and discuss their molecular basis.

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations.

Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

Neurofibromatosis type 1 is a common genetic disorder characterised by neurocutaneous manifestations and cognitive and behavioural problems. Statins were shown to reduce analogous learning deficits in a mouse model of the disease, but a short-term trial in humans was inconclusive. We aimed to assess the use of simvastatin for the improvement of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months. In this randomised, double-masked, placebo-controlled trial, we recruited children with genetically confirmed neurofibromatosis type 1 aged 8-16 years from two national referral centres in the Netherlands and Belgium. Those with symptomatic CNS abnormalities or on neurotropic medication, including stimulants, were excluded. Eligible patients were randomly assigned (1:1) via a computer-generated, permuted-block list to simvastatin (10 mg per day in month 1, 20 mg per day in month 2, and 20-40 mg per day in months 3-12) or placebo for 12 months. Investigators, participants, and parents were masked to treatment assignment. Primary outcome measures were full-scale intelligence (Wechsler intelligence scale for children), attention problems (child behaviour checklist, parent-rated [CBCL]), and internalising behavioural problems (CBCL). We did intention-to-treat analyses (of all patients who had outcome data) using linear regression of the 12 month outcome scores, adjusted for baseline performance. This trial is registered with the Netherlands Trial Register, number NTR2150. We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect compared with placebo -1·3 IQ points [95% CI -3·8 to 1·3]; p=0·33), attention problems (-1·6 T-score points [-4·3 to 1·0]; p=0·23), and internalising behavioural problems (-0·1 T-score points [-3·3 to 3·1]; p=0·96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively. 12 month simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with neurofibromatosis type 1. The use of 20-40 mg simvastatin per day for cognitive enhancement in children with neurofibromatosis type 1 is not recommended. The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).

The musculoskeletal phenotype of the RASopathies

The Ras/MAPK signal transduction pathway is critical for the regulation of proliferation and differentiation of multiple cell types. Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in the NF1 gene resulting in an increased Ras signaling cascade. Subsequently, additional syndromes with some overlapping physical manifestations such as Noonan syndrome, Costello syndrome, and cardiofaciocutaneous (CFC) syndrome were also shown to be due in many cases to mutations in genes encoding for proteins interacting with the Ras/MAPK pathway. Although neurocutaneous manifestations have been considered hallmark features for these disorders, multiple organ systems including the musculoskeletal system are affected. Some of the overlapping musculoskeletal phenotypes include scoliosis, kyphosis, anterior chest wall anomalies, pes planus, osteopenia, and hand anomalies. However, there are also discordant skeletal phenotypes such as sphenoid wing dysplasia and tibial pseudarthrosis seen only in NF1. We provide an overview of the concordant and discordant musculoskeletal manifestations in the RASopathies.