Aug 2026· Cerrahpasa Medical Journal· Vol 50, pp. 1-8· 0 citations· 48 references
TL;DR
Current evidence on the molecular basis, clinical manifestations, oral findings, diagnostic approaches, and management strategies of NF1 and related RASopathies is offered, with a focus on NF1.
Abstract
RASopathies constitute a group of inherited disorders caused by germline alterations that affect the RAS– MAPK pathway, a signaling cascade essential for regulating cellular growth and development. Among these disorders, neurofibromatosis type 1 (NF1) represents the most frequently encountered form. Other related conditions—including Noonan syndrome, its lentiginous variant, Costello syndrome, cardio-facio-cutaneous syndrome (CFCS), Legius syndrome, and capillary malformation–arteriovenous malformation syndrome—demonstrate significant genetic and phenotypic overlap. This review offers current evidence on the molecular basis, clinical manifestations, oral findings, diagnostic approaches, and management strategies of NF1 and related RASopathies. A structured literature review was performed using PubMed, Scopus, and Web of Science databases, including publications available up to June 2024. RASopathies commonly present with craniofacial abnormalities, cardiac defects, neurodevelopmental delays, and cutaneous manifestations, though each syndrome varies in genetic origin and clinical expression. Neurofibromatosis type 1 remains the most frequent, while Costello and CFCSs are comparatively rare. Oral findings—such as high-arched palate, gingival enlargement, and jawbone lesions—may serve as useful early diagnostic indicators. Recent advances in genetic testing and the emergence of targeted molecular therapies have significantly refined diagnostic accuracy and patient care. Recognizing genotype–phenotype correlations and integrating oral with systemic features are key to timely diagnosis and comprehensive management. Multidisciplinary collaboration and precision-based approaches are essential to improve long-term outcomes for individuals affected by RASopathies.
Cite this article as: Kabacıoğlu E, Elçioğlu N, Kökali F, Menteş A. Oral findings of RASopathies in children: molecular mechanisms and clinical spectrum with a focus on NF1. Cerrahpaşa Med J. 2026, 50, 0094, doi: 10.5152/cjm.2026.25094.
Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder characterized by marked phenotypic heterogeneity. This study aimed to describe the clinical spectrum and multisystem burden of NF1 in a regional retrospective cohort. Methods: We retrospectively analyzed 77 unique patients with NF1 after removal of duplicate records. Demographic characteristics, cutaneous manifestations, extracutaneous involvement, therapeutic interventions, and disease evolution were evaluated. An exploratory multisystem burden score was calculated using six extracutaneous clinical domains. Results: Café-au-lait macules were present in all patients, axillary/inguinal freckling in 93.5%, cutaneous neurofibromas in 63.6%, and plexiform tumors in 28.6%. Psychiatric/behavioral (67.5%), skeletal (57.1%), ophthalmological (51.9%), and neurological (45.5%) involvement were common. More than half of the cohort had involvement of at least three extracutaneous domains. Plexiform tumors were more common in patients with progressive or unfavorable disease compared to those with stationary disease. Progressive or unfavorable evolution was associated with a higher frequency of plexiform tumors. Therapeutic interventions were reported descriptively. Conclusions: NF1 showed substantial multisystem involvement beyond its characteristic cutaneous manifestations. Plexiform tumors were associated with a more complex clinical course. The proposed exploratory multisystem burden score may facilitate descriptive assessment of disease breadth but requires prospective validation.
A. Jurcă, T. Ghitea, Claudia Jurca et al.· Biomedicines· 0 citations
Background.
neurofibromatosis type 1 is a common hereditary autosomal dominant disorder caused by pathogenic genetic variants in the NF1 gene located on chromosome 17q11.2. the disease is characterized by high allelic heterogeneity and the absence of clear genotypic correlations, with the exception of large deletions associated with a more severe phenotype. Clinically, neurofibromatosis is characterized by the presence of multiple (>6) "café-au-lait” spots, neurofibromas of any type or plexiform neurofibromas, freckles in the axillary or inguinal areas, hamartomatous Lisch nodules of the iris, optic glioma, and bone dysplasia. therefore, the description of each new genetic variant is essential for expanding the spectrum of known variants and improving molecular diagnostics.
Case Report
. the article describes a clinical and molecular genetic study of a 10-year-old boy. since early childhood, the patient has had multiple “café-au-lait” spots, speech impairment, grade 1 hypotrophy, rickets, sequelae of perinatal CNs damage, myotonic syndrome, and a delay in motor development. Magnetic resonance imaging of the brain revealed signs of focal damage to both hemispheres, the cerebellar vermis, and the left subcortical nuclei, and a glioma of the right optic nerve was detected. Neurofibromatosis type 1 was diagnosed based on clinical criteria. Whole-genome DNA sequencing was performed, followed by bioinformatics analysis and confirmation of the results by direct sanger sequencing. A previously undescribed complex, likely pathogenic variant NM_001042492.3:c.40 60_4068delinsC of the NF1 gene was identified in the heterozygous state. this variant leads to a reading frameshift and premature translation termination after the synthesis of 23 amino acids (p.ser1354Leufs*23). this variant is not present in available population genetic variant databases.
Conclusion.
thus, wholegenome sequencing identified a new pathogenic variant in the NF1 gene associated with the development of neurofibromatosis type 1. the obtained data expand the range of variants for this pathology and can be used in medical genetic counseling, as well as in algorithms for molecular genetic diagnostics of patients with suspected neurofibromatosis type 1.
I. Z. Zhalsanova, E. Fonova, D. N. Erburova et al.· Siberian journal of oncology· 0 citations
Importance
Neurofibromatosis type 1 (NF1) is a multisystem, tumor predisposition syndrome in which vascular manifestations, including cutaneous lesions, remain poorly characterized. Cherry angiomas (CAs) have been sporadically reported in NF1, but their prevalence and biological basis are unknown.
Objective
To assess the association between NF1 and CAs and define the histopathologic, cellular, and genetic mechanisms underlying NF1-associated CAs.
Design, Setting, and Participants
This prospective, comparative, cross-sectional epidemiological study was conducted from October 2020 to March 2021 at a French national referral center for neurofibromatoses within the dermatology department at Henri-Mondor University Hospital, Créteil, France. It was followed by integrated histopathologic, genomic, and cell-specific molecular analyses. The epidemiological analysis included individuals 15 years or older with confirmed NF1 and controls without NF1. Pathophysiological analyses were conducted on CAs from individuals with NF1 and healthy volunteers following written consent. Data were analyzed in 2022.
Main Outcomes and Measures
Outcomes included the prevalence of CAs; age-adjusted and sex-adjusted odds ratios; histopathologic features; detection of somatic NF1 second-hit variants; identification of co-occurring oncogenic variants; localization of NF1 loss within vascular cell populations; and evidence of rat sarcoma-mitogen-activated protein kinase pathway activation.
Results
Of 259 participants (125 female individuals [48.3%]), 102 (39.4%) individuals had NF1 (median [range] age, 34 [18-70] years) and 157 (60.6%) were controls (median [range] age, 40 [15-91] years). CAs were more frequent in individuals with NF1 than controls (48% vs 18%; odds ratio, 4.26; 95% CI, 2.44-7.56) and occurred at a younger age. This association persisted after adjustment for age and sex and in propensity score-matched analyses. Somatic NF1 loss-of-function second hits were identified in 26 of 39 of NF1-associated CAs (67%) and none from controls, indicating biallelic NF1 inactivation. Comprehensive genomic profiling revealed frequent co-occurring activating variants, most commonly in GNAQ. Cell-specific sequencing showed that NF1 second hits arose predominantly in endothelial cells and telocytes, with higher variant allele frequencies in endothelial cells. Immunofluorescence demonstrated increased phosphoextracellular signal-regulated kinase signaling in these vascular cell populations.
Conclusions and Relevance
The results of this cross-sectional study suggest that CAs represent a frequent and previously unrecognized vascular manifestation of NF1, which is supported by epidemiological enrichment and mechanistic evidence of biallelic NF1 inactivation in vascular cells. These findings potentially expand the spectrum of NF1-associated neoplasms and establish CAs as a model for NF1-related vasculopathy.
L. Fertitta, É. Pasmant, C. Bergqvist et al.· JAMA dermatology· 0 citations
Two unrelated female pediatric patients evaluated for LZTR1‐related NS following whole‐exome sequencing are reported to illustrate the marked phenotypic variability of LZTR1‐related NS and underscore that, while cardiac defects may be absent in some individuals, appropriate cardiac surveillance remains necessary.
Karolina J Skrzynska, B. Kalina-Faska, Ewa Błaszczyk et al.· Clinical Genetics· 0 citations
RASopathies are a group of genetic disorders caused by germline variants affecting the RAS/MAPK pathway. Their shared phenotypic features—craniofacial anomalies, cardiac defects, cutaneous findings, neurodevelopmental issues, and cancer predisposition—make diagnosis challenging, especially since most lack standardized clinical criteria. This study aimed to develop a practical diagnostic algorithm based on high-frequency Human Phenotype Ontology (HPO) features. Key clinical variables for each RASopathy were identified through HPO, PubMed, and GeneReviews. Only findings present in 80–99% of cases or supported by expert consensus were included. A decision-tree algorithm was constructed and preliminarily evaluated using a blinded cohort of 50 individuals with confirmed molecular diagnoses. Patients were eligible for inclusion if they met the following criteria: (1) molecularly confirmed diagnosis of a RASopathy by next-generation sequencing identifying a pathogenic or likely pathogenic variant; (2) availability of complete phenotypic records in the institutional clinical database; and (3) age at evaluation between 0 and 18 years. Patients were excluded if phenotypic data were incomplete or if molecular confirmation was absent. The algorithm integrates phenotypic patterns and genotype–phenotype correlations. Validation showed 78% accuracy (95% CI: 64.0–88.4%) for clinical diagnosis and 66% accuracy (95% CI: 51.2–78.8%) for molecular prediction. To our knowledge, this is the first HPO-based diagnostic algorithm for the clinical and molecular approach to RASopathies. It provides a structured, accessible tool to improve early recognition and guide molecular testing, particularly for the RASopathy subtypes represented in the validation cohort. Further external validation including underrepresented subtypes is required.
Fernanda Meneses, C. Quintero, J. Lores et al.· International Journal of Mol...· 0 citations
OBJECTIVES
Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder characterized by café-au-lait macules, neurofibromas, and other clinical features. Patients with NF1 have an increased risk of developing various tumours, including pheochromocytomas and paragangliomas (PPGLs), rare neuroendocrine tumours that secrete catecholamines. The prevalence of PPGL in NF1 patients varies, with some studies reporting rates up to 7.7%. Diagnosis relies on clinical symptoms such as hypertension, headaches, and palpitations, alongside biochemical and imaging studies.
CASE PRESENTATION
This report presents a 50-year-old woman with a clinical diagnosis of NF1, based on family history and multiple diagnostic criteria, who presented with episodic abdominal pain and symptoms suggestive of pheochromocytoma. Imaging revealed a left adrenal mass, and biochemical urine analysis showed markedly elevated catecholamine metabolites. After appropriate medical management, she underwent surgical resection of the tumour. Genetic testing identified a pathogenic germline splice-site variant in the NF1 gene, confirming the hereditary nature of her condition.
CONCLUSIONS
The case highlights the importance of genetic testing in patients with PPGL, particularly those with NF1, as it influences management, prognosis, and family counseling. Early identification of pathogenic variants allows for tailored surveillance strategies and informs at-risk relatives. Current guidelines recommend routine biochemical screening in NF1 patients for PPGLs, though optimal imaging intervals remain debated. This case underlines the necessity of integrating clinical, biochemical, radiological, and genetic data for comprehensive care in NF1-associated pheochromocytoma.
N. Baena-Díez, Ruth Cano-Corres, E. Castellanos et al.· Clinica chimica acta; intern...· 0 citations
